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1. Oligoclonal CD4+CXCR5+ T cells with a cytotoxic phenotype appear in tonsils and blood

Author: Chunguang Liang, Silvia Spoerl, Yin Xiao, Katharina M. Habenicht, Sigrun S. Haeusl, Isabel Sandner, Julia Winkler, Nicholas Strieder, Rüdiger Eder, Hanna Stanewsky, Christoph Alexiou, Diana Dudziak, Andreas Rosenwald, Matthias Edinger, Michael Rehli, Petra Hoffmann, Thomas H. Winkler, and Friederike Berberich-Siebelt
Subjects: Biology (General), QH301-705.5
Abstract: Abstract In clinical situations, peripheral blood accessible CD3+CD4+CXCR5+ T-follicular helper (TFH) cells may have to serve as a surrogate indicator for dysregulated germinal center responses in tissues. To determine the heterogeneity of TFH cells in peripheral blood versus tonsils, CD3+CD4+CD45RA–CXCR5+ cells of both origins were sorted. Transcriptomes, TCR repertoires and cell-surface protein expression were analysed by single-cell RNA sequencing, flow cytometry and immunohistochemistry. Reassuringly, all blood-circulating CD3+CD4+CXCR5+ T-cell subpopulations also appear in tonsils, there with some supplementary TFH characteristics, while peripheral blood-derived TFH cells display markers of proliferation and migration. Three further subsets of TFH cells, however, with bona fide T-follicular gene expression patterns, are exclusively found in tonsils. One additional, distinct and oligoclonal CD4+CXCR5+ subpopulation presents pronounced cytotoxic properties. Those ‘killer TFH (TFK ) cells’ can be discovered in peripheral blood as well as among tonsillar cells but are located predominantly outside of germinal centers. They appear terminally differentiated and can be distinguished from all other TFH subsets by expression of NKG7 (TIA-1), granzymes, perforin, CCL5, CCR5, EOMES, CRTAM and CX3CR1. All in all, this study provides data for detailed CD4+CXCR5+ T-cell assessment of clinically available blood samples and extrapolation possibilities to their tonsil counterparts.
Published: 2024
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2. Donor regulatory T cells rapidly adapt to recipient tissues to control murine acute graft-versus-host disease

Author: David J. Dittmar, Franziska Pielmeier, Nicholas Strieder, Alexander Fischer, Michael Herbst, Hanna Stanewsky, Niklas Wenzl, Eveline Röseler, Rüdiger Eder, Claudia Gebhard, Lucia Schwarzfischer-Pfeilschifter, Christin Albrecht, Wolfgang Herr, Matthias Edinger, Petra Hoffmann, and Michael Rehli
Subjects: Science
Abstract: Abstract The adoptive transfer of regulatory T cells is a promising strategy to prevent graft-versus-host disease after allogeneic bone marrow transplantation. Here, we use a major histocompatibility complex-mismatched mouse model to follow the fate of in vitro expanded donor regulatory T cells upon migration to target organs. Employing comprehensive gene expression and repertoire profiling, we show that they retain their suppressive function and plasticity after transfer. Upon entering non-lymphoid tissues, donor regulatory T cells acquire organ-specific gene expression profiles resembling tissue-resident cells and activate hallmark suppressive and cytotoxic pathways, most evidently in the colon, when co-transplanted with graft-versus-host disease-inducing conventional T cells. Dominant T cell receptor clonotypes overlap between organs and across recipients and their relative abundance correlates with protection efficacy. Thus, this study reveals donor regulatory T cell selection and adaptation mechanisms in target organs and highlights protective features of Treg to guide the development of improved graft-versus-host disease prevention strategies.
Published: 2024
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3. Combination cell therapy leads to clonal deletion of donor-specific T cells in kidney transplant recipientsResearch in context

Author: Ana F. David, Andreas Heinzel, Michael Kammer, Constantin Aschauer, Roman Reindl-Schwaighofer, Karin Hu, Hao-Shan Chen, Moritz Muckenhuber, Anna Kubetz, Anna Marianne Weijler, Nina Worel, Matthias Edinger, Gabriela Berlakovich, Thomas Lion, Megan Sykes, Thomas Wekerle, and Rainer Oberbauer
Subjects: T cell receptor, Alloreactivity, Kidney transplantation, Cell therapy, Immunological tolerance, Medicine, Medicine (General), R5-920
Abstract: Summary: Background: Induction of donor-specific tolerance is a promising approach to achieve long-term graft patency in transplantation with little to no maintenance immunosuppression. Changes to the recipient’s T cell receptor (TCR) repertoire are understood to play a pivotal role in the establishment of a robust state of tolerance in chimerism-based transplantation protocols. Methods: We investigated changes to the TCR repertoires of patients participating in an ongoing prospective, controlled, phase I/IIa trial designed to evaluate the safety and efficacy of combination cell therapy in living donor kidney transplantation. Using high-throughput sequencing, we characterized the repertoires of six kidney recipients who also received bone marrow from the same donor (CKBMT), together with an infusion of polyclonal autologous Treg cells instead of myelosuppression. Findings: Patients undergoing combination cell therapy exhibited partial clonal deletion of donor-reactive CD4+ T cells at one, three, and six months post-transplant, compared to control patients receiving the same immunosuppression regimen but no cell therapy (p = 0.024). The clonality, R20 and turnover rates of the CD4+ and CD8+ TCR repertoires were comparable in both groups, showing our protocol caused no excessive repertoire shift or loss of diversity. Treg clonality was lower in the case group than in control (p = 0.033), suggesting combination cell therapy helps to preserve Treg diversity. Interpretation: Overall, our data indicate that combining Treg cell therapy with CKBMT dampens the alloimmune response to transplanted kidneys in humans in the absence of myelosuppression. Funding: This study was funded by the Vienna Science and Technology Fund (WWTF).
Published: 2024
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4. Tocilizumab administration in cytokine release syndrome is associated with hypofibrinogenemia after chimeric antigen receptor T-cell therapy for hematologic malignancies

Author: Markus Perl, Konstantin Herfeld, Dennis C. Harrer, Matthias Höpting, Marina Schweiger, Ulrich Sterz, Leonard Knödler, Susanne Heimerl, Leo Hansmann, Wolfgang Herr, Hendrik Poeck, Daniel Wolff, Matthias Edinger, Christina Hart, and Matthias A. Fante
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: Chimeric antigen receptor (CAR-) T cell therapy causes serious side effects including cytokine release syndrome (CRS). CRS-related coagulopathy is associated with hypofibrinogenemia that is thus far considered the result of disseminated intravascular coagulation (DIC) and liver dysfunction. We investigated incidence and risk factors for hypofibrinogenemia in 41 consecutive adult patients with hematologic malignancies (median age 69 years, range 38-83 years) receiving CAR-T cell therapy between 01/2020 and 05/2023 at the University Medical Center Regensburg. CRS occurred in 93% of patients and was accompanied by hypofibrinogenemia already from CRS grade 1. Yet, DIC and liver dysfunction mainly occurred in severe CRS (≥ grade 3). After an initial increase during CRS, fibrinogen levels dropped after administration of tocilizumab in a dose dependent manner (r = -0.44, p = 0.004). In contrast, patients who did not receive tocilizumab had increased fibrinogen levels. Logistic regression analysis identified tocilizumab as an independent risk factor for hypofibrinogenemia (odds ratio = 486, p < 0.001). We thus hypothesize that fibrinogen synthesis in CRS is upregulated in an interleukin-6-dependent acute phase reaction compensating for CRS-induced consumption of coagulation factors. Tocilizumab inhibits fibrinogen upregulation resulting in prolonged hypofibrinogenemia. These observations provide novel insights into the pathophysiology of hypofibrinogenemia following CAR-T cell therapy and emphasize the need for close fibrinogen monitoring after tocilizumab treatment of CRS.
Published: 2024
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5. Retrospective analysis of the incidence and outcome of late acute and chronic graft-versus-host disease—an analysis from transplant centers across Europe

Author: Ronja Langer, Antonela Lelas, Michael Rittenschober, Agnieszka Piekarska, Alicja Sadowska-Klasa, Ivan Sabol, Lana Desnica, Hildegard Greinix, Anne Dickinson, Marit Inngjerdingen, Anita Lawitschka, Radovan Vrhovac, Drazen Pulanic, Sibel Güneş, Stefan Klein, Jan Moritz Middeke, Matthias Grube, Matthias Edinger, Wolfgang Herr, and Daniel Wolff
Subjects: chronic graft-versus-host disease (cGvHD), acute GvHD, aGvHD, stem cell transplantation, bone marrow transplantation, Specialties of internal medicine, RC581-951
Abstract: IntroductionChronic graft-versus-host disease (cGvHD) is a serious late complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT).MethodsThis multicenter analysis determined the cumulative incidence (CI) of cGvHD and late acute GvHD (laGvHD) and its impact on transplantation-related mortality (TRM), relapse (R), and overall survival (OS) in 317 patients [296 adults, 21 pediatrics (
Published: 2024
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6. Impact of chronic graft-versus-host disease on quality of life and cognitive function of long-term transplant survivors after allogeneic hematopoietic stem cell transplantation with total body irradiation

Author: Isabella Gruber, Oliver Koelbl, Wolfgang Herr, Ernst Holler, Matthias Edinger, and Daniel Wolff
Subjects: Total body irradiation, Acute myeloid leukemia, Chronic graft-versus-host disease, Allogeneic hematopoietic cell transplantation, Quality of life, Cognitive function, Medical physics. Medical radiology. Nuclear medicine, R895-920, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Total body irradiation (TBI)-based-conditioning before allogeneic hematopoietic stem cell transplantation (allo-HSCT) is standard of care in patients with acute myeloid leukemia (AML) but can cause long-term morbidity. Data on the impact of chronic Graft-versus-host disease (cGvHD) on cognitive function (CF) and quality of life (QoL) of long-term transplant survivors are sparse. Methods We analyzed patient-reported outcomes focusing on progression-free AML patients and 1st allo-HSCT applying a standardized TBI-technique with an average dose rate of 4 cGy/min to the total body and lung shielding in case of doses > 8 Gy. Instruments included the Functional Assessment of Cancer Therapy-Bone marrow transplant (FACT-BMT, version 4), the FACT-Cognition Function (FACT-Cog, version 3) and the Patient Health Questionaire-4 (PHQ-4). We put focus on the impact of cGvHD and compared the results to normative data derived from the general population. Results Out of 41 eligible patients contacted, 32 (78.0%) patients with a medium follow-up of 154 months (Interquartile range 113, 191 months) participated in the study. Eleven patients (34.4%) had active cGvHD, 11 (34.4%) resolved cGvHD and 10 (31.3%) never had cGvHD. Patients with active cGvHD had poorer FACT-BMT, FACT-Cog and higher PHQ-4 scores compared to patients with resolved cGvHD or who never had cGvHD. Outcomes were similar in patients with resolved cGvHD and those who never had cGvHD. Patients with active cGvHD had similar FACT-Cog, but lower FACT-BMT in comparison to normative data. However, the overall patient sample had similar FACT-BMT and FACT-Cog in comparison to normative data. Conclusion Our data indicate that CF of long-term survivors upon TBI-based allo-HSCT is not impaired, even in the presence of active cGvHD. However, active cGvHD has a negative impact on QoL. Trial registration The local Ethics Board of the University of Regensburg approved this study (Number 20-1810_1-101).
Published: 2022
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7. Intestinal IgA-positive plasma cells are highly sensitive indicators of alloreaction early after allogeneic transplantation and associate with both graft-versus-host disease and relapse-related mortality

Author: Lucia Scheidler, Katrin Hippe, Sakhila Ghimire, Daniela Weber, Markus Weber, Elisabeth Meedt, Petra Hoffmann, Petra Lehn, Ralph Burkhardt, Andreas Mamilos, Matthias Edinger, Daniel Wolff, Hendrik Poeck, Matthias Evert, Andre Gessner, Wolfgang Herr, and Ernst Holler
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: Intestinal immunoglobulin A (IgA) is strongly involved in microbiota homeostasis. Since microbiota disruption is a major risk factor of acute graft-versus-host disease (GvHD), we addressed the kinetics of intestinal IgA-positive (IgA+) plasma cells by immunohistology in a series of 430 intestinal biopsies obtained at a median of 1,5 months after allogeneic stem cell transplantation (allo-SCT) from 115 patients (pts) at our center. IgA+ plasma cells were located in the subepithelial lamina propria and suppressed in the presence of histological aGvHD (GvHD Lerner stage 0: 131+/-8 IgA+ plasma cells/mm2; stage 1-2: 108+/-8 IgA+ plasma cells/mm2; stage 3-4: 89+/-16 IgA+ plasma cells/mm2; P=0.004). Overall, pts with IgA+ plasma cells below median had an increased treatment related mortality (P=0.04). Time courses suggested a gradual recovery of IgA+ plasma cells after day 100 in the absence but not in the presence of GvHD. Vice versa IgA+ plasma cells above median early after allo-SCT were predictive of relapse and relapse-related mortality (RRM): pts with low IgA+ cells had a 15% RRM at 2 and at 5 years, while pts with high IgA+ cells had a 31% RRM at 2 years and more than 46% at 5 years; multivariate analysis indicated high IgA+ plasma cells in biopsies (hazard ratio =2.7; 95% confidence interval: 1.04-7.00) as independent predictors of RRM, whereas Lerner stage and disease stage themselves did not affect RRM. In contrast, IgA serum levels at the time of biopsy were not predictive for RRM. In summary, our data indicate that IgA+ cells are highly sensitive indicators of alloreaction early after allo-SCT showing association with TRM but also allowing prediction of relapse independently from the presence of overt GvHD.
Published: 2023
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8. Unusually swift response of relapsed Burkitt leukemia to R‐DHAP

Author: Dennis Christoph Harrer, Alexander Denk, Felix Keil, Karin Menhart, Stephanie Mayer, Daniel Wolff, Matthias Edinger, Wolfgang Herr, and Matthias Grube
Subjects: allogeneic stem cell transplantation, Burkit leukemia, R‐DHAP, relapse, salvage therapy, Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: Abstract Burkitt leukemia (BL) represents a highly aggressive lymphoma characterized by proliferation rates of around 100%, and a frequent spread into the central nervous system. If standard frontline chemotherapy fails, the prognosis is usually dismal, and reports on successful effective salvage therapy strategies for patients with relapsed/refractory BL are scant. Here, we report on a 40‐year‐old female patient who suffered an early relapse of BL three months after the completion of frontline chemoimmunotherapy. Strikingly, after only one cycle of R‐DHAP chemotherapy, the patient showed CR of BL enabling swift transition to a consolidating allogeneic stem cell transplantation. A 40‐year‐old previously healthy woman presented to the hospital with fatigue and incessant epistaxis, and a diagnosis of BL was made upon histological examination of a bone marrow biopsy. Treatment was initiated according to the GMALL 2002 B‐NHL/ALL protocol, which could induce complete molecular remission. Nevertheless, three months after chemotherapy, the patient exhibited BL relapse in the bone marrow, and on Fluorodeoxyglucose (FDG)–PET‐imaging. The relapse therapy was started with R‐DHAP, and after only one cycle, the patient once again entered complete remission (CR) paving the way for allogeneic stem cell transplantation. Unfortunately, the patient again relapsed five months after transplantation prompting salvage therapy with R‐DHAC and the execution of the second stem cell transplantation. However, one month after the second transplantation the patient presented with chemorefractory meningeosis leukemia resulting in the initiation of palliative care treatment. In summary, we report on rapid CR of relapsed BL after a single cycle of rituximab‐DHAP. Given a paucity of clinical trials on the treatment of patients with r/r BL, we intend to highlight the potential efficacy of rituximab‐DHAP as salvage therapy in those patients.
Published: 2022
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9. Murine cytomegalovirus reactivation concomitant with acute graft-versus-host disease is controlled by antibodies

Author: Martina Seefried, Nadine Hundhausen, Irena Kroeger, Maike Büttner-Herold, Petra Hoffmann, Matthias Edinger, Evelyn Ullrich, Friederike Berberich-Siebelt, William J. Britt, Michael Mach, and Thomas H. Winkler
Subjects: Hematology, Immunology, Medicine
Abstract: Reactivation of human cytomegalovirus (HCMV) from latency is a frequent complication following hematopoietic stem cell transplantation (HSCT). The development of acute graft-versus-host disease (GVHD) is a significant risk factor for HCMV disease. Using a murine GVHD model in animals latently infected with murine CMV (MCMV), we studied preventive and therapeutic interventions in this high-risk scenario of HSCT. Mice latently infected with MCMV experienced reactivated MCMV and developed disseminated MCMV infection concomitant with the manifestations of GVHD. Dissemination was accompanied by accelerated mortality. We demonstrate that MCMV reactivation and dissemination was modulated by MCMV-specific antibodies, thus demonstrating in vivo protective activity of antiviral antibodies. However, the efficacy of serum therapy required repetitive doses of high-titer immune serum secondary to the shortened serum half-life of IgG in animals with GVHD. In a complementary approach, treatment of GVHD by adoptive transfer of donor-derived Tregs facilitated production of MCMV-specific antibodies from newly developing donor-derived B cells. Together, our findings strongly suggest that antibodies play a major role in controlling recurrent MCMV infection that follows GVHD, and they argue for reassessing the potential of antibody treatments as well as therapeutic strategies that enhance de novo antibody development against HCMV.
Published: 2023
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10. Reduced 8-Gray Compared to Standard 12-Gray Total Body Irradiation for Allogeneic Transplantation in First Remission Acute Lymphoblastic Leukemia: A Study of the Acute Leukemia Working Party of the EBMT

