15 results on '"Heidt S"'
Search Results
2. Memory B-cell derived donor-specific antibodies do not predict outcome in sensitized kidney transplant recipients: a retrospective single-center study.
- Author
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Altulea D, van den Born JC, Diepstra A, Bungener L, Terpstra D, Hepkema BG, Lammerts R, Heeringa P, Heidt S, Otten H, Reteig L, Karahan GE, Berger SP, and Sanders JS
- Subjects
- Humans, Retrospective Studies, Male, Female, Middle Aged, Adult, Memory B Cells immunology, Tissue Donors, Aged, Transplant Recipients, Graft Survival immunology, Kidney Transplantation adverse effects, Graft Rejection immunology, Isoantibodies immunology, Isoantibodies blood, HLA Antigens immunology
- Abstract
Background: Repeated exposure to sensitizing events can activate HLA-specific memory B cells, leading to the production of donor-specific memory B cell antibodies (DSAm) that pose a risk for antibody-mediated rejection (ABMR) in kidney transplant recipients (KTRs). This single-center retrospective study aimed to identify DSAm and assess their association with outcomes in a cohort of KTRs with pretransplant serum donor-specific antibodies (DSA)., Methods: We polyclonally activated pretransplant peripheral blood mononuclear cells (PBMCs) from 60 KTRs in vitro, isolated and quantified IgG from the culture supernatant using ELISA, and analyzed the HLA antibodies of eluates with single antigen bead (SAB) assays, comparing them to the donor HLA typing for potential DSAm. Biopsies from 41 KTRs were evaluated for rejection based on BANFF 2019 criteria., Results: At transplantation, a total of 37 DSAm were detected in 26 of 60 patients (43%), of which 13 (35%) were found to be undetectable in serum. No significant association was found between pretransplant DSAm and ABMR (P=0.53). Similar results were observed in a Kaplan-Meier analysis for ABMR within the first year posttransplant (P=0.29). Additionally, MFI levels of DSAm showed no significant association with ABMR (P=0.28)., Conclusion: This study suggests no significant association between DSAm and biopsy-proven clinical ABMR. Further prospective research is needed to determine whether assessing DSAm could enhance existing immunological risk assessment methods for monitoring KTRs, particularly in non-sensitized KTRs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Altulea, van den Born, Diepstra, Bungener, Terpstra, Hepkema, Lammerts, Heeringa, Heidt, Otten, Reteig, Karahan, Berger and Sanders.)
- Published
- 2024
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3. Cell-free DNA measurement of three genomes after allogeneic MSC therapy in kidney transplant recipients indicates early cell death of infused MSC.
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Dreyer GJ, Drabbels JJ, de Fijter JW, van Kooten C, Reinders ME, and Heidt S
- Subjects
- Cell Death, Kidney Transplantation adverse effects, Mesenchymal Stem Cell Transplantation methods, Mesenchymal Stem Cells, Hematopoietic Stem Cell Transplantation, Cell-Free Nucleic Acids genetics
- Abstract
Introduction: Mesenchymal stromal cell (MSC) therapy is a promising treatment that allows for drug minimization in clinical kidney transplantation. While it is thought that MSCs rapidly go into apoptosis after infusion, clinical evidence for this is scarce since methods to detect cell death of infused cells in vivo are lacking. Cell-free DNA (cfDNA) has recently gained attention as a biomarker for cell death., Methods: In this study, we longitudinally measured cfDNA in plasma samples of the recipient, kidney donor, and allogeneic third-party MSC in the context of the Neptune study. cfDNA levels were measured at several time points before and after allogeneic MSC infusion in the 10 recipients who participated in the Neptune study. cfDNA ratios between the recipient, kidney graft, and MSC were determined., Results: We observed a peak in MSC-derived cfDNA 4 h after the first and second infusions, after which MSC-derived cfDNA became undetectable. Generally, kidney graft-derived cfDNA remained in the baseline-level range., Discussion: Our results support preclinical data that MSC are short-lived after infusion, also in a clinical in vivo setting, and are relevant for further research into the mechanism of action of MSC therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dreyer, Drabbels, de Fijter, van Kooten, Reinders and Heidt.)
- Published
- 2023
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4. Inhibition of complement activation by CD55 overexpression in human induced pluripotent stem cell derived kidney organoids.