Author: Alexandros Spyridonidis, Myriam Labopin, Bipin Savani, Sebastian Giebel, Gesine Bug, Stefan Schönland, Nicolaus Kröger, Matthias Stelljes, Thomas Schroeder, Andrew McDonald, Igor-Wolfgang Blau, Martin Bornhäuser, Montse Rovira, Wolfgang Bethge, Andreas Neubauer, Arnold Ganser, Jean Henri Bourhis, Matthias Edinger, Bruno Lioure, Gerald Wulf, Kerstin Schäfer-Eckart, Mutlu Arat, Zinaida Peric, Christoph Schmid, Ali Bazarbachi, Fabio Ciceri, Arnon Nagler, and Mohamad Mohty
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: In this registry-based study, we compared outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) in adult patients with acute lymphoblastic leukemia (ALL) transplanted in first complete remission (CR-1), following conditioning with total body irradiation (TBI) at a standard 12-Gray or at a lower 8-Gray total dose. Patients received fludarabine (flu) as the sole chemotherapy complementing TBI. Eight-Gray TBI/flu was used in 494 patients and 12-Gray TBI/flu in 145 patients. Eighty-eight (23.1%) and 36 (29%) of the patients had Ph-negative B-ALL, 222 (58.3%) and 53 (42.7%) had Ph-positive B-ALL, 71 (18.6%) and 35 (28.2%) T-ALL, respectively (P = 0.008). Patients treated with 8-Gray were older than ones received 12-Gray (median 55.7 versus 40.3 years, P < 0.0001) and were more frequently administered in vivo T-cell depletion (71% versus 40%, P
Published: 2023
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11. Downregulation of the vitamin D receptor expression during acute gastrointestinal graft versus host disease is associated with poor outcome after allogeneic stem cell transplantation

Author: Carina Matos, Andreas Mamilos, Pranali N. Shah, Elisabeth Meedt, Daniela Weber, Saroj Ghimire, Andreas Hiergeist, André Gessner, Anne Dickinson, Ralf Dressel, Lutz Walter, Klaus Stark, Iris M. Heid, Hendrik Poeck, Matthias Edinger, Daniel Wolff, Wolfgang Herr, Ernst Holler, Marina Kreutz, and Sakhila Ghimire
Subjects: VDR, HSCT, acute GI-GvHD, TRM, defensins, Immunologic diseases. Allergy, RC581-607
Abstract: The vitamin D receptor (VDR) is critical in regulating intestinal homeostasis and emerging evidence demonstrates that VDR deficiency is a critical factor in inflammatory bowel disease pathology. However, no clinical data exist regarding the intestinal expression of VDR in patients after allogeneic haematopoietic stem cell transplantation (HSCT). Analyzing intestinal biopsies from 90 patients undergoing HSCT with mortality follow-up, we demonstrated that patients with severe acute gastrointestinal graft versus host disease (GI-GvHD) showed significant downregulation of VDR gene expression compared to mild or no acute GI-GvHD patients (p = 0.007). Reduced VDR expression was already detectable at acute GI-GvHD onset compared to GvHD-free patients (p = 0.01). These results were confirmed by immunohistochemistry (IHC) where patients with severe acute GI-GvHD showed fewer VDR+ cells (p = 0.03) and a reduced VDR staining score (p = 0.02) as compared to mild or no acute GI-GvHD patients. Accordingly, low VDR gene expression was associated with a higher cumulative incidence of treatment-related mortality (TRM) (p = 1.6x10-6) but not with relapse-related mortality (RRM). A multivariate Cox regression analysis identified low VDR as an independent risk factor for TRM (p = 0.001, hazard ratio 4.14, 95% CI 1.78-9.63). Furthermore, VDR gene expression significantly correlated with anti-microbial peptides (AMPs) gene expression (DEFA5: r = 0.637, p = 7x10-5, DEFA6: r 0 0.546, p = 0.001). In conclusion, our findings suggest an essential role of the VDR in the pathogenesis of gut GvHD and the prognosis of patients undergoing HSCT.
Published: 2022
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12. A qualitative study on patients’ and their support persons’ preferences for receiving one longer consultation or two shorter consultations when being informed about allogeneic hematopoietic stem cell transplantation

Author: Anne Herrmann, Ernst Holler, Matthias Edinger, Sascha Eickmann, and Daniel Wolff
Subjects: Hematological cancer, Stem cell transplantation, Patient preferences, Interviews, Qualitative research, Patient-centered care, Public aspects of medicine, RA1-1270
Abstract: Abstract Background Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only potentially curative treatment option for many patients with hematological disorders but it includes a significant risk of mortality and long-term morbidity. Many patients and their support persons feel overwhelmed when being informed about alloHSCT and may benefit from improvements in consultation style and timing. Aims To explore, qualitatively, in a sample of hematological cancer patients and their support persons, their preferences for receiving one longer consultation or two shorter consultations when being informed about alloHSCT. Participants’ perceptions of when and how different consultation styles should be offered were also examined. Methods Semi-structured face-to-face and phone interviews were conducted. A purposeful sampling frame was used. Data were analysed using framework analysis. Results Twenty patients and 13 support persons were recruited (consent rate: 96%, response rate: 91%). Most patients (60%) and support persons (62%) preferred two shorter consultations over one longer consultation. This helped them digest and recall the information provided, remember questions they had, involve significant others and search for additional information. Patients would have liked to be offered paper and pen to take notes, take a break after 30 min and have their understanding checked at the end of the first consultation, e.g. using question prompt lists. Some patients and support persons preferred both consultations to happen on the same day to reduce waiting times as well as travel times and costs. Others preferred having a few days in-between both consultations to better help them prepare the second consultation. Participants reported varying preferences for different consultation styles depending on personal and disease-related characteristics, such as age, health literacy level and previous treatment. Conclusion To our knowledge, this is the first qualitative study to explore patients’ and their support persons’ preferences for having one longer consultation or two shorter consultations when being informed about alloHSCT. Receiving two shorter consultations may help patients process and recall the information provided and more actively involve their support persons. Clinicians should consider offering patients and their support persons to take a break after 30 min, provide paper and pen as well as question prompt lists.
Published: 2021
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13. Low Intestinal IL22 Associates With Increased Transplant-Related Mortality After Allogeneic Stem Cell Transplantation

Author: Sakhila Ghimire, Katharina U. Ederer, Elisabeth Meedt, Daniela Weber, Carina Matos, Andreas Hiergeist, Florian Zeman, Daniel Wolff, Matthias Edinger, Hendrik Poeck, Wolfgang Herr, André Gessner, Ernst Holler, and Sigrid Bülow
Subjects: IL22, allogeneic SCT, GvHD, TRM, antibiotics, GPR41, Immunologic diseases. Allergy, RC581-607
Abstract: The role of IL-22 in adult patients undergoing allogeneic stem cell transplantation (SCT) is of major interest since animal studies showed a protective and regenerative effect of IL-22 in graft versus host disease (GvHD). However, no clinical data exist on the tissue expression. Here we demonstrate that patients not suffering from transplant-related mortality (TRM) show significantly upregulated IL22 expression during histological and clinical GI-GvHD (p = 0.048 and p = 0.022, respectively). In contrast, in GvHD patients suffering from TRM, IL22 was significantly lower (p = 0.007). Accordingly, lower IL22 was associated with a higher probability of TRM in survival analysis (p = 0.005). In a multivariable competing risk Cox regression analysis, low IL22 was identified as an independent risk factor for TRM (p = 0.007, hazard ratio 2.72, 95% CI 1.32 to 5.61). The expression of IL22 seemed to be microbiota dependent as broad-spectrum antibiotics significantly diminished IL22 expression (p = 0.019). Furthermore, IL22 expression significantly correlated with G-protein coupled receptor (GPR)43 (r = 0.263, p = 0.015) and GPR41 expression (r = 0.284, p = 0.009). In conclusion, our findings reveal an essential role of IL22 for the prognosis of patients undergoing allogeneic SCT.
Published: 2022
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14. Mechanisms governing the pioneering and redistribution capabilities of the non-classical pioneer PU.1

Author: Julia Minderjahn, Andreas Schmidt, Andreas Fuchs, Rudolf Schill, Johanna Raithel, Magda Babina, Christian Schmidl, Claudia Gebhard, Sandra Schmidhofer, Karina Mendes, Anna Ratermann, Dagmar Glatz, Margit Nützel, Matthias Edinger, Petra Hoffmann, Rainer Spang, Gernot Längst, Axel Imhof, and Michael Rehli
Subjects: Science
Abstract: PU.1 is a master TF of hematopoietic lineage differentiation. Here the authors analyse properties of PU.1 DNA-binding in vitro and genome-wide in vivo across different cell types with native or ectopic PU.1 expression, and uncover the mechanisms governing the pioneering and redistribution capabilities of the non-classical pioneer PU.1.
Published: 2020
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15. GPR Expression in Intestinal Biopsies From SCT Patients Is Upregulated in GvHD and Is Suppressed by Broad-Spectrum Antibiotics

Author: Sakhila Ghimire, Daniela Weber, Katrin Hippe, Elisabeth Meedt, Matthias Hoepting, Anna-Sophia Kattner, Andreas Hiergeist, André Gessner, Carina Matos, Saroj Ghimire, Daniel Wolff, Matthias Edinger, Petra Hoffmann, Hendrik Poeck, Wolfgang Herr, and Ernst Holler
Subjects: broad-spectrum antibiotics, GPR, Foxp3, GvHD, microbiota, SCFA, Immunologic diseases. Allergy, RC581-607
Abstract: Microbiota can exert immunomodulatory effects by short-chain fatty acids (SCFA) in experimental models of graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-SCT). Therefore we aimed to analyze the expression of SCFAs sensing G-protein coupled receptor GPR109A and GPR43 by quantitative PCR in 338 gastrointestinal (GI) biopsies obtained from 199 adult patients undergoing allo-SCT and assessed the interaction of GPR with FOXP3 expression and regulatory T cell infiltrates. GPR expression was strongly upregulated in patients with stage II-IV GvHD (p=0.000 for GPR109A, p=0.01 for GPR43) and at the onset of GvHD (p 0.000 for GPR109A, p=0.006 for GPR43) and correlated strongly with FOXP3 and NLRP3 expression. The use of broad-spectrum antibiotics (Abx) drastically suppressed GPR expression as well as FOXP3 expression in patients’ gut biopsies (p=0.000 for GPRs, FOXP3 mRNA and FOXP3+ cellular infiltrates). Logistic regression analysis revealed treatment with Abx as an independent factor associated with GPR and FOXP3 loss. The upregulation of GPRs was evident only in the absence of Abx (p=0.001 for GPR109A, p=0.014 for GPR43) at GvHD onset. Thus, GPR expression seems to be upregulated in the presence of commensal bacteria and associates with infiltration of FOXP3+ T regs, suggesting a protective, regenerative immunomodulatory response. However, Abx, which has been shown to induce dysbiosis, interferes with this protective response.
Published: 2021
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16. 'This Graft-vs.-Host Disease Determines My Life. That's It.'—A Qualitative Analysis of the Experiences and Needs of Allogenic Hematopoietic Stem Cells Transplantation Survivors in Germany

Author: Mira Parisek, Julika Loss, Ernst Holler, Anna Barata, Daniela Weber, Matthias Edinger, Daniel Wolff, Helene Schoemans, and Anne Herrmann
Subjects: allogeneic hematopoietic stem cells transplantation, survivorship, patients view, framework analysis, qualitative research, GvHD, Public aspects of medicine, RA1-1270
Abstract: Background: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only curative treatment modality for many patients affected by hematologic malignancies. However, it can cause debilitating long-term effects. Understanding the impact of alloHSCT on all aspects of the patients' life is required for optimal survivorship management.Aim: To explore in-depth HSCT-survivors' experiences and needs post-transplant. Partners were included to provide further information on survivors' needs and how care could be improved in this area.Methods: We conducted semi-structured face-to-face and phone interviews with alloHSCT-survivors and their partners referred to a survivorship clinic in Germany. Theoretical sampling was used to recruit participants. Data were analyzed using framework analysis.Results: Thirty-two survivors (consent rate: 100%, response rate: 100%) and eighteen partners (consent rate: 84%, response rate: 72%) participated. Survivors were aged between 25 and 68 years (Median: 48, IQR: 25.3) and partners were aged between 26 and 64 years (Median: 54, IQR: 16, SD: 12.8). The themes emerging from the data involved survivors' needs included (i) the diversity of long-term treatment side-effects; and (ii) time post discharge as a dynamic process with individual peaks of burden. Survivors and their partners also suggested strategies for mitigating these unmet needs, i.e., (iii) transparent communication and patient empowerment; and (iv) improvement in continuity of care system and help with claiming social benefits as cornerstones of optimal survivorship care.Conclusion: To our knowledge, this is one of the first qualitative studies focused on the views of German alloHSCT-survivors on the long-term effects of alloHSCT and the first study integrating the view of their partners. Healthcare providers could better support survivors with managing their symptoms and adhering to their prescribed care by ensuring comprehensive, transparent communication that helps increase survivors' understanding and involvement in their care. Further efforts should be made to provide patient-centered, continuous survivorship care that involves additional support with navigating the healthcare and social service system. Intervention studies are required to test the effectiveness of the suggested strategies.
Published: 2021
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17. A Prospective Controlled Trial to Evaluate Safety and Efficacy of in vitro Expanded Recipient Regulatory T Cell Therapy and Tocilizumab Together With Donor Bone Marrow Infusion in HLA-Mismatched Living Donor Kidney Transplant Recipients (Trex001)

Author: Rainer Oberbauer, Matthias Edinger, Gabriela Berlakovich, Peter Kalhs, Nina Worel, Georg Heinze, Michael Wolzt, Thomas Lion, and Thomas Wekerle
Subjects: kidney transplantation, cell therapy, regulatory T cells, chimerism, tolerance, bone marrow, Medicine (General), R5-920
Abstract: Background: The induction of donor-specific immunological tolerance could improve outcome after kidney transplantation. However, no tolerance protocol is available for routine clinical use. Chimerism-based regimens hold promise, but their widespread application is impeded in part by unresolved safety issues. This study tests the hypothesis that therapy with polyclonal recipient regulatory T cells (Tregs) and anti-IL6R (tocilizumab) leads to transient chimerism and achieves pro-tolerogenic immunomodulation in kidney transplant recipients also receiving donor bone marrow (BM) without myelosuppressive conditioning of the recipient.Methods/design: A prospective, open-label, controlled, single-center, phase I/IIa academic study is performed in HLA-mismatched living donor kidney transplant recipients.Study group: Recipients of the study group receive in vitro expanded recipient Tregs and a donor bone marrow cell infusion within 3 days after transplantation and tocilizumab for the first 3 weeks post-transplant. In addition they are treated with thymoglobulin, belatacept, sirolimus, and steroids as immunosuppression. Starting 6 months post-transplant, sirolimus and steroids are withdrawn in a step-wise manner in stable patients.Control group: Recipients of the control group are treated with thymoglobulin, belatacept, sirolimus, and steroids as immunosuppression. Co-primary endpoints of safety (impaired graft function [eGFR
Published: 2021
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18. Evaluation of the Cost of Survivorship Care After Allogeneic Hematopoeitic Stem Cell Transplantation–An Analysis of 2 German Transplantation Centers

Author: Daniel Wolff, Jelena Bardak, Matthias Edinger, Ursula Klinger-Schindler, Ernst Holler, Anita Lawitschka, Helene Schoemans, Wolfgang Herr, Nikolaus Kröger, and Francis Ayuk Ayuketang
Subjects: GvHD, Graft vs. Host disease, haematopoietic stem cell transplant, survivorship care model, costs, re-imbursement, Public aspects of medicine, RA1-1270
Abstract: The aim of the presented study was to analyze the care expenditure for outpatients after allogeneic hematopoietic stem cell transplantation (alloHSCT) done in accordance with the national, European guidelines and the German Social Law. We performed an analysis of the National and European survivorship care guidelines and in parallel recorded the time expenditure and staff costs separated according to different occupational groups involved in outpatient care at two German transplantation centers [University Hospital Regensburg (UKR) and University Hospital Hamburg-Eppendorf (UKE)]. In addition, we performed a comparison of real costs vs. reimbursed costs according to the standard rating benchmark catalog (EBM), which was supplemented by a survey of German transplantation centers. The results showed that the staff costs are only covered by the EBM for patients without complications during long-term follow-up care—notably, this accounts for 15% of alloHSCT patients. Staff costs for patients requiring treatment of graft-vs.-host disease or relapse of the malignant underlying malignancy exceed to the factor 6.5 (UKR) to 12 (UKE) of the EBM revenue, caused both by the increased duration and frequency of the outpatient visits. As a result of the survey at German transplant centers, 15 out of 18 responding centers reported a lack of cost coverage for follow-up care. Two/15 centers reported that survivorship care is limited to a restricted time, independent of patient's needs, due to a lack of cost reimbursement. The results show that alloHSCT survivorship care of patients requires significant staff resources, which are not covered by the current version of the German EBM catalog. New approaches to finance labor intensive after care of transplant patients are required.
Published: 2020
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19. Imatinib dose reduction in major molecular response of chronic myeloid leukemia: results from the German Chronic Myeloid Leukemia-Study IV

Author: Christian Michel, Andreas Burchert, Andreas Hochhaus, Susanne Saussele, Andreas Neubauer, Michael Lauseker, Stefan W. Krause, Hans-Jochem Kolb, Dieter Kurt Hossfeld, Christoph Nerl, Gabriela M. Baerlocher, Dominik Heim, Tim H Brümmendorf, Alice Fabarius, Claudia Haferlach, Brigitte Schlegelberger, Leopold Balleisen, Maria-Elisabeth Goebeler, Mathias Hänel, Anthony Ho, Jolanta Dengler, Christiane Falge, Robert Möhle, Stephan Kremers, Michael Kneba, Frank Stegelmann, Claus-Henning Köhne, Hans-Walter Lindemann, Cornelius F. Waller, Karsten Spiekermann, Wolfgang E. Berdel, Lothar Müller, Matthias Edinger, Jiri Mayer, Dietrich W. Beelen, Martin Bentz, Hartmut Link, Bernd Hertenstein, Roland Fuchs, Martin Wernli, Frank Schlegel, Rudolf Schlag, Maike de Wit, Lorenz Trümper, Holger Hebart, Markus Hahn, Jörg Thomalla, Christof Scheid, Philippe Schafhausen, Walter Verbeek, Michael J. Eckart, Winfried Gassmann, Michael Schenk, Peter Brossart, Thomas Wündisch, Thomas Geer, Stephan Bildat, Erhardt Schäfer, Joerg Hasford, Rüdiger Hehlmann, and Markus Pfirrmann
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800 mg (‘high-dose’) imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown. To gain insights into this clinically relevant question, we analyzed the outcome of imatinib dose reductions from 800 mg to 400 mg daily in the Chronic Myeloid Leukemia-Study IV. Of the 422 patients that were randomized to the 800 mg arm, 68 reduced imatinib to 400 mg after they had achieved at least a stable major molecular response. Of these 68 patients, 61 (90%) maintained major molecular remission on imatinib at 400 mg. Five of the seven patients who lost major molecular remission on the imatinib standard dose regained major molecular remission while still on 400 mg imatinib. Only two of 68 patients had to switch to more potent kinase inhibition to regain major molecular remission. Importantly, the lengths of the intervals between imatinib high-dose treatment before and after achieving major molecular remission were associated with the probabilities of maintaining major molecular remission with the standard dose of imatinib. Taken together, the data support the view that a deep molecular remission achieved with high-dose imatinib can be safely maintained with standard dose in most patients. Study protocol registered at clinicaltrials.gov 00055874.
Published: 2019
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20. Parametric Imaging of Contrast-Enhanced Ultrasound (CEUS) for the Evaluation of Acute Gastrointestinal Graft-Versus-Host Disease

Author: Antonia-Maria Pausch, Sylvia Kammerer, Florian Weber, Wolfgang Herr, Christian Stroszczynski, Ernst Holler, Matthias Edinger, Daniel Wolff, Daniela Weber, Ernst-Michael Jung, and Tobias Wertheimer
Subjects: GvHD, CEUS, parametric imaging, allogeneic stem cell transplantation, dynamic vascularization, Cytology, QH573-671
Abstract: In recent years contrast-enhanced ultrasound (CEUS) has been an emerging diagnostic modality for the detection of acute gastrointestinal (GI) graft-versus-host disease (GvHD) in patients after allogeneic stem cell transplantation. However, broad clinical usage has been partially limited by its high dependence on the expertise of an experienced examiner. Thus, the aim of this study was to facilitate detection of acute GI GvHD by implementing false color-coded parametric imaging of CEUS. As such, two inexperienced examiners with basic knowledge in abdominal and vascular ultrasound analyzed parametric images obtained from patients with clinical suspicion for acute GvHD in a blinded fashion. As diagnostic gold standard, histopathological GvHD severity score on intestinal biopsies obtained from lower GI tract endoscopy was performed. The evaluation of parametric images by the two inexperienced ultrasound examiners in patients with histological confirmation of acute GI GvHD was successful in 17 out of 19 patients (89%) as opposed to analysis of combined B-mode ultrasound, strain elastography, and CEUS by an experienced examiner, which was successful in 18 out of 19 of the patients (95%). Therefore, CEUS with parametric imaging of the intestine was technically feasible and has the potential to become a valuable diagnostic tool for rapid and widely accessible detection of acute GvHD in clinical practice.
Published: 2021
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21. Author Correction: Mechanisms governing the pioneering and redistribution capabilities of the non-classical pioneer PU.1

Author: Julia Minderjahn, Andreas Schmidt, Andreas Fuchs, Rudolf Schill, Johanna Raithel, Magda Babina, Christian Schmidl, Claudia Gebhard, Sandra Schmidhofer, Karina Mendes, Anna Ratermann, Dagmar Glatz, Margit Nützel, Matthias Edinger, Petra Hoffmann, Rainer Spang, Gernot Längst, Axel Imhof, and Michael Rehli
Subjects: Science
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Published: 2020
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22. Secondary solid malignancies and precancerous lesions after allogeneic hematopoietic stem cell transplantation using non-total body irradiation-based conditioning in acute myeloid leukemia

Author: Isabella, Gruber, Katharina, Appel, Matthias, Edinger, Oliver, Koelbl, and Daniel, Wolff
Published: 2024
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23. Noninvasive Assessment of Tumor Cell Proliferation in Animal Models

Author: Matthias Edinger, Thomas J. Sweeney, Amanda A. Tucker, Adesuwa B. Olomu, Robert S. Negrin, and Christopher H. Contag
Subjects: luciferase, noninvasive monitoring, cancer, tumor progression, imaging, in vivo, therapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Revealing the mechanisms of neoplastic disease and enhancing our ability to intervene in these processes requires an increased understanding of cellular and molecular changes as they occur in intact living animal models. We have begun to address these needs by developing a method of labeling tumor cells through constitutive expression of an optical reporter gene, noninvasively monitoring cellular proliferation in vivo using a sensitive photon detection system. A stable line of HeLa cells that expressed a modified firefly luciferase gene was generated, proliferation of these cells in irradiated severe combined immunodeficiency (SCID) mice was monitored. Tumor cells were introduced into animals via subcutaneous, intraperitoneal and intravenous inoculation and whole body images, that revealed tumor location and growth kinetics, were obtained. The number of photons that were emitted from the labeled tumor cells and transmitted through murine tissues was sufficient to detect 1×103 cells in the peritoneal cavity, 1×104 cells at subcutaneous sites and 1×106 circulating cells immediately following injection. The kinetics of cell proliferation, as measured by photon emission, was exponential in the peritoneal cavity and at subcutaneous sites. Intravenous inoculation resulted in detectable colonies of tumor cells in animals receiving more than 1×103 cells. Our demonstrated ability to detect small numbers of tumor cells in living animals noninvasively suggests that therapies designed to treat minimal disease states, as occur early in the disease course and after elimination of the tumor mass, may be monitored using this approach. Moreover, it may be possible to monitor micrometastases and evaluate the molecular steps in the metastatic process. Spatiotemporal analyses of neoplasia will improve the predictability of animal models of human disease as study groups can be followed over time, this method will accelerate development of novel therapeutic strategies.
Published: 1999
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24. Novel serial positive enrichment technology enables clinical multiparameter cell sorting.

Author: Christian Stemberger, Stefan Dreher, Claudia Tschulik, Christine Piossek, Jeannette Bet, Tori N Yamamoto, Matthias Schiemann, Michael Neuenhahn, Klaus Martin, Martin Schlapschy, Arne Skerra, Thomas Schmidt, Matthias Edinger, Stanley R Riddell, Lothar Germeroth, and Dirk H Busch
Subjects: Medicine, Science
Abstract: A general obstacle for clinical cell preparations is limited purity, which causes variability in the quality and potency of cell products and might be responsible for negative side effects due to unwanted contaminants. Highly pure populations can be obtained best using positive selection techniques. However, in many cases target cell populations need to be segregated from other cells by combinations of multiple markers, which is still difficult to achieve--especially for clinical cell products. Therefore, we have generated low-affinity antibody-derived Fab-fragments, which stain like parental antibodies when multimerized via Strep-tag and Strep-Tactin, but can subsequently be removed entirely from the target cell population. Such reagents can be generated for virtually any antigen and can be used for sequential positive enrichment steps via paramagnetic beads. First protocols for multiparameter enrichment of two clinically relevant cell populations, CD4(high)/CD25(high)/CD45RA(high) 'regulatory T cells' and CD8(high)/CD62L(high)/CD45RA(neg) 'central memory T cells', have been established to determine quality and efficacy parameters of this novel technology, which should have broad applicability for clinical cell sorting as well as basic research.
Published: 2012
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25. Multi-modality Imaging Identifies Key Times for Annexin V Imaging as an Early Predictor of Therapeutic Outcome

Author: Stefanie J. Mandl, Carina Mari, Matthias Edinger, Robert S. Negrin, Jonathan F. Tait, Christopher H. Contag, and Francis G. Blankenberg
Subjects: Biology (General), QH301-705.5, Medical technology, R855-855.5
Abstract: Radiolabeled annexin V may provide an early indication of the success or failure of anticancer therapy on a patient-by-patient basis as an in vivo marker of tumor cell killing. An important question that remains is when, after initiation of treatment, should annexin V imaging be performed. To address this issue, we obtained simultaneous in vivo measurements of tumor burden and uptake of radiolabeled annexin V in the syngeneic orthotopic murine BCL 1 lymphoma model using in vivo bioluminescence imaging (BLI) and small animal single-photon emission computed tomography (SPECT). BCL 1 cells labeled for fluorescence and bioluminescence assays (BCL 1 − gfp/luc ) were injected into mice at a dose that leads to progressive disease within two to three weeks. Tumor response was followed by BLI and SPECT before and after treatment with a single dose of 10 mg/kg doxorubicin. Biodistribution analyses revealed a biphasic increase of annexin V uptake within the tumor-bearing tissues of mice. An early peak occurring before actual tumor cells loss was observed between 1 and 5 hr after treatment, and a second longer sustained rise from 9 to 24 hr after therapy, which heralds the onset of tumor cell loss as confirmed by BLI. Multimodality imaging revealed the temporal patterns of tumor cell loss and annexin V uptake revealing a better understanding of the timing of radiolabeled annexin V uptake for its development as a marker of therapeutic efficacy.
Published: 2004
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26. Optimum timing of antithymocyte globulin in relation to adoptive regulatory T cell therapy

Author: Moritz Muckenhuber, Jasmin Mucha, Konstantinos Mengrelis, Christopher How, Roman Reindl-Schwaighofer, Andreas Heinzel, Verena Kainz, Nina Worel, Gabriela Berlakovich, Matthias Edinger, Rainer Oberbauer, and Thomas Wekerle
Subjects: Transplantation, Immunology and Allergy, Pharmacology (medical)
Published: 2023

27. Longitudinal Outcome over Two Decades of Unrelated Allogeneic Stem Cell Transplantation for Relapsed/Refractory Acute Myeloid Leukemia: An ALWP/EBMT Analysis

Author: Arnon Nagler, Maud Ngoya, Jacques-Emmanuel Galimard, Myriam Labopin, Martin Bornhäuser, Matthias Stelljes, Jürgen Finke, Arnold Ganser, Herman Einsele, Nicolaus Kröger, Arne Brecht, Wolfgang Bethge, Matthias Edinger, Aleksandr Kulagin, Jakob Passweg, Igor Wolfgang Blau, Ahmet Elmaagacli, Kerstin Schäfer-Eckart, Uwe Platzbecker, Thomas Schroeder, Donald Bunjes, Johanna Tischer, Sonja Martin, Alexandros Spyridonidis, Sebastian Giebel, Bipin Savani, and Mohamad Mohty
Subjects: Leukemia, Myeloid, Acute, Cancer Research, Transplantation Conditioning, Oncology, Recurrence, Hematopoietic Stem Cell Transplantation, Graft vs Host Disease, Humans, Middle Aged, Retrospective Studies, Stem Cell Transplantation
Abstract: Purpose: We evaluated outcomes of unrelated transplantation for primary refractory/relapsed (ref/rel) acute myeloid leukemia (AML), comparing two cohorts according to the year of transplant, 2000–2009 and 2010–2019. Patients and Methods: Multivariable analyses were performed using the Cox proportional-hazards regression model. Results: 3,430 patients were included; 876 underwent a transplant between 2000–2009 and 2554 in 2010–2019. Median follow-up was 8.7 (95% CI, 7.8–9.4) and 3.4 (95% CI, 3.1–3.6) years (P < 0.001). Median age was 52 (18–77) and 56 (18–79) years (P > 0.0001); 45.5% and 55.5% had refractory AML while 54.5% and 44.5% had relapsed AML. Conditioning was myeloablative in 60% and 52%, respectively. Neutrophil recovery and day 100 incidence of acute and 2-year incidence of chronic graft-versus-host disease (GvHD) were similar between the two periods. Two-year relapse incidence was higher for patients undergoing transplant in the 2000–2009 period versus those undergoing transplant in 2010–2019: 50.2% versus 45.1% (HR, 0.85; 95% CI, 0.74–0.97; P = 0. 002). Leukemia-free survival; overall survival; and GvHD-free, relapse-free survival were lower for the 2000–2009 period: 26% versus 32.1% (HR, 0.87; 95% CI, 0.78–0.97; P = 0.01), 32.1% versus 38.1% (HR, 0.86; 95% CI, 0.77–0.96; P = 0.01), and 21.5% versus 25.3% (HR, 0.89; 95% CI, 0.81–0.99; P = 0.03), respectively. Two-year nonrelapse mortality was not significantly different (23.8% vs. 23.7%; HR, 0.91; 95% CI, 0.76–1.11; P = 0.34). Conclusions: Outcome of unrelated transplantation for patients with ref/rel AML has improved in the last two decades, rescuing about one third of the patients. See related commentary by Adrianzen-Herrera and Shastri, p. 4167
Published: 2022

28. Data from Longitudinal Outcome over Two Decades of Unrelated Allogeneic Stem Cell Transplantation for Relapsed/Refractory Acute Myeloid Leukemia: An ALWP/EBMT Analysis

Author: Mohamad Mohty, Bipin Savani, Sebastian Giebel, Alexandros Spyridonidis, Sonja Martin, Johanna Tischer, Donald Bunjes, Thomas Schroeder, Uwe Platzbecker, Kerstin Schäfer-Eckart, Ahmet Elmaagacli, Igor Wolfgang Blau, Jakob Passweg, Aleksandr Kulagin, Matthias Edinger, Wolfgang Bethge, Arne Brecht, Nicolaus Kröger, Herman Einsele, Arnold Ganser, Jürgen Finke, Matthias Stelljes, Martin Bornhäuser, Myriam Labopin, Jacques-Emmanuel Galimard, Maud Ngoya, and Arnon Nagler
Abstract: Purpose:We evaluated outcomes of unrelated transplantation for primary refractory/relapsed (ref/rel) acute myeloid leukemia (AML), comparing two cohorts according to the year of transplant, 2000–2009 and 2010–2019.Patients and Methods:Multivariable analyses were performed using the Cox proportional-hazards regression model.Results:3,430 patients were included; 876 underwent a transplant between 2000–2009 and 2554 in 2010–2019. Median follow-up was 8.7 (95% CI, 7.8–9.4) and 3.4 (95% CI, 3.1–3.6) years (P < 0.001). Median age was 52 (18–77) and 56 (18–79) years (P > 0.0001); 45.5% and 55.5% had refractory AML while 54.5% and 44.5% had relapsed AML. Conditioning was myeloablative in 60% and 52%, respectively. Neutrophil recovery and day 100 incidence of acute and 2-year incidence of chronic graft-versus-host disease (GvHD) were similar between the two periods. Two-year relapse incidence was higher for patients undergoing transplant in the 2000–2009 period versus those undergoing transplant in 2010–2019: 50.2% versus 45.1% (HR, 0.85; 95% CI, 0.74–0.97; P = 0. 002). Leukemia-free survival; overall survival; and GvHD-free, relapse-free survival were lower for the 2000–2009 period: 26% versus 32.1% (HR, 0.87; 95% CI, 0.78–0.97; P = 0.01), 32.1% versus 38.1% (HR, 0.86; 95% CI, 0.77–0.96; P = 0.01), and 21.5% versus 25.3% (HR, 0.89; 95% CI, 0.81–0.99; P = 0.03), respectively. Two-year nonrelapse mortality was not significantly different (23.8% vs. 23.7%; HR, 0.91; 95% CI, 0.76–1.11; P = 0.34).Conclusions:Outcome of unrelated transplantation for patients with ref/rel AML has improved in the last two decades, rescuing about one third of the patients.See related commentary by Adrianzen-Herrera and Shastri, p. 4167
Published: 2023