- Author
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Gaykema LH, van Nieuwland RY, Dekkers MC, van Essen MF, Heidt S, Zaldumbide A, van den Berg CW, Rabelink TJ, and van Kooten C
- Subjects
- Humans, Kidney, CD55 Antigens, Complement Activation, Complement System Proteins, Induced Pluripotent Stem Cells
- Abstract
End stage renal disease is an increasing problem worldwide driven by aging of the population and increased prevalence of metabolic disorders and cardiovascular disease. Currently, kidney transplantation is the only curative option, but donor organ shortages greatly limit its application. Regenerative medicine has the potential to solve the shortage by using stem cells to grow the desired tissues, like kidney tissue. Immune rejection poses a great threat towards the implementation of stem cell derived tissues and various strategies have been explored to limit the immune response towards these tissues. However, these studies are limited by targeting mainly T cell mediated immune rejection while the rejection process also involves innate and humoral immunity. In this study we investigate whether inhibition of the complement system in human induced pluripotent stem cells (iPSC) could provide protection from such immune injury. To this end we created knock-in iPSC lines of the membrane bound complement inhibitor CD55 to create a transplant-specific protection towards complement activation. CD55 inhibits the central driver of the complement cascade, C3 convertase, and we show that overexpression is able to decrease complement activation on both iPSCs as well as differentiated kidney organoids upon stimulation with anti-HLA antibodies to mimic the mechanism of humoral rejection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gaykema, van Nieuwland, Dekkers, van Essen, Heidt, Zaldumbide, van den Berg, Rabelink and van Kooten.)
- Published
- 2023
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5. Chimeric Antigen Receptor (CAR) Regulatory T-Cells in Solid Organ Transplantation.
- Author
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Gille I, Claas FHJ, Haasnoot GW, Heemskerk MHM, and Heidt S
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- Animals, HLA-A2 Antigen immunology, Humans, Transplantation Tolerance, Organ Transplantation, Receptors, Chimeric Antigen immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Solid organ transplantation is the treatment of choice for various end-stage diseases, but requires the continuous need for immunosuppression to prevent allograft rejection. This comes with serious side effects including increased infection rates and development of malignancies. Thus, there is a clinical need to promote transplantation tolerance to prevent organ rejection with minimal or no immunosuppressive treatment. Polyclonal regulatory T-cells (Tregs) are a potential tool to induce transplantation tolerance, but lack specificity and therefore require administration of high doses. Redirecting Tregs towards mismatched donor HLA molecules by modifying these cells with chimeric antigen receptors (CAR) would render Tregs far more effective at preventing allograft rejection. Several studies on HLA-A2 specific CAR Tregs have demonstrated that these cells are highly antigen-specific and show a superior homing capacity to HLA-A2+ allografts compared to polyclonal Tregs. HLA-A2 CAR Tregs have been shown to prolong survival of HLA-A2+ allografts in several pre-clinical humanized mouse models. Although promising, concerns about safety and stability need to be addressed. In this review the current research, obstacles of CAR Treg therapy, and its potential future in solid organ transplantation will be discussed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gille, Claas, Haasnoot, Heemskerk and Heidt.)
- Published
- 2022
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6. A Comprehensive Evaluation of the Antibody-Verified Status of Eplets Listed in the HLA Epitope Registry.
- Author
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Bezstarosti S, Bakker KH, Kramer CSM, de Fijter JW, Reinders MEJ, Mulder A, Claas FHJ, and Heidt S
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- Alleles, Amino Acid Sequence, Antibodies, Monoclonal immunology, Databases, Genetic, Epitopes chemistry, Epitopes genetics, HLA Antigens chemistry, HLA Antigens genetics, Histocompatibility genetics, Histocompatibility immunology, Histocompatibility Testing, Humans, Isoantibodies immunology, Models, Molecular, Registries, Structure-Activity Relationship, Transplantation, Epitopes immunology, HLA Antigens immunology
- Abstract
Matching strategies based on HLA eplets instead of HLA antigens in solid organ transplantation may not only increase the donor pool for highly sensitized patients, but also decrease the incidence of de novo donor-specific antibody formation. However, since not all eplets are equally capable of inducing an immune response, antibody verification is needed to confirm their ability to be bound by antibodies, such that only clinically relevant eplets are considered. The HLA Epitope Registry has documented all theoretically defined HLA eplets along with their antibody verification status and has been the foundation for many clinical studies investigating eplet mismatch in transplantation. The verification methods for eplets in the Registry range from polyclonal sera from multi- and uni-parous women to murine and human monoclonal antibodies (mAbs), and antibodies purified by adsorption and elution from sera of HLA immunized individuals. The classification of antibody verification based on different methods for validation is problematic, since not all approaches represent the same level of evidence. In this study, we introduce a classification system to evaluate the level of evidence for the antibody-verified status of all eplets in the HLA Epitope Registry. We demonstrate that for a considerable number of eplets, the antibody-verified status is solely based on polyclonal serum reactivity of multiparous women or on reactivity of murine mAbs. Furthermore, we noted that a substantial proportion of patient sera analyses and human mAb data presented in the HLA Epitope Registry Database has never been published in a peer-reviewed journal. Therefore, we tested several unpublished human HLA-specific mAbs by luminex single antigen beads assay to analyze their HLA reactivity for eplet antibody verification. Although the majority of analyzed mAbs indeed verified their assigned eplets, this was not the case for a number of eplets. This comprehensive overview of evidence for antibody verification of eplets in the HLA Epitope Registry is instrumental for future investigations towards eplet immunogenicity and clinical studies considering antibody-verified eplet mismatch in transplantation and warrants further standardization of antibody verification using high quality data., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bezstarosti, Bakker, Kramer, de Fijter, Reinders, Mulder, Claas and Heidt.)