29. Supplementary Data from Longitudinal Outcome over Two Decades of Unrelated Allogeneic Stem Cell Transplantation for Relapsed/Refractory Acute Myeloid Leukemia: An ALWP/EBMT Analysis

Author: Mohamad Mohty, Bipin Savani, Sebastian Giebel, Alexandros Spyridonidis, Sonja Martin, Johanna Tischer, Donald Bunjes, Thomas Schroeder, Uwe Platzbecker, Kerstin Schäfer-Eckart, Ahmet Elmaagacli, Igor Wolfgang Blau, Jakob Passweg, Aleksandr Kulagin, Matthias Edinger, Wolfgang Bethge, Arne Brecht, Nicolaus Kröger, Herman Einsele, Arnold Ganser, Jürgen Finke, Matthias Stelljes, Martin Bornhäuser, Myriam Labopin, Jacques-Emmanuel Galimard, Maud Ngoya, and Arnon Nagler
Abstract: Supplementary Data from Longitudinal Outcome over Two Decades of Unrelated Allogeneic Stem Cell Transplantation for Relapsed/Refractory Acute Myeloid Leukemia: An ALWP/EBMT Analysis
Published: 2023

30. A non-antibiotic-disrupted gut microbiome associated with clinical responses to CD19-CAR-T cell cancer immunotherapy

Author: Christoph K. Stein-Thoeringer, Neeraj Y. Saini, Eli Zamir, Viktoria Blumenberg, Maria-Luisa Schubert, Uria Mor, Matthias A. Fante, Sabine Schmidt, Eiko Hayase, Tomo Hayase, Roman Rohrbach, Chia-Chi Chang, Lauren McDaniel, Ivonne Flores, Rogier Gaiser, Matthias Edinger, Daniel Wolff, Martin Heidenreich, Paolo Strati, Ranjit Nair, Dai Chihara, Luis E. Fayad, Sairah Ahmed, Swaminathan P. Iyer, Raphael E. Steiner, Preetesh Jain, Loretta J. Nastoupil, Jason Westin, Reetakshi Arora, Michael L. Wang, Joel Turner, Meghan Menges, Melanie Hidalgo-Vargas, Kayla Reid, Peter Dreger, Anita Schmitt, Carsten Müller-Tidow, Frederick L. Locke, Marco L. Davila, Richard E. Champlin, Christopher R. Flowers, Elizabeth J. Shpall, Hendrik Poeck, Sattva S. Neelapu, Michael Schmitt, Marion Subklewe, Michael D. Jain, Robert R. Jenq, and Eran Elinav
Subjects: General Medicine, General Biochemistry, Genetics and Molecular Biology, Article
Abstract: Increasing evidence suggests that the gut microbiome may modulate the efficacy of cancer immunotherapy. In a B cell-lymphoma patient cohort from five centers in Germany and the United States (Germany, N=66; US, N=106, Total, N=172), we demonstrate that wide-spectrum antibiotics treatment (‘high-risk antibiotics’) prior to CD19-targeted chimeric antigen receptor (CAR)-T cell therapy is associated with adverse outcomes, but this effect is likely confounded by an increased pre-treatment tumor burden and systemic inflammation in high-risk antibiotics-pre-treated patients. To resolve this confounding effect and gain insights into antibiotics-masked microbiome signals impacting CAR-T efficacy, we focused on the high-risk antibiotics non-exposed patient population. Indeed, in these patients, significant correlations were uncovered between pre-CAR-T-infusion Bifidobacterium longum and microbiome-encoded peptidoglycan biosynthesis, and CAR-T treatment-associated 6-months survival or lymphoma progression. Furthermore, predictive pre-CAR-T treatment microbiome-based machine-learning algorithms trained on the high-risk antibiotics non-exposed German cohort and validated by the respective US cohort robustly segregated long-term responders from non-responders. Bacteroides, Ruminococcus, Eubacterium and Akkermansia were most important in determining CAR-T responsiveness, with Akkermansia also associating with pre-infusion peripheral T cell levels in these patients. Collectively, we uncover conserved microbiome features across clinical and geographical variations, which may enable cross-cohort microbiome-based predictions of outcomes in CAR-T cell immunotherapy.
Published: 2023

31. Chronic Active Epstein-Barr Virus Infection Controlled by Allogeneic Stem Cell Transplantation and EBV-specific T Cells

Author: Elisabeth Meedt, Daniela Weber, Agnes Bonifacius, Britta Eiz-Vesper, Britta Maecker-Kolhoff, Susanne Delecluse, Henri-Jacques Delecluse, Myriam Lorenz, Klaus Schwarz, Stefan T Meedt, Jan Braess, Wolfgang Herr, Ernst Holler, Matthias Edinger, and Daniel Wolff
Subjects: Microbiology (medical), Infectious Diseases
Abstract: We report sustained remission of chronic active Epstein-Barr virus (EBV) infection in a 27-year-old female patient treated with third-party EBV-specific T cells followed by allogeneic hematopoietic stem cell transplantation (HSCT). The viremia cleared after administration of anti-T-lymphocyte globulin for graft-versus-host disease (GvHD) prophylaxis. Subsequent expansion of EBV-infected host T cells was controlled by transfusion of donor-derived EBV-specific T cells.
Published: 2023

32. Identification of Bacterial and Viral Consortia for the Production of Intestinal Microbiota-Derived Metabolites Associated with Protection in Allogeneic Stem Cell Transplantation Patients

Author: Erik Thiele Orberg, Elisabeth Meedt, Andreas Hiergeist, Jinling Xue, Paul Heinrich, Sakhila Ghimire, Melanie Tiefgraber, Sophia Göldel, Tina Eismann, Alix Schwarz, Sebastian Jarosch, Katja Steiger, Karin Kleigrewe, Julius Clemens Fischer, Klaus-Peter Janssen, Michael Quante, Simon Heidegger, Peter Herhaus, Mareike Verbeek, Jürgen Ruland, Christian Schulz, Daniela Weber, Matthias Edinger, Daniel Wolff, Dirk Busch, Wolfgang Herr, Florian Bassermann, Li Deng, Andre Gessner, Ernst Holler, and Hendrik Poeck
Subjects: Immunology, Cell Biology, Hematology, Biochemistry
Published: 2022

33. Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation from Different Donor Types in Primary Refractory Acute Myeloid Leukemia: A Report from the ALWP of the EBMT

Author: Kordelia Barbullushi, Myriam Labopin, Nicolaus Kröger, Jürgen Finke, Matthias Stelljes, Arnold Ganser, Wolfgang Bethge, Hermann Einsele, Johannes Schetelig, Renato Fanin, Pavel Jindra, Jochen Casper, Thomas Schroeder, Matthias Edinger, Jakob Passweg, Edouard Forcade, Johanna Tischer, Arnon Nagler, Fabio Ciceri, and Mohamad Mohty
Subjects: Immunology, Cell Biology, Hematology, Biochemistry
Published: 2022

34. Biosensors for inflammation as a strategy to engineer regulatory T cells for cell therapy

Author: Sebastian Bittner, Brigitte Ruhland, Veronika Hofmann, Lisa Schmidleithner, Kathrin Schambeck, Asmita Pant, Philipp Stüve, Michael Delacher, Bernd Echtenacher, Matthias Edinger, Petra Hoffmann, Michael Rehli, Claudia Gebhard, Nicholas Strieder, Thomas Hehlgans, and Markus Feuerer
Subjects: Inflammation, Multidisciplinary, Tumor Necrosis Factor-alpha, Cell- and Tissue-Based Therapy, Receptors, Antigen, T-Cell, Biosensing Techniques, Ligands, T-Lymphocytes, Regulatory, Receptors, Tumor Necrosis Factor, Mice, CD28 Antigens, Lymphotoxin beta Receptor, Animals, Humans, Cell Engineering
Abstract: Engineered regulatory T cell (Treg cell) therapy is a promising strategy to treat patients suffering from inflammatory diseases, autoimmunity, and transplant rejection. However, in many cases, disease-related antigens that can be targeted by Treg cells are not available. In this study, we introduce a class of synthetic biosensors, named artificial immune receptors (AIRs), for murine and human Treg cells. AIRs consist of three domains: (a) extracellular binding domain of a tumor necrosis factor (TNF)-receptor superfamily member, (b) intracellular costimulatory signaling domain of CD28, and (c) T cell receptor signaling domain of CD3-ζ chain. These AIR receptors equip Treg cells with an inflammation-sensing machinery and translate this environmental information into a CD3-ζ chain–dependent TCR-activation program. Different AIRs were generated, recognizing the inflammatory ligands of the TNF-receptor superfamily, including LIGHT, TNFα, and TNF-like ligand 1A (TL1A), leading to activation, differentiation, and proliferation of AIR–Treg cells. In a graft-versus-host disease model, Treg cells expressing lymphotoxin β receptor–AIR, which can be activated by the ligand LIGHT, protect significantly better than control Treg cells. Expression and signaling of the corresponding human AIR in human Treg cells prove that this concept can be translated. Engineering Treg cells that target inflammatory ligands leading to TCR signaling and activation might be used as a Treg cell–based therapy approach for a broad range of inflammation-driven diseases.
Published: 2022

35. Primary vaccination in adult patients after allogeneic hematopoietic stem cell transplantation – A single center retrospective efficacy analysis

Author: Julia Winkler, Philipp Yorck Herzberg, Wolfgang Herr, Ute Fehn, Ernst Holler, Daniela Weber, Philipp Beckhove, Annelie Plentz, Barbara Holler, Petra Hoffmann, Clara Sattler, Daniel Wolff, and Matthias Edinger
Subjects: Adult, Bordetella pertussis, medicine.medical_treatment, 030231 tropical medicine, Hematopoietic stem cell transplantation, Pneumococcal conjugate vaccine, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Humans, Vaccines, Combined, 030212 general & internal medicine, Diphtheria-Tetanus-Pertussis Vaccine, Haemophilus Vaccines, Retrospective Studies, Vaccines, Conjugate, General Veterinary, General Immunology and Microbiology, biology, Tetanus, business.industry, Diphtheria, Vaccination, Hematopoietic Stem Cell Transplantation, Public Health, Environmental and Occupational Health, Antibody titer, Infant, medicine.disease, biology.organism_classification, Antibodies, Bacterial, Poliovirus Vaccine, Inactivated, Infectious Diseases, Immunology, Molecular Medicine, business, medicine.drug
Abstract: Allogeneic hematopoietic stem cell transplantation (alloHSCT) results in a loss of humoral immunity and subsequent risk for severe infections. Thus, re-vaccination is required but may fail due to incomplete immune reconstitution. We retrospectively analyzed predictors of immune response to primary vaccination applied according to the EBMT (European Blood and Marrow Transplantation Group) recommendations. Serologic response to vaccination against diphtheria (D), tetanus (T), Bordetella pertussis (aP) and Haemophilus influenzae (Hib) (administrated as combined DTaP-Hib-IPV vaccination) was studied in 84 alloHSCT patients transplanted between 2008 and 2015 (age at alloHSCT: 18.6-70.6 years). All patients with a relapse-free survival of ≥9 months, at least 3 consecutive vaccinations and absence of intravenous immunoglobulin administration within 3 months before and after vaccination met the primary inclusion criteria. Additionally, immunological response to a pneumococcal conjugate vaccine was analyzed in a subgroup of 67 patients. Patients' characteristics at the time of first vaccination were recorded. Responses were measured as vaccine-specific antibody titers. Regarding DTaP-Hib-IPV vaccination, 89.3% (n = 75) of all patients achieved protective titers to at least 3 of the 4 vaccine components and were thus considered responders. 10.7% (n = 9) of the patients were classified as non-responders with positive immune response to less than 3 components. Highest response was observed for Hib (97.4%), tetanus (95.2%) and pneumococcal vaccination (83.6%) while only 68.3% responded to vaccination against Bordetella pertussis. Significant risk factors for failure of vaccination response included low B cell counts (p 0.001; cut-off: 0.05 B cells/nl) and low IgG levels (p = 0.026; mean IgG of responders 816 mg/dl vs. 475 mg/dl of non-responders). Further, a trend was observed that prior cGvHD impairs vaccination response as 88.9% of the non-responders but only 54.7% of the responders had prior cGvHD (p = 0.073). The results demonstrate, that the currently proposed vaccination strategy leads to seroprotection in the majority of alloHSCT patients.
Published: 2021

36. Second allogeneic haematopoietic cell transplantation using HLA‐matched unrelated versus T‐cell replete haploidentical donor and survival in relapsed acute myeloid leukaemia

Author: Matthias Edinger, Arnold Ganser, Annalisa Ruggeri, Martin Gramatzki, Arnon Nagler, Myriam Labopin, Patrice Chevallier, Nicolaus Kröger, Eolia Brissot, Didier Blaise, Bipin N. Savani, Fabio Ciceri, Jürgen Finke, Mohamed A. Kharfan-Dabaja, Jaime Sanz, Matthias Stelljes, Eric Deconinck, Mohamad Mohty, Kharfan-Dabaja, M. A., Labopin, M., Brissot, E., Kroger, N., Finke, J., Ciceri, F., Deconinck, E., Blaise, D., Chevallier, P., Gramatzki, M., Ganser, A., Stelljes, M., Edinger, M., Savani, B., Ruggeri, A., Sanz, J., Nagler, A., Mohty, M., Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, Oncology, medicine.medical_specialty, T-Lymphocytes, [SDV.CAN]Life Sciences [q-bio]/Cancer, Human leukocyte antigen, second allogeneic haematopoietic cell transplant, Disease-Free Survival, Lymphocyte Depletion, 03 medical and health sciences, 0302 clinical medicine, HLA Antigens, Interquartile range, hemic and lymphatic diseases, Internal medicine, medicine, Humans, acute myeloid leukaemia, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, relapse, Acute leukemia, business.industry, Histocompatibility Testing, Hazard ratio, Hematopoietic Stem Cell Transplantation, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Hematology, Middle Aged, Allografts, Haploidentical Donor, Confidence interval, Survival Rate, Leukemia, Myeloid, Acute, Haematopoiesis, 030220 oncology & carcinogenesis, Female, Myeloid leukaemia, Unrelated Donors, business, 030215 immunology
Abstract: Optimal donor choice for a second allogeneic haematopoietic cell transplant (allo-HCT) in relapsed acute myeloid leukaemia (AML) remains unknown. We compared overall survival (OS) using registry data from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) involving 455 adults who received a second allo-HCT from a human leucocyte antigen (HLA)-matched unrelated (MUD) (n = 320) or a haploidentical (n = 135) donor. Eligibility criteria required adults aged >= 18 years who received a second allo-HCT for treating AML relapse between 2005 and 2019. The primary end-point was OS. There was no statistically significant difference in the median (interquartile range) age between the groups, MUD 46 (35-58) versus haploidentical 44 (33-53) years (P = 0 center dot 07). The median OS was not different between the MUD and the haploidentical groups (10 vs. 11 months, P = 0 center dot 57). Similarly, the 2-year OS was 31% for the MUD and 29% for the haploidentical donor groups. The OS was worse if the procedure was performed with active AML [hazard ratio (HR) 1 center dot 42, 95% confidence interval (CI) 1 center dot 07-1 center dot 89; P = 0 center dot 02]. Conversely, a longer time from first allo-HCT to relapse (>13 center dot 2 months) was associated with better OS (HR 0 center dot 50, 95% CI 0 center dot 37-0 center dot 69; P < 0 center dot 0001). The results of the present analysis limit the ability to recommend one donor type over another when considering a second allo-HCT for relapsed AML. Our findings highlight that best OS is achieved when receiving the second allo-HCT in complete remission.
Published: 2021

37. Abatacept as salvage therapy in chronic graft-versus-host disease—a retrospective analysis

Author: Daniel Wolff, Wolfgang Herr, Martin Heidenreich, Daniela Weber, Matthias Edinger, Andreas Neubauer, Gabriel Afram, Matthias Fante, Stephan Mielke, Marius Dohse, Per Ljungman, Anna-Sophia Kattner, Tobias Wertheimer, Antonio Pérez Martínez, Barbara Holler, Ernst Holler, and UAM. Departamento de Pediatría
Subjects: musculoskeletal diseases, Adult, Male, medicine.medical_specialty, Adolescent, Drug-Related Side Effects and Adverse Reactions, Medicina, medicine.medical_treatment, 610 Medizin, Salvage therapy, Phases of clinical research, Bronchiolitis obliterans, Graft vs Host Disease, Hematopoietic stem cell transplantation, Malignancy, Abatacept, Young Adult, Internal medicine, Germany, medicine, Humans, Transplantation, Homologous, Child, Bronchiolitis Obliterans, Aged, Retrospective Studies, Sweden, ddc:610, business.industry, Chronic graft-versus-host disease . Abatacept . Salvage therapy . Bronchiolitis obliterans syndrome, Bronchiolitis obliterans syndrome, Hematopoietic Stem Cell Transplantation, Retrospective cohort study, Hematology, General Medicine, Chronic graft-versus-host disease, Middle Aged, medicine.disease, Graft-versus-host disease, Spain, Child, Preschool, Hematologic Neoplasms, Original Article, Female, business, medicine.drug, Follow-Up Studies
Abstract: The immunomodulatory fusion protein abatacept has recently been investigated for the treatment of steroid-refractory chronic graft-versus-host disease (cGvHD) in a phase 1 clinical trial. We analyzed the safety and efficacy of abatacept for cGvHD therapy in a retrospective study with 15 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) and received abatacept for cGvHD with a median age of 49 years. Grading was performed as part of the clinical routine according to the National Institute of Health’s (NIH) consensus criteria at initiation of abatacept and 1, 3, 6, 9 and 12 months thereafter. The median time of follow-up was 191 days (range 55–393 days). Best overall response rate (ORR) was 40%. In particular, patients with bronchiolitis obliterans syndrome showed significant clinical improvement and durable responses following abatacept treatment with a response rate of 89% based on improvement in lung severity score (n = 6) or stabilized lung function (n = 4) or both (n = 3). Infectious complications CTCAE °III or higher were observed in 3/15 patients. None of the patients relapsed from the underlying malignancy. Thus, abatacept appears to be a promising treatment option for cGvHD, in particular for patients with lung involvement. However, further evaluation within a phase 2 clinical trial is required., Open Access funding enabled and organized by Projekt DEAL. This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Projekt-ID 324392634 -TRR221, subproject B10 (D.W.), and by the ReForM program of the University of Regensburg (T.W.).
Published: 2021

38. Expansion of Plasmablasts at Day 90 after Allogeneic Stem Cell Transplantation Predict Chronic Gvhd

Author: Katharina M. Habenicht, Anna Bootz, Simon Schäfer, Ingrid Vasova, Matthias Fante, Andrea Schneider, Michael Rehli, Petra Hoffmann, Wolf Roesler, Matthias Edinger, Wolfgang Herr, Andreas Mackensen, Daniel Wolff, Julia Winkler, and Thomas H. Winkler
Subjects: Immunology, Cell Biology, Hematology, Biochemistry
Published: 2022

39. Identification of Protective, Metabolite-producing Bacterial and Viral Consortia in Allogeneic Stem Cell Transplantation Patients

Author: Erik Thiele Orberg, Elisabeth Meedt, Andreas Hiergeist, Jinling Xue, Sakhila Ghimire, Melanie Tiefgraber, Sophia Göldel, Tina Eismann, Alix Schwarz, Sebastian Jarosch, Katja Steiger, Michael Gigl, Karin Kleigrewe, Julius Fischer, Klaus-Peter Janssen, Michael Quante, Simon Heidegger, Peter Herhaus, Mareike Verbeek, Jürgen Ruland, Daniela Weber, Daniel Wolff, Matthias Edinger, Dirk Busch, Wolfgang Herr, Florian Bassermann, André Gessner, Li Deng, Ernst Holler, and Hendrik Poeck
Abstract: The intestinal bacteriome directly affects outcome in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT). Besides bacteria, fungal and viral communities as well as microbiota-derived metabolites play a role. Yet, it is still unclear how dynamic shifts in these three communities contribute to (1) clinical outcome of allo-SCT patients, (2) production of metabolites and (3) how they are affected by microbiome modulation via antibiotics or fecal microbiota transplantation (FMT). Here, we performed a prospective, longitudinal study that combined transkingdom (bacteria, fungi, viruses) analysis of intestinal microbial communities with targeted metabolomics in allo-SCT patients (n=78) at two different transplantation centers. We uncovered a microbiome signature of metabolite-producing bacteria from the Lachnospiraceae and Oscillospiraceae families and their corresponding bacteriophages, which correlated with the production of immunomodulatory metabolites including short-chain fatty acids (SCFAs), metabolites associated with induction of type-I IFN signaling (IIMs) and bile acids. Sustained production of these “protective” metabolites after allo-SCT was associated with improved survival and reduced transplantation-related mortality, whereas antibiotic exposure significantly impaired metabolite expression. We demonstrate that single taxa domination and metabolite depletion in a patient suffering from graft versus host disease (GvHD) could be rescued by transfer of metabolite-producing bacterial consortia via fecal microbiota transplantation (FMT). FMT led to resolution of steroid refractory GvHD and was accompanied by an increase of bacterial and viral alpha diversity, restoration of SCFAs and IIMs and accumulation of regulatory T cells to the intestine. Our study demonstrates that microbiome modulation (via antibiotics or FMT) can affect the identified bacterial/bacteriophage network and their associated protective metabolites thereby determining clinical outcomes and provides a rationale for the development of engineered metabolite-producing consortia and defined metabolite combination drugs as novel microbiome-based therapies.
Published: 2022

40. Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

Author: Lara Gibellini, Sussan Nourshargh, Susanna Cardell, Wlodzimierz Maslinski, Mar Felipo-Benavent, Florian Mair, Hans-Martin Jäck, Lilly Lopez, Klaus Warnatz, John Trowsdale, Diana Ordonez, Marcus Eich, William Hwang, Anne Cooke, Dirk Mielenz, Alberto Orfao, Winfried F. Pickl, Vladimir Benes, Alice Yue, T. Vincent Shankey, Maria Tsoumakidou, Virginia Litwin, Gelo Victoriano Dela Cruz, Andrea Cavani, Sara De Biasi, Larissa Nogueira Almeida, Jonathan J M Landry, Claudia Haftmann, Charlotte Esser, Ana Cumano, Anneke Wilharm, Francesco Dieli, Rudi Beyaert, Alessio Mazzoni, Burkhard Ludewig, Carlo Pucillo, Dirk H. Busch, Joe Trotter, Stipan Jonjić, Marc Veldhoen, Josef Spidlen, Aja M. Rieger, Dieter Adam, Srijit Khan, Todd A. Fehniger, Giuseppe Matarese, Maximilien Evrard, Christian Maueröder, Steffen Schmitt, Kristin A. Hogquist, Barry Moran, Raghavendra Palankar, Markus Feuerer, S Schmid, Susann Rahmig, Amy E. Lovett-Racke, James V. Watson, Megan K. Levings, Susanne Melzer, Dinko Pavlinic, Christopher M. Harpur, Christina Stehle, A. Graham Pockley, Toshinori Nakayama, Attila Tárnok, Juhao Yang, Michael Lohoff, Paulo Vieira, Francisco Sala-de-Oyanguren, Christian Kurts, Anastasia Gangaev, Alfonso Blanco, Hans Scherer, Regine J. Dress, Bruno Silva-Santos, Kiyoshi Takeda, Bimba F. Hoyer, Ilenia Cammarata, Daryl Grummitt, Isabel Panse, Günnur Deniz, Bianka Baying, Friederike Ebner, Esther Schimisky, Leo Hansmann, Thomas Kamradt, Edwin van der Pol, Daniel Scott-Algara, Anna Iannone, Giorgia Alvisi, Sebastian R. Schulz, Francesco Liotta, Irmgard Förster, Beatriz Jávega, Hans-Peter Rahn, Caetano Reis e Sousa, Livius Penter, Xuetao Cao, David P. Sester, Keisuke Goda, Peter Wurst, Iain B. McInnes, Ricardo T. Gazzinelli, Federica Piancone, Gerald Willimsky, Yotam Raz, Pärt Peterson, Wolfgang Fritzsche, Yvonne Samstag, Martin Büscher, Thomas Schüler, Susanne Hartmann, Robert J. Wilkinson, Anna E. S. Brooks, Steven L. C. Ketelaars, Catherine Sautès-Fridman, Anna Rubartelli, Petra Bacher, Katja Kobow, Marco A. Cassatella, Andrea Hauser, Henrik E. Mei, Kilian Schober, Silvia Della Bella, Graham Anderson, Michael D. Ward, Garth Cameron, Sebastian Lunemann, Katharina Kriegsmann, Katarzyna M. Sitnik, Brice Gaudilliere, Chantip Dang-Heine, Marcello Pinti, Paul Klenerman, Frank A. Schildberg, Joana Barros-Martins, Laura G. Rico, Hanlin Zhang, Christian Münz, Thomas Dörner, Jakob Zimmermann, Andrea M. Cooper, Jonni S. Moore, Andreas Diefenbach, Yanling Liu, Wolfgang Bauer, Tobit Steinmetz, Katharina Pracht, Leonard Tan, Peter K. Jani, Alan M. Stall, Petra Hoffmann, Christine S. Falk, Jasmin Knopf, Simon Fillatreau, Hans-Dieter Volk, Luis E. Muñoz, David L. Haviland, William W. Agace, Jonathan Rebhahn, Ljiljana Cvetkovic, Mohamed Trebak, Jordi Petriz, Mario Clerici, Diether J. Recktenwald, Anders Ståhlberg, Tristan Holland, Helen M. McGuire, Sa A. Wang, Christian Kukat, Thomas Kroneis, Laura Cook, Wan Ting Kong, Xin M. Wang, Britta Engelhardt, Pierre Coulie, Genny Del Zotto, Sally A. Quataert, Kata Filkor, Gabriele Multhoff, Bartek Rajwa, Federica Calzetti, Hans Minderman, Cosima T. Baldari, Jens Geginat, Hervé Luche, Gert Van Isterdael, Linda Schadt, Sophia Urbanczyk, Giovanna Borsellino, Liping Yu, Dale I. Godfrey, Achille Anselmo, Rachael C. Walker, Andreas Grützkau, David W. Hedley, Birgit Sawitzki, Silvia Piconese, Maria Yazdanbakhsh, Burkhard Becher, Ramon Bellmas Sanz, Michael Delacher, Hyun-Dong Chang, Immanuel Andrä, Hans-Gustaf Ljunggren, José-Enrique O'Connor, Ahad Khalilnezhad, Sharon Sanderson, Federico Colombo, Götz R. A. Ehrhardt, Inga Sandrock, Enrico Lugli, Christian Bogdan, James B. Wing, Susann Müller, Tomohiro Kurosaki, Derek Davies, Ester B. M. Remmerswaal, Kylie M. Quinn, Christopher A. Hunter, Andreas Radbruch, Timothy P. Bushnell, Anna Erdei, Sabine Adam-Klages, Pascale Eede, Van Duc Dang, Rieke Winkelmann, Thomas Korn, Gemma A. Foulds, Dirk Baumjohann, Matthias Schiemann, Manfred Kopf, Jan Kisielow, Lisa Richter, Jochen Huehn, Gloria Martrus, Alexander Scheffold, Jessica G. Borger, Sidonia B G Eckle, John Bellamy Foster, Anna Katharina Simon, Alicia Wong, Mübeccel Akdis, Gisa Tiegs, Toralf Kaiser, James McCluskey, Anna Vittoria Mattioli, Aaron J. Marshall, Hui-Fern Koay, Eva Orlowski-Oliver, Anja E. Hauser, J. Paul Robinson, Jay K. Kolls, Luca Battistini, Mairi McGrath, Jane L. Grogan, Natalio Garbi, Timothy Tree, Kingston H. G. Mills, Stefan H. E. Kaufmann, Wolfgang Schuh, Ryan R. Brinkman, Tim R. Mosmann, Vincenzo Barnaba, Andreas Dolf, Lorenzo Cosmi, Bo Huang, Andreia C. Lino, Baerbel Keller, René A. W. van Lier, Alexandra J. Corbett, Paul S. Frenette, Pleun Hombrink, Helena Radbruch, Sofie Van Gassen, Olivier Lantz, Lorenzo Moretta, Désirée Kunkel, Kirsten A. Ward-Hartstonge, Armin Saalmüller, Leslie Y. T. Leung, Salvador Vento-Asturias, Paola Lanuti, Alicia Martínez-Romero, Sarah Warth, Zhiyong Poon, Diana Dudziak, Andrea Cossarizza, Kovit Pattanapanyasat, Konrad von Volkmann, Jessica P. Houston, Agnès Lehuen, Andrew Filby, Pratip K. Chattopadhyay, Stefano Casola, Annika Wiedemann, Hannes Stockinger, Jürgen Ruland, Arturo Zychlinsky, Claudia Waskow, Katrin Neumann, Ari Waisman, Lucienne Chatenoud, Sudipto Bari, Kamran Ghoreschi, David W. Galbraith, Yvan Saeys, Hamida Hammad, Andrea Gori, Miguel López-Botet, Gabriel Núñez, Sabine Ivison, Michael Hundemer, Dorothea Reimer, Mark C. Dessing, Günter J. Hämmerling, Rudolf A. Manz, Tomas Kalina, Jonas Hahn, Holden T. Maecker, Hendy Kristyanto, Martin S. Davey, Henning Ulrich, Michael L. Dustin, Takashi Saito, Yousuke Takahama, Milena Nasi, Johanna Huber, Jürgen Wienands, Paolo Dellabona, Andreas Schlitzer, Michael D. Leipold, Kerstin H. Mair, Christian Peth, Immo Prinz, Chiara Romagnani, José M. González-Navajas, Josephine Schlosser, Marina Saresella, Matthias Edinger, Dirk Brenner, Nicole Baumgarth, Rikard Holmdahl, Fang-Ping Huang, Guadalupe Herrera, Malte Paulsen, Gergely Toldi, Luka Cicin-Sain, Reiner Schulte, Christina E. Zielinski, Thomas Winkler, Christoph Goettlinger, Philip E. Boulais, Jennie H M Yang, Antonio Celada, Heike Kunze-Schumacher, Julia Tornack, Florian Ingelfinger, Jenny Mjösberg, Andy Riddell, Leonie Wegener, Thomas Höfer, Christoph Hess, James P. Di Santo, Anna E. Oja, J. Kühne, Willem van de Veen, Mary Bebawy, Alberto Mantovani, Bart Everts, Giovanna Lombardi, Laura Maggi, Anouk von Borstel, Pia Kvistborg, Elisabetta Traggiai, A Ochel, Nima Aghaeepour, Charles-Antoine Dutertre, Matthieu Allez, Thomas Höllt, Wenjun Ouyang, Regina Stark, Maries van den Broek, Shimon Sakaguchi, Paul K. Wallace, Silvano Sozzani, Francesca LaRosa, Annette Oxenius, Malgorzata J. Podolska, Ivana Marventano, Wilhelm Gerner, Oliver F. Wirz, Britta Frehse, Gevitha Ravichandran, Martin Herrmann, Carl S. Goodyear, Gary Warnes, Helen Ferry, Stefan Frischbutter, Tim R. Radstake, Salomé LeibundGut-Landmann, Yi Zhao, Axel Schulz, Angela Santoni, Pablo Engel, Daniela C. Hernández, Andreas Acs, Cristiano Scottà, Francesco Annunziato, Thomas Weisenburger, Wolfgang Beisker, Sue Chow, Fritz Melchers, Daniel E. Speiser, Immanuel Kwok, Florent Ginhoux, Dominic A. Boardman, Natalie Stanley, Carsten Watzl, Marie Follo, Erik Lubberts, Andreas Krueger, Susanne Ziegler, Göran K. Hansson, David Voehringer, Antonia Niedobitek, Eleni Christakou, Lai Guan Ng, Sabine Baumgart, Nicholas A Gherardin, Antonio Cosma, Orla Maguire, Jolene Bradford, Daniel Schraivogel, Linda Quatrini, Stephen D. Miller, Rheumatology, Università degli Studi di Modena e Reggio Emilia (UNIMORE), Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, Swiss Institute of Allergy and Asthma Research (SIAF), Universität Zürich [Zürich] = University of Zurich (UZH), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Department of Internal Medicine, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)-DENOTHE Center, Institute of Clinical Molecular Biology, Kiel University, Department of Life Sciences [Siena, Italy], Università degli Studi di Siena = University of Siena (UNISI), Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP), Dulbecco Telethon Institute/Department of Biology, Caprotec Bioanalytics GmbH, International Occultation Timing Association European Section (IOTA ES), International Occultation Timing Association European Section, European Molecular Biology Laboratory [Heidelberg] (EMBL), VIB-UGent Center for Inflammation Research [Gand, Belgique] (IRC), VIB [Belgium], Fondazione Santa Lucia (IRCCS), Department of Immunology, Chinese Academy of Medical Sciences, FIRC Institute of Molecular Oncology Foundation, IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Physiopatology and Transplantation, University of Milan (DEPT), University of Milan, Monash University [Clayton], Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institute of Cellular Pathology, Université Catholique de Louvain = Catholic University of Louvain (UCL), Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Experimental Immunology Unit, Dept. of Oncology, DIBIT San Raffaele Scientific Institute, Immunité Innée - Innate Immunity, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Biopharmacy [Bruxelles, Belgium] (Institute for Medical Immunology IMI), Université libre de Bruxelles (ULB), Charité Hospital, Humboldt-Universität zu Berlin, Agency for science, technology and research [Singapore] (A*STAR), Laboratory of Molecular Immunology and the Howard Hughes Institute, Rockefeller University [New York], Kennedy Institute of Rheumatology [Oxford, UK], Imperial College London, Theodor Kocher Institute, University of Bern, Leibniz Research Institute for Environmental Medicine [Düsseldorf, Germany] ( IUF), Université Lumière - Lyon 2 (UL2), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), University of Edinburgh, Integrative Biology Program [Milano], Istituto Nazionale Genetica Molecolare [Milano] (INGM), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Universitat de Barcelona (UB), Rheumatologie, Cell Biology, Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Department for Internal Medicine 3, Institute for Clinical Immunology, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Delft University of Technology (TU Delft), Medical Inflammation Research, Karolinska Institutet [Stockholm], Department of Photonics Engineering [Lyngby], Technical University of Denmark [Lyngby] (DTU), Dpt of Experimental Immunology [Braunschweig], Helmholtz Centre for Infection Research (HZI), Department of Internal Medicine V, Universität Heidelberg [Heidelberg], Department of Histology and Embryology, University of Rijeka, Freiburg University Medical Center, Nuffield Dept of Clinical Medicine, University of Oxford [Oxford]-NIHR Biomedical Research Centre, Institute of Integrative Biology, Molecular Biomedicine, Berlin Institute of Health (BIH), Laboratory for Lymphocyte Differentiation, RIKEN Research Center, Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Department of Surgery [Vancouver, BC, Canada] (Child and Family Research Institute), University of British Columbia (UBC)-Child and Family Research Institute [Vancouver, BC, Canada], College of Food Science and Technology [Shangai], Shanghai Ocean University, Institute for Medical Microbiology and Hygiene, University of Marburg, King‘s College London, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre d'Immunophénomique (CIPHE), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Brustzentrum Kantonsspital St. Gallen, Immunotechnology Section, Vaccine Research Center, National Institutes of Health [Bethesda] (NIH)-National Institute of Allergy and Infectious Diseases, Heinrich Pette Institute [Hamburg], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Department of Immunology and Cell Biology, Mario Negri Institute, Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi ONLUS Foundation, Institute of Translational Medicine, Klinik für Dermatologie, Venerologie und Allergologie, School of Biochemistry and Immunology, Department of Medicine Huddinge, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm]-Lipid Laboratory, Università di Genova, Dipartimento di Medicina Sperimentale, Department of Environmental Microbiology, Helmholtz Zentrum für Umweltforschung = Helmholtz Centre for Environmental Research (UFZ), Department of Radiation Oncology [Munich], Ludwig-Maximilians-Universität München (LMU), Centre de Recherche Publique- Santé, Université du Luxembourg (Uni.lu), William Harvey Research Institute, Barts and the London Medical School, University of Michigan [Ann Arbor], University of Michigan System, Centro de Investigacion del Cancer (CSIC), Universitario de Salamanca, Molecular Pathology [Tartu, Estonia], University of Tartu, Hannover Medical School [Hannover] (MHH), Centre d'Immunologie de Marseille - Luminy (CIML), Monash Biomedicine Discovery Institute, Cytometry Laboratories and School of Veterinary Medicine, Purdue University [West Lafayette], Data Mining and Modelling for Biomedicine [Ghent, Belgium], VIB Center for Inflammation Research [Ghent, Belgium], Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, RIKEN Research Center for Allergy and Immunology, Osaka University [Osaka], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institute of Medical Immunology [Berlin, Germany], FACS and Array Core Facility, Johannes Gutenberg - Universität Mainz (JGU), Otto-von-Guericke University [Magdeburg] (OVGU), SUPA School of Physics and Astronomy [University of St Andrews], University of St Andrews [Scotland]-Scottish Universities Physics Alliance (SUPA), Biologie Cellulaire des Lymphocytes - Lymphocyte Cell Biology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), General Pathology and Immunology (GPI), University of Brescia, Université de Lausanne (UNIL), Terry Fox Laboratory, BC Cancer Agency (BCCRC)-British Columbia Cancer Agency Research Centre, Department of Molecular Immunology, Medizinische Universität Wien = Medical University of Vienna, Dept. Pediatric Cardiology, Universität Leipzig [Leipzig], Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Center for Cardiovascular Sciences, Albany Medical College, Dept Pathol, Div Immunol, University of Cambridge [UK] (CAM), Department of Information Technology [Gent], Universiteit Gent, Department of Plant Systems Biology, Department of Plant Biotechnology and Genetics, Universiteit Gent = Ghent University [Belgium] (UGENT), Division of Molecular Immunology, Institute for Immunology, Department of Geological Sciences, University of Oregon [Eugene], Centers for Disease Control and Prevention [Atlanta] (CDC), Centers for Disease Control and Prevention, University of Colorado [Colorado Springs] (UCCS), FACS laboratory, Cancer Research, London, Cancer Research UK, Regeneration in Hematopoiesis and Animal Models of Hematopoiesis, Faculty of Medicine, Dresden University of Technology, Barbara Davis Center for Childhood Diabetes (BDC), University of Colorado Anschutz [Aurora], School of Computer and Electronic Information [Guangxi University], Guangxi University [Nanning], School of Materials Science and Engineering, Nanyang Technological University [Singapour], Max Planck Institute for Infection Biology (MPIIB), Max-Planck-Gesellschaft, Work in the laboratory of Dieter Adam is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Projektnummer 125440785 – SFB 877, Project B2.Petra Hoffmann, Andrea Hauser, and Matthias Edinger thank BD Biosciences®, San José, CA, USA, and SKAN AG, Bale, Switzerland for fruitful cooperation during the development, construction, and installation of the GMP‐compliant cell sorting equipment and the Bavarian Immune Therapy Network (BayImmuNet) for financial support.Edwin van der Pol and Paola Lanuti acknowledge Aleksandra Gąsecka M.D. for excellent experimental support and Dr. Rienk Nieuwland for textual suggestions. This work was supported by the Netherlands Organisation for Scientific Research – Domain Applied and Engineering Sciences (NWO‐TTW), research program VENI 15924.Jessica G Borger, Kylie M Quinn, Mairi McGrath, and Regina Stark thank Francesco Siracusa and Patrick Maschmeyer for providing data.Larissa Nogueira Almeida was supported by DFG research grant MA 2273/14‐1. Rudolf A. Manz was supported by the Excellence Cluster 'Inflammation at Interfaces' (EXC 306/2).Susanne Hartmann and Friederike Ebner were supported by the German Research Foundation (GRK 2046).Hans Minderman was supported by NIH R50CA211108.This work was funded by the Deutsche Forschungsgemeinschaft through the grant TRR130 (project P11 and C03) to Thomas H. Winkler.Ramon Bellmàs Sanz, Jenny Kühne, and Christine S. Falk thank Jana Keil and Kerstin Daemen for excellent technical support. The work was funded by the Germany Research Foundation CRC738/B3 (CSF).The work by the Mei laboratory was supported by German Research Foundation Grant ME 3644/5‐1 and TRR130 TP24, the German Rheumatism Research Centre Berlin, European Union Innovative Medicines Initiative ‐ Joint Undertaking ‐ RTCure Grant Agreement 777357, the Else Kröner‐Fresenius‐Foundation, German Federal Ministry of Education and Research e:Med sysINFLAME Program Grant 01ZX1306B and KMU‐innovativ 'InnoCyt', and the Leibniz Science Campus for Chronic Inflammation (http://www.chronische-entzuendung.org).Axel Ronald Schulz, Antonio Cosma, Sabine Baumgart, Brice Gaudilliere, Helen M. McGuire, and Henrik E. Mei thank Michael D. Leipold for critically reading the manuscript.Christian Kukat acknowledges support from the ISAC SRL Emerging Leaders program.John Trowsdale received funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (Grant Agreement 695551)., European Project: 7728036(1978), Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Università degli Studi di Firenze = University of Florence (UniFI)-DENOTHE Center, Università degli Studi di Milano = University of Milan (UNIMI), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humboldt University Of Berlin, Leibniz Research Institute for Environmental Medicine [Düsseldorf, Germany] (IUF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Universität Heidelberg [Heidelberg] = Heidelberg University, Universitäts Klinikum Freiburg = University Medical Center Freiburg (Uniklinik), University of Oxford-NIHR Biomedical Research Centre, Universität Bonn = University of Bonn, Università degli Studi di Firenze = University of Florence (UniFI), Università degli studi di Genova = University of Genoa (UniGe), Universidad de Salamanca, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Otto-von-Guericke-Universität Magdeburg = Otto-von-Guericke University [Magdeburg] (OVGU), Université de Lausanne = University of Lausanne (UNIL), Universität Leipzig, Universiteit Gent = Ghent University (UGENT), HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany., Cossarizza, A., Chang, H. -D., Radbruch, A., Acs, A., Adam, D., Adam-Klages, S., Agace, W. W., Aghaeepour, N., Akdis, M., Allez, M., Almeida, L. N., Alvisi, G., Anderson, G., Andra, I., Annunziato, F., Anselmo, A., Bacher, P., Baldari, C. T., Bari, S., Barnaba, V., Barros-Martins, J., Battistini, L., Bauer, W., Baumgart, S., Baumgarth, N., Baumjohann, D., Baying, B., Bebawy, M., Becher, B., Beisker, W., Benes, V., Beyaert, R., Blanco, A., Boardman, D. A., Bogdan, C., Borger, J. G., Borsellino, G., Boulais, P. E., Bradford, J. A., Brenner, D., Brinkman, R. R., Brooks, A. E. S., Busch, D. H., Buscher, M., Bushnell, T. P., Calzetti, F., Cameron, G., Cammarata, I., Cao, X., Cardell, S. L., Casola, S., Cassatella, M. A., Cavani, A., Celada, A., Chatenoud, L., Chattopadhyay, P. K., Chow, S., Christakou, E., Cicin-Sain, L., Clerici, M., Colombo, F. S., Cook, L., Cooke, A., Cooper, A. M., Corbett, A. J., Cosma, A., Cosmi, L., Coulie, P. G., Cumano, A., Cvetkovic, L., Dang, V. D., Dang-Heine, C., Davey, M. S., Davies, D., De Biasi, S., Del Zotto, G., Dela Cruz, G. V., Delacher, M., Della Bella, S., Dellabona, P., Deniz, G., Dessing, M., Di Santo, J. P., Diefenbach, A., Dieli, F., Dolf, A., Dorner, T., Dress, R. J., Dudziak, D., Dustin, M., Dutertre, C. -A., Ebner, F., Eckle, S. B. G., Edinger, M., Eede, P., Ehrhardt, G. R. A., Eich, M., Engel, P., Engelhardt, B., Erdei, A., Esser, C., Everts, B., Evrard, M., Falk, C. S., Fehniger, T. A., Felipo-Benavent, M., Ferry, H., Feuerer, M., Filby, A., Filkor, K., Fillatreau, S., Follo, M., Forster, I., Foster, J., Foulds, G. A., Frehse, B., Frenette, P. S., Frischbutter, S., Fritzsche, W., Galbraith, D. W., Gangaev, A., Garbi, N., Gaudilliere, B., Gazzinelli, R. T., Geginat, J., Gerner, W., Gherardin, N. A., Ghoreschi, K., Gibellini, L., Ginhoux, F., Goda, K., Godfrey, D. I., Goettlinger, C., Gonzalez-Navajas, J. M., Goodyear, C. S., Gori, A., Grogan, J. L., Grummitt, D., Grutzkau, A., Haftmann, C., Hahn, J., Hammad, H., Hammerling, G., Hansmann, L., Hansson, G., Harpur, C. M., Hartmann, S., Hauser, A., Hauser, A. E., Haviland, D. L., Hedley, D., Hernandez, D. C., Herrera, G., Herrmann, M., Hess, C., Hofer, T., Hoffmann, P., Hogquist, K., Holland, T., Hollt, T., Holmdahl, R., Hombrink, P., Houston, J. P., Hoyer, B. F., Huang, B., Huang, F. -P., Huber, J. E., Huehn, J., Hundemer, M., Hunter, C. A., Hwang, W. Y. K., Iannone, A., Ingelfinger, F., Ivison, S. M., Jack, H. -M., Jani, P. K., Javega, B., Jonjic, S., Kaiser, T., Kalina, T., Kamradt, T., Kaufmann, S. H. E., Keller, B., Ketelaars, S. L. C., Khalilnezhad, A., Khan, S., Kisielow, J., Klenerman, P., Knopf, J., Koay, H. -F., Kobow, K., Kolls, J. K., Kong, W. T., Kopf, M., Korn, T., Kriegsmann, K., Kristyanto, H., Kroneis, T., Krueger, A., Kuhne, J., Kukat, C., Kunkel, D., Kunze-Schumacher, H., Kurosaki, T., Kurts, C., Kvistborg, P., Kwok, I., Landry, J., Lantz, O., Lanuti, P., Larosa, F., Lehuen, A., LeibundGut-Landmann, S., Leipold, M. D., Leung, L. Y. T., Levings, M. K., Lino, A. C., Liotta, F., Litwin, V., Liu, Y., Ljunggren, H. -G., Lohoff, M., Lombardi, G., Lopez, L., Lopez-Botet, M., Lovett-Racke, A. E., Lubberts, E., Luche, H., Ludewig, B., Lugli, E., Lunemann, S., Maecker, H. T., Maggi, L., Maguire, O., Mair, F., Mair, K. H., Mantovani, A., Manz, R. A., Marshall, A. J., Martinez-Romero, A., Martrus, G., Marventano, I., Maslinski, W., Matarese, G., Mattioli, A. V., Maueroder, C., Mazzoni, A., Mccluskey, J., Mcgrath, M., Mcguire, H. M., Mcinnes, I. B., Mei, H. E., Melchers, F., Melzer, S., Mielenz, D., Miller, S. D., Mills, K. H. G., Minderman, H., Mjosberg, J., Moore, J., Moran, B., Moretta, L., Mosmann, T. R., Muller, S., Multhoff, G., Munoz, L. E., Munz, C., Nakayama, T., Nasi, M., Neumann, K., Ng, L. G., Niedobitek, A., Nourshargh, S., Nunez, G., O'Connor, J. -E., Ochel, A., Oja, A., Ordonez, D., Orfao, A., Orlowski-Oliver, E., Ouyang, W., Oxenius, A., Palankar, R., Panse, I., Pattanapanyasat, K., Paulsen, M., Pavlinic, D., Penter, L., Peterson, P., Peth, C., Petriz, J., Piancone, F., Pickl, W. F., Piconese, S., Pinti, M., Pockley, A. G., Podolska, M. J., Poon, Z., Pracht, K., Prinz, I., Pucillo, C. E. M., Quataert, S. A., Quatrini, L., Quinn, K. M., Radbruch, H., Radstake, T. R. D. J., Rahmig, S., Rahn, H. -P., Rajwa, B., Ravichandran, G., Raz, Y., Rebhahn, J. A., Recktenwald, D., Reimer, D., Reis e Sousa, C., Remmerswaal, E. B. M., Richter, L., Rico, L. G., Riddell, A., Rieger, A. M., Robinson, J. P., Romagnani, C., Rubartelli, A., Ruland, J., Saalmuller, A., Saeys, Y., Saito, T., Sakaguchi, S., Sala-de-Oyanguren, F., Samstag, Y., Sanderson, S., Sandrock, I., Santoni, A., Sanz, R. B., Saresella, M., Sautes-Fridman, C., Sawitzki, B., Schadt, L., Scheffold, A., Scherer, H. U., Schiemann, M., Schildberg, F. A., Schimisky, E., Schlitzer, A., Schlosser, J., Schmid, S., Schmitt, S., Schober, K., Schraivogel, D., Schuh, W., Schuler, T., Schulte, R., Schulz, A. R., Schulz, S. R., Scotta, C., Scott-Algara, D., Sester, D. P., Shankey, T. V., Silva-Santos, B., Simon, A. K., Sitnik, K. M., Sozzani, S., Speiser, D. E., Spidlen, J., Stahlberg, A., Stall, A. M., Stanley, N., Stark, R., Stehle, C., Steinmetz, T., Stockinger, H., Takahama, Y., Takeda, K., Tan, L., Tarnok, A., Tiegs, G., Toldi, G., Tornack, J., Traggiai, E., Trebak, M., Tree, T. I. M., Trotter, J., Trowsdale, J., Tsoumakidou, M., Ulrich, H., Urbanczyk, S., van de Veen, W., van den Broek, M., van der Pol, E., Van Gassen, S., Van Isterdael, G., van Lier, R. A. W., Veldhoen, M., Vento-Asturias, S., Vieira, P., Voehringer, D., Volk, H. -D., von Borstel, A., von Volkmann, K., Waisman, A., Walker, R. V., Wallace, P. K., Wang, S. A., Wang, X. M., Ward, M. D., Ward-Hartstonge, K. A., Warnatz, K., Warnes, G., Warth, S., Waskow, C., Watson, J. V., Watzl, C., Wegener, L., Weisenburger, T., Wiedemann, A., Wienands, J., Wilharm, A., Wilkinson, R. J., Willimsky, G., Wing, J. B., Winkelmann, R., Winkler, T. H., Wirz, O. F., Wong, A., Wurst, P., Yang, J. H. M., Yang, J., Yazdanbakhsh, M., Yu, L., Yue, A., Zhang, H., Zhao, Y., Ziegler, S. M., Zielinski, C., Zimmermann, J., Zychlinsky, A., UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/GECE - Génétique cellulaire, Netherlands Organization for Scientific Research, German Research Foundation, European Commission, European Research Council, Repositório da Universidade de Lisboa, CCA - Imaging and biomarkers, Experimental Immunology, AII - Infectious diseases, AII - Inflammatory diseases, Biomedical Engineering and Physics, ACS - Atherosclerosis & ischemic syndromes, and Landsteiner Laboratory
Subjects: 0301 basic medicine, Consensus, Immunology, Consensu, Cell Separation, Biology, Article, Flow cytometry, 03 medical and health sciences, 0302 clinical medicine, Guidelines, Allergy and Immunology, medicine, Cell separation, Immunology and Allergy, Humans, guidelines, flow cytometry, immunology, medicine.diagnostic_test, BIOMEDICINE AND HEALTHCARE. Basic Medical Sciences, Cell sorting, Flow Cytometry, Cell selection, Data science, 3. Good health, 030104 developmental biology, Phenotype, [SDV.IMM]Life Sciences [q-bio]/Immunology, BIOMEDICINA I ZDRAVSTVO. Temeljne medicinske znanosti, 030215 immunology, Human
Abstract: All authors: Andrea Cossarizza Hyun‐Dong Chang Andreas Radbruch Andreas Acs Dieter Adam Sabine Adam‐Klages William W. Agace Nima Aghaeepour Mübeccel Akdis Matthieu Allez Larissa Nogueira Almeida Giorgia Alvisi Graham Anderson Immanuel Andrä Francesco Annunziato Achille Anselmo Petra Bacher Cosima T. Baldari Sudipto Bari Vincenzo Barnaba Joana Barros‐Martins Luca Battistini Wolfgang Bauer Sabine Baumgart Nicole Baumgarth Dirk Baumjohann Bianka Baying Mary Bebawy Burkhard Becher Wolfgang Beisker Vladimir Benes Rudi Beyaert Alfonso Blanco Dominic A. Boardman Christian Bogdan Jessica G. Borger Giovanna Borsellino Philip E. Boulais Jolene A. Bradford Dirk Brenner Ryan R. Brinkman Anna E. S. Brooks Dirk H. Busch Martin Büscher Timothy P. Bushnell Federica Calzetti Garth Cameron Ilenia Cammarata Xuetao Cao Susanna L. Cardell Stefano Casola Marco A. Cassatella Andrea Cavani Antonio Celada Lucienne Chatenoud Pratip K. Chattopadhyay Sue Chow Eleni Christakou Luka Čičin‐Šain Mario Clerici Federico S. Colombo Laura Cook Anne Cooke Andrea M. Cooper Alexandra J. Corbett Antonio Cosma Lorenzo Cosmi Pierre G. Coulie Ana Cumano Ljiljana Cvetkovic Van Duc Dang Chantip Dang‐Heine Martin S. Davey Derek Davies Sara De Biasi Genny Del Zotto Gelo Victoriano Dela Cruz Michael Delacher Silvia Della Bella Paolo Dellabona Günnur Deniz Mark Dessing James P. Di Santo Andreas Diefenbach Francesco Dieli Andreas Dolf Thomas Dörner Regine J. Dress Diana Dudziak Michael Dustin Charles‐Antoine Dutertre Friederike Ebner Sidonia B. G. Eckle Matthias Edinger Pascale Eede Götz R.A. Ehrhardt Marcus Eich Pablo Engel Britta Engelhardt Anna Erdei Charlotte Esser Bart Everts Maximilien Evrard Christine S. Falk Todd A. Fehniger Mar Felipo‐Benavent Helen Ferry Markus Feuerer Andrew Filby Kata Filkor Simon Fillatreau Marie Follo Irmgard Förster John Foster Gemma A. Foulds Britta Frehse Paul S. Frenette Stefan Frischbutter Wolfgang Fritzsche David W. Galbraith Anastasia Gangaev Natalio Garbi Brice Gaudilliere Ricardo T. Gazzinelli Jens Geginat Wilhelm Gerner Nicholas A. Gherardin Kamran Ghoreschi Lara Gibellini Florent Ginhoux Keisuke Goda Dale I. Godfrey Christoph Goettlinger Jose M. González‐Navajas Carl S. Goodyear Andrea Gori Jane L. Grogan Daryl Grummitt Andreas Grützkau Claudia Haftmann Jonas Hahn Hamida Hammad Günter Hämmerling Leo Hansmann Goran Hansson Christopher M. Harpur Susanne Hartmann Andrea Hauser Anja E. Hauser David L. Haviland David Hedley Daniela C. Hernández Guadalupe Herrera Martin Herrmann Christoph Hess Thomas Höfer Petra Hoffmann Kristin Hogquist Tristan Holland Thomas Höllt Rikard Holmdahl Pleun Hombrink Jessica P. Houston Bimba F. Hoyer Bo Huang Fang‐Ping Huang Johanna E. Huber Jochen Huehn Michael Hundemer Christopher A. Hunter William Y. K. Hwang Anna Iannone Florian Ingelfinger Sabine M Ivison Hans‐Martin Jäck Peter K. Jani Beatriz Jávega Stipan Jonjic Toralf Kaiser Tomas Kalina Thomas Kamradt Stefan H. E. Kaufmann Baerbel Keller Steven L. C. Ketelaars Ahad Khalilnezhad Srijit Khan Jan Kisielow Paul Klenerman Jasmin Knopf Hui‐Fern Koay Katja Kobow Jay K. Kolls Wan Ting Kong Manfred Kopf Thomas Korn Katharina Kriegsmann Hendy Kristyanto Thomas Kroneis Andreas Krueger Jenny Kühne Christian Kukat Désirée Kunkel Heike Kunze‐Schumacher Tomohiro Kurosaki Christian Kurts Pia Kvistborg Immanuel Kwok Jonathan Landry Olivier Lantz Paola Lanuti Francesca LaRosa Agnès Lehuen Salomé LeibundGut‐Landmann Michael D. Leipold Leslie Y.T. Leung Megan K. Levings Andreia C. Lino Francesco Liotta Virginia Litwin Yanling Liu Hans‐Gustaf Ljunggren Michael Lohoff Giovanna Lombardi Lilly Lopez Miguel López‐Botet Amy E. Lovett‐Racke Erik Lubberts Herve Luche Burkhard Ludewig Enrico Lugli Sebastian Lunemann Holden T. Maecker Laura Maggi Orla Maguire Florian Mair Kerstin H. Mair Alberto Mantovani Rudolf A. Manz Aaron J. Marshall Alicia Martínez‐Romero Glòria Martrus Ivana Marventano Wlodzimierz Maslinski Giuseppe Matarese Anna Vittoria Mattioli Christian Maueröder Alessio Mazzoni James McCluskey Mairi McGrath Helen M. McGuire Iain B. McInnes Henrik E. Mei Fritz Melchers Susanne Melzer Dirk Mielenz Stephen D. Miller Kingston H.G. Mills Hans Minderman Jenny Mjösberg Jonni Moore Barry Moran Lorenzo Moretta Tim R. Mosmann Susann Müller Gabriele Multhoff Luis Enrique Muñoz Christian Münz Toshinori Nakayama Milena Nasi Katrin Neumann Lai Guan Ng Antonia Niedobitek Sussan Nourshargh Gabriel Núñez José‐Enrique O'Connor Aaron Ochel Anna Oja Diana Ordonez Alberto Orfao Eva Orlowski‐Oliver Wenjun Ouyang Annette Oxenius Raghavendra Palankar Isabel Panse Kovit Pattanapanyasat Malte Paulsen Dinko Pavlinic Livius Penter Pärt Peterson Christian Peth Jordi Petriz Federica Piancone Winfried F. Pickl Silvia Piconese Marcello Pinti A. Graham Pockley Malgorzata Justyna Podolska Zhiyong Poon Katharina Pracht Immo Prinz Carlo E. M. Pucillo Sally A. Quataert Linda Quatrini Kylie M. Quinn Helena Radbruch Tim R. D. J. Radstake Susann Rahmig Hans‐Peter Rahn Bartek Rajwa Gevitha Ravichandran Yotam Raz Jonathan A. Rebhahn Diether Recktenwald Dorothea Reimer Caetano Reis e Sousa Ester B.M. Remmerswaal Lisa Richter Laura G. Rico Andy Riddell Aja M. Rieger J. Paul Robinson Chiara Romagnani Anna Rubartelli Jürgen Ruland Armin Saalmüller Yvan Saeys Takashi Saito Shimon Sakaguchi Francisco Sala‐de‐Oyanguren Yvonne Samstag Sharon Sanderson Inga Sandrock Angela Santoni Ramon Bellmàs Sanz Marina Saresella Catherine Sautes‐Fridman Birgit Sawitzki Linda Schadt Alexander Scheffold Hans U. Scherer Matthias Schiemann Frank A. Schildberg Esther Schimisky Andreas Schlitzer Josephine Schlosser Stephan Schmid Steffen Schmitt Kilian Schober Daniel Schraivogel Wolfgang Schuh Thomas Schüler Reiner Schulte Axel Ronald Schulz Sebastian R. Schulz Cristiano Scottá Daniel Scott‐Algara David P. Sester T. Vincent Shankey Bruno Silva‐Santos Anna Katharina Simon Katarzyna M. Sitnik Silvano Sozzani Daniel E. Speiser Josef Spidlen Anders Stahlberg Alan M. Stall Natalie Stanley Regina Stark Christina Stehle Tobit Steinmetz Hannes Stockinger Yousuke Takahama Kiyoshi Takeda Leonard Tan Attila Tárnok Gisa Tiegs Gergely Toldi Julia Tornack Elisabetta Traggiai Mohamed Trebak Timothy I.M. Tree Joe Trotter John Trowsdale Maria Tsoumakidou Henning Ulrich Sophia Urbanczyk Willem van de Veen Maries van den Broek Edwin van der Pol Sofie Van Gassen Gert Van Isterdael René A.W. van Lier Marc Veldhoen Salvador Vento‐Asturias Paulo Vieira David Voehringer Hans‐Dieter Volk Anouk von Borstel Konrad von Volkmann Ari Waisman Rachael V. Walker Paul K. Wallace Sa A. Wang Xin M. Wang Michael D. Ward Kirsten A Ward‐Hartstonge Klaus Warnatz Gary Warnes Sarah Warth Claudia Waskow James V. Watson Carsten Watzl Leonie Wegener Thomas Weisenburger Annika Wiedemann Jürgen Wienands Anneke Wilharm Robert John Wilkinson Gerald Willimsky James B. Wing Rieke Winkelmann Thomas H. Winkler Oliver F. Wirz Alicia Wong Peter Wurst Jennie H. M. Yang Juhao Yang Maria Yazdanbakhsh Liping Yu Alice Yue Hanlin Zhang Yi Zhao Susanne Maria Ziegler Christina Zielinski Jakob Zimmermann Arturo Zychlinsky., These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer‐reviewed by leading experts in the field, making this an essential research companion., This work was supported by the Netherlands Organisation for Scientific Research – Domain Applied and Engineering Sciences (NWO-TTW), research program VENI 15924. This work was funded by the Deutsche Forschungsgemeinschaft. European Union Innovative Medicines Initiative - Joint Undertaking - RTCure Grant Agreement 777357 and innovation program (Grant Agreement 695551).
Published: 2019