- Published
- 2022
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7. HLA-DQ-Specific Recombinant Human Monoclonal Antibodies Allow for In-Depth Analysis of HLA-DQ Epitopes.
- Author
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Bezstarosti S, Kramer CSM, Franke-van Dijk MEI, Vergunst M, Bakker KH, Uyar-Mercankaya M, Buchli R, Roelen DL, de Fijter JW, Claas FHJ, and Heidt S
- Subjects
- Antibodies, Monoclonal chemistry, Antibodies, Monoclonal genetics, Epitopes chemistry, Epitopes genetics, HLA-DQ Antigens chemistry, HLA-DQ Antigens genetics, Humans, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins immunology, Antibodies, Monoclonal immunology, Epitopes immunology, HLA-DQ Antigens immunology
- Abstract
HLA-DQ donor-specific antibodies (DSA) are the most prevalent type of DSA after renal transplantation and have been associated with eplet mismatches between donor and recipient HLA. Eplets are theoretically defined configurations of surface exposed amino acids on HLA molecules that require verification to confirm that they can be recognized by alloantibodies and are therefore clinically relevant. In this study, we isolated HLA-DQ specific memory B cells from immunized individuals by using biotinylated HLA-DQ monomers to generate 15 recombinant human HLA-DQ specific monoclonal antibodies (mAb) with six distinct specificities. Single antigen bead reactivity patterns were analyzed with HLA-EMMA to identify amino acids that were uniquely shared by the reactive HLA alleles to define functional epitopes which were mapped to known eplets. The HLA-DQB1*03:01-specific mAb LB_DQB0301_A and the HLA-DQB1*03-specific mAb LB_DQB0303_C supported the antibody-verification of eplets 45EV and 55PP respectively, while mAbs LB_DQB0402_A and LB_DQB0602_B verified eplet 55R on HLA-DQB1*04/05/06. For three mAbs, multiple uniquely shared amino acid configurations were identified, warranting further studies to define the inducing functional epitope and corresponding eplet. Our unique set of HLA-DQ specific mAbs will be further expanded and will facilitate the in-depth analysis of HLA-DQ epitopes, which is relevant for further studies of HLA-DQ alloantibody pathogenicity in transplantation., Competing Interests: RB is employed by Pure Protein LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bezstarosti, Kramer, Franke-van Dijk, Vergunst, Bakker, Uyar-Mercankaya, Buchli, Roelen, de Fijter, Claas and Heidt.)
- Published
- 2022
- Full Text
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8. T-Cell Epitopes Shared Between Immunizing HLA and Donor HLA Associate With Graft Failure After Kidney Transplantation.
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Peereboom ETM, Matern BM, Tomosugi T, Niemann M, Drylewicz J, Joosten I, Allebes WA, van der Meer A, Hilbrands LB, Baas MC, van Reekum FE, Verhaar MC, Kamburova EG, Seelen MAJ, Sanders JS, Hepkema BG, Lambeck AJ, Bungener LB, Roozendaal C, Tilanus MGJ, Voorter CE, Wieten L, van Duijnhoven EM, Gelens MACJ, Christiaans MHL, van Ittersum FJ, Nurmohamed A, Lardy NM, Swelsen W, van der Pant KA, van der Weerd NC, Ten Berge IJM, Bemelman FJ, de Vries APJ, de Fijter JW, Betjes MGH, Roelen DL, Claas FH, Otten HG, Heidt S, van Zuilen AD, Kobayashi T, Geneugelijk K, and Spierings E
- Subjects
- Adult, Aged, Epitopes, T-Lymphocyte genetics, Female, Graft Rejection genetics, Graft vs Host Disease diagnosis, Graft vs Host Disease etiology, Graft vs Host Disease mortality, HLA Antigens genetics, Humans, Male, Middle Aged, Retrospective Studies, T-Lymphocytes metabolism, Tissue Donors, Transplant Recipients, Transplantation, Homologous, Treatment Failure, Young Adult, Epitopes, T-Lymphocyte immunology, Graft Rejection immunology, Graft Survival immunology, HLA Antigens immunology, Kidney Transplantation adverse effects, Kidney Transplantation methods, T-Lymphocytes immunology
- Abstract
CD4
+ T-helper cells play an important role in alloimmune reactions following transplantation by stimulating humoral as well as cellular responses, which might lead to failure of the allograft. CD4+ memory T-helper cells from a previous immunizing event can potentially be reactivated by exposure to HLA mismatches that share T-cell epitopes with the initial immunizing HLA. Consequently, reactivity of CD4+ memory T-helper cells toward T-cell epitopes that are shared between immunizing HLA and donor HLA could increase the risk of alloimmunity following transplantation, thus affecting transplant outcome. In this study, the amount of T-cell epitopes shared between immunizing and donor HLA was used as a surrogate marker to evaluate the effect