41. IL6-receptor antibody tocilizumab as salvage therapy in severe chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: a retrospective analysis

Author: Matthias Edinger, Sebastian Klobuch, Anna-Sophia Kattner, Ernst Holler, Danilo Martinovic, Wolfgang Herr, Barbara Holler, Daniel Wolff, and Daniela Weber
Subjects: Adult, Male, medicine.medical_specialty, medicine.medical_treatment, 610 Medizin, Salvage therapy, Graft vs Host Disease, Hematopoietic stem cell transplantation, Antibodies, Monoclonal, Humanized, Gastroenterology, Sepsis, chemistry.chemical_compound, Tocilizumab, immune system diseases, Recurrence, Internal medicine, medicine, Humans, Transplantation, Homologous, Retrospective Studies, Salvage Therapy, ddc:610, business.industry, Interleukin-6, Hematopoietic Stem Cell Transplantation, Immunosuppression, Hematology, General Medicine, Chronic graft-versus-host disease, Middle Aged, medicine.disease, Graft-versus-host disease, Treatment Outcome, chemistry, Ibrutinib, Concomitant, Allogeneic hematopoietic stem cell transplantation, Chronic Disease, Original Article, Female, business, Immunosuppressive Agents, Allogeneic hematopoietic stem cell transplantation . Chronic graft-versus-host disease . Tocilizumab . Interleukin-6, Follow-Up Studies
Abstract: Chronic graft-versus-host disease (cGvHD) remains the most relevant factor affecting survival after allogeneic hematopoietic stem cell transplantation (alloHSCT). Besides corticosteroids (and ibrutinib in the USA), there is no established therapy for cGvHD. Tocilizumab, a humanized IgG1 IL6-receptor antibody, has shown efficacy in acute GvHD and cGvHD. We retrospectively analyzed the efficacy and safety of tocilizumab for the treatment of advanced cGvHD. Eleven patients with severe steroid refractory cGvHD (median age 49; range 21–62 years) that received at least two prior lines of therapy for cGvHD (range 2–8 regimens) were treated with tocilizumab (q4w, dosage 8 mg/kg IV) with a median number of 15 cycles (range 2–31). NIH consensus criteria grading for cGvHD were recorded prior to tocilizumab administration and after 3, 6, and 12 months of therapy. All patients received additional concomitant immunosuppression (IS) but no new IS within the last 4 weeks before start of tocilizumab and response assessment was terminated before start of any new IS. The median number of days between alloHSCT and initiation of tocilizumab therapy was 1033 days. Organs involved at initiation of tocilizumab therapy were skin (100%, all grade 3), eyes (82%), fascia (82%), mouth (64%), lungs (55%), and genitals (18%). Overall, 7/10 patients (70%) showed partial remission, 2/10 patients (20%) showed progressive cGvHD, 1/10 patient (10%) showed mixed response, and 1 patient died due to sepsis before first response assessment 1.5 months after initiation of treatment. Four patients required subsequent new immunosuppressive treatment. Two patients developed bacterial sepsis, one of whom died. The overall survival and relapse-free survival were 82% with an average follow-up of 22 months (range 1.5–52 months). Tocilizumab seems a promising treatment option in advanced cGvHD but further evaluation within a phase II trial is required.
Published: 2020

42. Mechanisms governing the pioneering and redistribution capabilities of the non-classical pioneer PU.1

Author: Petra Hoffmann, Matthias Edinger, Andreas Schmidt, Magda Babina, Sandra Schmidhofer, Gernot Längst, Andreas Fuchs, Michael Rehli, Johanna Raithel, Rudolf Schill, Claudia Gebhard, Dagmar Glatz, Rainer Spang, Margit Nützel, Anna Ratermann, Christian Schmidl, Karina Mendes, Julia Minderjahn, and Axel Imhof
Subjects: 0301 basic medicine, Cell type, Science, Protein domain, genetic processes, Gene regulatory network, 610 Medizin, General Physics and Astronomy, RNA-Seq, Chromatin remodelling, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Redistribution (chemistry), lcsh:Science, Transcription factor, ddc:610, Multidisciplinary, General Chemistry, humanities, Chromatin, Cell biology, Gene regulation, Nucleosomes, 030104 developmental biology, Haematopoiesis, lcsh:Q, Reprogramming, Transcription, 030217 neurology & neurosurgery
Abstract: Establishing gene regulatory networks during differentiation or reprogramming requires master or pioneer transcription factors (TFs) such as PU.1, a prototype master TF of hematopoietic lineage differentiation. To systematically determine molecular features that control its activity, here we analyze DNA-binding in vitro and genome-wide in vivo across different cell types with native or ectopic PU.1 expression. Although PU.1, in contrast to classical pioneer factors, is unable to access nucleosomal target sites in vitro, ectopic induction of PU.1 leads to the extensive remodeling of chromatin and redistribution of partner TFs. De novo chromatin access, stable binding, and redistribution of partner TFs both require PU.1’s N-terminal acidic activation domain and its ability to recruit SWI/SNF remodeling complexes, suggesting that the latter may collect and distribute co-associated TFs in conjunction with the non-classical pioneer TF PU.1., PU.1 is a master TF of hematopoietic lineage differentiation. Here the authors analyse properties of PU.1 DNA-binding in vitro and genome-wide in vivo across different cell types with native or ectopic PU.1 expression, and uncover the mechanisms governing the pioneering and redistribution capabilities of the non-classical pioneer PU.1.
Published: 2020

43. Phase I/II Clinical Trials of Donor-Derived Purified Regulatory T Cells for the Treatment of Steroid-Refractory Chronic Graft Versus Host Disease

Author: Maria VD Soares, Virginia Escamilla Gomez, Rita I Azevedo, Paulo N.G. Pereira, Teresa Caballero Velázquez, Clara B. Garcia-Calderón, Kukatharmini Tharmaratnam, Inês A Cabral, Ana C Ribeiro, Laura Mendes, Clara Juncal, Susana Roncon, Ana Teresa Pais, Ana C Alho, Alfonso Rodriguez Gil, Eduardo L Espada, Anabela Rodrigues, Ana Garção, Marie-Laure Yaspo, Hans-Jörg Warnatz, Hans Lehrach, Nuno L. Barbosa-Morais, Ana Miguel Quintas, Paulo Palmela, Cecilia Caldas, Rosa Ferreira, Luis Leite, Carlos Martins, Fernanda Lourenço, Raúl Moreno, João Raposo, Fernando Campilho, Christopher Paul Cheyne, Marta Garcia-Fiñana, António Campos, Frédéric Baron, Mario Arpinati, Matthias Edinger, Jerome Ritz, Carlos Pinho Vaz, Jose A. Perez-Simon, and Joao F Lacerda
Subjects: Immunology, Cell Biology, Hematology, Biochemistry
Published: 2022
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44. 'Uninformierte Einwilligungen' im Rahmen klinischer Studien – eine Multimethodenstudie zu Ursachen und Lösungsansätzen

Author: J Hies, A Herrmann-Johns, A Hartl, Wolfgang Herr, Matthias Edinger, Daniel Wolff, and Julika Loss
Published: 2021

45. Evaluation of Trends in Outcome over 2 Decades of Patients with Relapsed/Refractory Acute Myelogenous Leukemia Undergoing Allogeneic Stem Cell Transplantation from Unrelated Donors: An ALWP/EBMT Analysis

Author: Arnon Nagler, Maud Ngoya, Myriam Labopin, Martin Bornhauser, Matthias Stelljes, Jürgen Finke, Arnold Ganser, Hermann Einsele, Nicolaus Kroger, Arne Brecht, Wolfgang Bethge, Matthias Edinger, Aleksandr Kulagin, Jakob Passweg, Ahmet Elmaagacli, K. Schafer-Eckart, Uwe Platzbecker, Thomas Schroeder, Donald Bunjes, Johanna Tischer, Sonja Martin, Alexandros Spyridonidis, Sebastian Giebel, Bipin Savani, and Mohamad Mohty
Subjects: Transplantation, Molecular Medicine, Immunology and Allergy, Cell Biology, Hematology
Published: 2022

46. Human bocavirus 1 respiratory tract re-activations or re-infections in two adults, contributing to neurologic deficits and death

Author: D. Wolff, Maria Söderlund-Venermo, Klemens Angstwurm, Annelie Plentz, Matthias Edinger, Rajita Rayamajhi Thapa, Human Parvoviruses: Epidemiology, Molecular Biology and Clinical Impact, Department of Virology, and Biosciences
Subjects: 0301 basic medicine, reactivation, respiratory tract infection, 030106 microbiology, education, Case Reports, original antigenic sin, 3124 Neurology and psychiatry, Serology, reinfection, 03 medical and health sciences, 0302 clinical medicine, Immunity, Medicine, General Materials Science, 030212 general & internal medicine, Respiratory system, Seroconversion, Young adult, fatal, Respiratory tract infections, biology, business.industry, Human bocavirus, parvovirus, biology.organism_classification, 3. Good health, medicine.anatomical_structure, 3121 General medicine, internal medicine and other clinical medicine, Immunology, business, Respiratory tract
Abstract: Human bocavirus 1 (HBoV1) of the family Parvoviridae causes mild to life-threatening respiratory tract infections in young children, but, due to widespread immunity, it is uncommon in adults. HBoV1 reinfections or reactivations leading to casualties are rare, but might be underdiagnosed. We report two young adults, one previously healthy and one immunosuppressed, with rare diagnostic patterns of HBoV1 respiratory tract infection. Both patients exhibited very high loads of HBoV1 DNA in respiratory samples. The immunosuppressed patient was also HBoV1 DNA-positive in blood, stool and a colon biopsy, but exhibited prior HBoV1-specific high-avidity IgG and weak IgM positivity 9 months before the respiratory symptoms. Likewise, the previously healthy patient exhibited HBoV1 IgG of high avidity and very weak IgM in serum, pointing to prior immunity, but with a seroconversion in cerebrospinal fluid. This patient also showed strong HBoV2 cross-reactivity. The molecular and serological results, together with their ages, suggest that both patients exhibited unusual reinfection or reactivation of HBoV1, contributing to neurological deficits and death.
Published: 2021

47. A qualitative study on patients’ and their support persons’ preferences for receiving one longer consultation or two shorter consultations when being informed about allogeneic hematopoietic stem cell transplantation

Author: Sascha Eickmann, Anne Herrmann, Matthias Edinger, Ernst Holler, and Daniel Wolff
Subjects: medicine.medical_specialty, Patient-centered care, 610 Medizin, Health literacy, Health informatics, Health administration, Interviews, Qualitative research, Medicine, Humans, Referral and Consultation, Response rate (survey), Physician-Patient Relations, ddc:610, Recall, business.industry, Health Policy, Public health, Nursing research, Research, Hematopoietic Stem Cell Transplantation, Hematological cancer, Stem cell transplantation, Patient preferences, Health Literacy, Family medicine, Public aspects of medicine, RA1-1270, business, Hematological cancer, Stem cell transplantation, Patient preferences, Interviews, Qualitative research, Patient-centered care
Abstract: Background Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only potentially curative treatment option for many patients with hematological disorders but it includes a significant risk of mortality and long-term morbidity. Many patients and their support persons feel overwhelmed when being informed about alloHSCT and may benefit from improvements in consultation style and timing. Aims To explore, qualitatively, in a sample of hematological cancer patients and their support persons, their preferences for receiving one longer consultation or two shorter consultations when being informed about alloHSCT. Participants’ perceptions of when and how different consultation styles should be offered were also examined. Methods Semi-structured face-to-face and phone interviews were conducted. A purposeful sampling frame was used. Data were analysed using framework analysis. Results Twenty patients and 13 support persons were recruited (consent rate: 96%, response rate: 91%). Most patients (60%) and support persons (62%) preferred two shorter consultations over one longer consultation. This helped them digest and recall the information provided, remember questions they had, involve significant others and search for additional information. Patients would have liked to be offered paper and pen to take notes, take a break after 30 min and have their understanding checked at the end of the first consultation, e.g. using question prompt lists. Some patients and support persons preferred both consultations to happen on the same day to reduce waiting times as well as travel times and costs. Others preferred having a few days in-between both consultations to better help them prepare the second consultation. Participants reported varying preferences for different consultation styles depending on personal and disease-related characteristics, such as age, health literacy level and previous treatment. Conclusion To our knowledge, this is the first qualitative study to explore patients’ and their support persons’ preferences for having one longer consultation or two shorter consultations when being informed about alloHSCT. Receiving two shorter consultations may help patients process and recall the information provided and more actively involve their support persons. Clinicians should consider offering patients and their support persons to take a break after 30 min, provide paper and pen as well as question prompt lists.
Published: 2021

48. Single-cell chromatin accessibility landscape identifies tissue repair program in human regulatory T cells

Author: Benedikt Brors, Matthias Edinger, Till Strowig, Sebastian Bittner, Lisa Schmidleithner, Michael Rehli, Jens M. Werner, Lukas Prantl, Uwe Ritter, Michael Delacher, Marina Wuttke, Nicholas Strieder, Kathrin Schambeck, Markus Feuerer, Dania Riegel, Claudia Gebhard, Jochen Huehn, Agnes Hotz-Wagenblatt, Andreas Eigenberger, Thomas Hehlgans, Alexander Fischer, Asmita Pant, Florian Groeber-Becker, Petra Hoffmann, Charles D. Imbusch, Verena Schneider, Christian Schmidl, Malte Simon, Lieke Sanderink, Publica, and HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Subjects: 0301 basic medicine, Adult, Male, T Follicular Helper Cells, Immunology, Population, chemical and pharmacologic phenomena, Biology, CCR8, T-Lymphocytes, Regulatory, Receptors, CCR8, Cell Line, 03 medical and health sciences, Chemokine receptor, Mice, 0302 clinical medicine, BATF, Immunology and Allergy, Animals, HaCaT Cells, Humans, education, Tissue homeostasis, education.field_of_study, Wound Healing, Gene Expression Profiling, hemic and immune systems, Cell Differentiation, Middle Aged, Chromatin, Cell biology, Mice, Inbred C57BL, 030104 developmental biology, Infectious Diseases, Basic-Leucine Zipper Transcription Factors, Gene Expression Regulation, Cell culture, 030220 oncology & carcinogenesis, Female, Wound healing
Abstract: Murine regulatory T (Treg) cells in tissues promote tissue homeostasis and regeneration. We sought to identify features that characterize human Treg cells with these functions in healthy tissues. Single-cell chromatin accessibility profiles of murine and human tissue Treg cells defined a conserved, microbiota-independent tissue-repair Treg signature with a prevailing footprint of the transcription factor BATF. This signature, combined with gene expression profiling and TCR fate mapping, identified a population of tissue-like Treg cells in human peripheral blood that expressed BATF, chemokine receptor CCR8 and HLA-DR. Human BATF+CCR8+ Treg cells from normal skin and adipose tissue shared features with nonlymphoid T follicular helper-like (Tfh-like) cells, and induction of a Tfh-like differentiation program in naive human Treg cells partially recapitulated tissue Treg regenerative characteristics, including wound healing potential. Human BATF+CCR8+ Treg cells from healthy tissue share features with tumor-resident Treg cells, highlighting the importance of understanding the context-specific functions of these cells.
Published: 2021
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49. Prolonged Suppression of Butyrate-Producing Bacteria Is Associated With Acute Gastrointestinal Graft-vs-Host Disease and Transplantation-Related Mortality After Allogeneic Stem Cell Transplantation

Author: Elisabeth Meedt, Ernst Holler, Wolfgang Herr, Sakhila Ghimire, Daniela Weber, Hendrik Poeck, Katja Dettmer, Andreas Hiergeist, Daniel Wolff, André Gessner, Gerhard Liebisch, and Matthias Edinger
Subjects: 0301 basic medicine, Microbiology (medical), medicine.drug_class, Antibiotics, Graft vs Host Disease, Butyrate, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Transplantation, Homologous, Microbiome, Bacteria, business.industry, Hematopoietic Stem Cell Transplantation, Transplant-Related Mortality, medicine.disease, Transplantation, Butyrates, 030104 developmental biology, Infectious Diseases, Graft-versus-host disease, Butyrate-Producing Bacteria, 030220 oncology & carcinogenesis, Immunology, business
Abstract: Background Butyrogenic bacteria play an important role in gut microbiome homeostasis and intestinal epithelial integrity. Previous studies have demonstrated an association between administration of short-chain fatty acids like butyrate and protection from acute graft-vs-host disease (GvHD) after allogeneic stem cell transplantation (ASCT). Methods In the current study, we examined the abundance and butyrogenic capacity of butyrate-producing bacteria in 28 healthy donors and 201 patients after ASCT. We prospectively collected serial stool samples and performed polymerase chain reaction analysis of the butyrate-producing bacterial enzyme butyryl–coenzyme A (CoA):acetate CoA-transferase (BCoAT) in fecal nucleic acid extracts. Results Our data demonstrate a strong and prolonged suppression of butyrogenic bacteria early in the course of ASCT. In a multivariable analysis, early use of broad-spectrum antibiotics before day 0 (day of transplantation) was identified as an independent factor associated with low BCoAT copy numbers (odds ratio, 0.370 [95% confidence interval, .175–.783]; P = .009). Diminished butyrogens correlated with other biomarkers of microbial diversity, such as low 3-indoxylsulfate levels, reduced abundance of Clostridiales and low inverse Simpson and effective Shannon indices (all P Conclusions Our results are consistent with the hypothesis that alterations in the microbiome play an important role in GvHD pathogenesis and that microbial parameters such as BCoAT might serve as biomarkers to identify patients at high risk of lethal GI-GvHD.
Published: 2020

50. Regulatory cell therapy in kidney transplantation (The ONE Study):a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials

Author: Kathryn J. Wood, Birgit Sawitzki, James A. Hutchinson, Leslie Brent, Cristiano Scottà, Christoph Meyenberg, P Friend, Kerry Crisalli, Manuela Battaglia, Natalie M Otto, Ben James, Eva C. Guinan, M. C. Cuturi, Alexander Scheffold, William Petchey, Ulrich Kunzendorf, William J. Burlingham, Fadi Issa, Antonio Secchi, Petra Reinke, Giovanna Lombardi, James F. Markmann, Hans-Dieter Volk, David Game, Matthias Edinger, Norbert Ahrens, Ian S.D. Roberts, Michael Kapinsky, Maria P. Hernandez-Fuentes, Bernhard Banas, Sandra Karitzky, Nathalie Dupas, Carsten A. Böger, Edward K. Geissler, Tewfik Miloud, Stephan Schlickeiser, Paul N. Harden, Qizhi Tang, Gilles Blancho, Tobias Bergler, Karsten Juerchott, Robert I. Lechler, Hans J. Schlitt, Josep M. Grinyó, Laura Contreras-Ruiz, Rossana Caldara, Joanna Hester, Mathias Streitz, A. Bushell, Rachel Hilton, Régis Josien, Stuart J. Knechtle, Robert Öllinger, Laurence A. Turka, Cécile Braudeau, Aurélie Moreau, Peter J. Morris, Jeffrey A. Bluestone, Sang-Mo Kang, Ingrid Mutzbauer, Jeroen B. van der Net, Sawitzki, B., Harden, P. N., Reinke, P., Moreau, A., Hutchinson, J. A., Game, D. S., Tang, Q., Guinan, E. C., Battaglia, M., Burlingham, W. J., Roberts, I. S. D., Streitz, M., Josien, R., Boger, C. A., Scotta, C., Markmann, J. F., Hester, J. L., Juerchott, K., Braudeau, C., James, B., Contreras-Ruiz, L., van der Net, J. B., Bergler, T., Caldara, R., Petchey, W., Edinger, M., Dupas, N., Kapinsky, M., Mutzbauer, I., Otto, N. M., Ollinger, R., Hernandez-Fuentes, M. P., Issa, F., Ahrens, N., Meyenberg, C., Karitzky, S., Kunzendorf, U., Knechtle, S. J., Grinyo, J., Morris, P. J., Brent, L., Bushell, A., Turka, L. A., Bluestone, J. A., Lechler, R. I., Schlitt, H. J., Cuturi, M. C., Schlickeiser, S., Friend, P. J., Miloud, T., Scheffold, A., Secchi, A., Crisalli, K., Kang, S. -M., Hilton, R., Banas, B., Blancho, G., Volk, H. -D., Lombardi, G., Wood, K. J., Geissler, E. K., and Publica
Subjects: Graft Rejection, medicine.medical_specialty, Kidney Disease, Basiliximab, medicine.medical_treatment, T-Lymphocytes, Clinical Trials and Supportive Activities, Cell- and Tissue-Based Therapy, Renal and urogenital, 030204 cardiovascular system & hematology, T-Lymphocytes, Regulatory, Medical and Health Sciences, Organ transplantation, 03 medical and health sciences, 0302 clinical medicine, Maintenance therapy, Clinical Research, Internal medicine, General & Internal Medicine, medicine, Clinical endpoint, Humans, 030212 general & internal medicine, Adverse effect, Kidney transplantation, Immunosuppression Therapy, Transplantation, business.industry, Macrophages, Immunosuppression, General Medicine, Dendritic Cells, Organ Transplantation, medicine.disease, Kidney Transplantation, Regulatory, Patient Safety, business, Immunosuppressive Agents, medicine.drug
Abstract: Background:Use of cell-based medicinal products (CBMPs) represents a state-of-the-art approach for reducing general immunosuppression in organ transplantation. We tested multiple regulatory CBMPs in kidney transplant trials to establish the safety of regulatory CBMPs when combined with reduced immunosuppressive treatment. Methods:The ONE Study consisted of seven investigator-led, single-arm trials done internationally at eight hospitals in France, Germany, Italy, the UK, and the USA (60 week follow-up). Included patients were living-donor kidney transplant recipients aged 18 years and older. The reference group trial (RGT) was a standard-of-care group given basiliximab, tapered steroids, mycophenolate mofetil, and tacrolimus. Six non-randomised phase 1/2A cell therapy group (CTG) trials were pooled and analysed, in which patients received one of six CBMPs containing regulatory T cells, dendritic cells, or macrophages; patient selection and immunosuppression mirrored the RGT, except basiliximab induction was substituted with CBMPs and mycophenolate mofetil tapering was allowed. None of the trials were randomised and none of the individuals involved were masked. The primary endpoint was biopsy-confirmed acute rejection (BCAR) within 60 weeks after transplantation; adverse event coding was centralised. The RTG and CTG trials are registered withClinicalTrials.gov,NCT01656135,NCT02252055,NCT02085629,NCT02244801,NCT02371434,NCT02129881, andNCT02091232. Findings:The seven trials took place between Dec 11, 2012, and Nov 14, 2018. Of 782 patients assessed for eligibility, 130 (17%) patients were enrolled and 104 were treated and included in the analysis. The 66 patients who were treated in the RGT were 73% male and had a median age of 47 years. The 38 patients who were treated across six CTG trials were 71% male and had a median age of 45 years. Standard-of-care immunosuppression in the recipients in the RGT resulted in a 12% BCAR rate (expected range 3·2–18·0). The overall BCAR rate for the six parallel CTG trials was 16%. 15 (40%) patients given CBMPs were successfully weaned from mycophenolate mofetil and maintained on tacrolimus monotherapy. Combined adverse event data and BCAR episodes from all six CTG trials revealed no safety concerns when compared with the RGT. Fewer episodes of infections were registered in CTG trials versus the RGT. Interpretation:Regulatory cell therapy is achievable and safe in living-donor kidney transplant recipients, and is associated with fewer infectious complications, but similar rejection rates in the first year. Therefore, immune cell therapy is a potentially useful therapeutic approach in recipients of kidney transplant to minimise the burden of general immunosuppression.
Published: 2020

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