of donor-reactive CD4+ memory T-helper cells on the 10-year risk of death-censored kidney graft failure in 190 donor/recipient combinations using the PIRCHE-II algorithm. The T-cell epitopes of the initial theoretical immunizing HLA and the donor HLA were estimated and the number of shared PIRCHE-II epitopes was calculated. We show that the natural logarithm-transformed PIRCHE-II overlap score, or Shared T-cell EPitopes (STEP) score, significantly associates with the 10-year risk of death-censored kidney graft failure, suggesting that the presence of pre-transplant donor-reactive CD4+ memory T-helper cells might be a strong indicator for the risk of graft failure following kidney transplantation., Competing Interests: The authors of this manuscript have conflicts of interest to disclose. The UMC Utrecht has filed a patent application on the prediction of an alloimmune response against mismatched HLA. ES is listed as inventor on this patent. MN is employed by PIRCHE AG, which publishes the PIRCHE web-portal. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Peereboom, Matern, Tomosugi, Niemann, Drylewicz, Joosten, Allebes, van der Meer, Hilbrands, Baas, van Reekum, Verhaar, Kamburova, Seelen, Sanders, Hepkema, Lambeck, Bungener, Roozendaal, Tilanus, Voorter, Wieten, van Duijnhoven, Gelens, Christiaans, van Ittersum, Nurmohamed, Lardy, Swelsen, van der Pant, van der Weerd, ten Berge, Bemelman, de Vries, de Fijter, Betjes, Roelen, Claas, Otten, Heidt, van Zuilen, Kobayashi, Geneugelijk and Spierings.)- Published
- 2021
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9. Highly Sensitized Patients Are Well Served by Receiving a Compatible Organ Offer Based on Acceptable Mismatches.
- Author
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Heidt S, Haasnoot GW, van der Linden-van Oevelen MJH, and Claas FHJ
- Subjects
- Graft Rejection immunology, Humans, Predictive Value of Tests, Risk Assessment, Risk Factors, Treatment Outcome, Donor Selection, Graft Rejection prevention & control, Graft Survival, HLA Antigens immunology, Histocompatibility, Histocompatibility Testing, Isoantibodies blood, Kidney Transplantation adverse effects
- Abstract
Highly sensitized kidney patients accrue on the transplant waiting list due to their broad immunization against non-self Human Leucocyte Antigens (HLA). Although challenging, the best option for highly sensitized patients is transplantation with a crossmatch negative donor without any additional therapeutic intervention. The Eurotransplant Acceptable Mismatch (AM) program was initiated more than 30 years ago with the intention to increase the chance for highly sensitized patients to be transplanted with such a compatible donor. The AM program allows for enhanced transplantation to this difficult to transplant patient group by allocating deceased donor kidneys on the basis of a match with the recipient's own HLA antigens in combination with predefined acceptable antigens. Acceptable antigens are those HLA antigens towards which the patients has never formed antibodies, as determined by extensive laboratory testing. By using this extended HLA phenotype for allocation and giving priority whenever a compatible donor organ becomes available, organ offers are made for roughly 80% of patients in this program. Up till now, more than 1700 highly sensitized patients have been transplanted through the AM program. Recent studies have shown that the concept of acceptable mismatches being truly immunologically acceptable holds true for both rejection rates and long-term graft survival. Patients that were transplanted through the AM program had a similar rejection incidence and long-term graft survival rates identical to non-sensitized patients transplanted through regular allocation. However, a subset of patients included in the AM program does not receive an organ offer within a reasonable time frame. As these are often patients with a rare HLA phenotype in comparison to the Eurotransplant donor population, extension of the donor pool for these specific patients through further European collaboration would significantly increase their chances of being transplanted. For those patients that will not benefit from such strategy, desensitization is the ultimate solution., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Heidt, Haasnoot, van der Linden-van Oevelen and Claas.)
- Published
- 2021
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10. Visualizing Dynamic Changes at the Maternal-Fetal Interface Throughout Human Pregnancy by Mass Cytometry.
- Author
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van der Zwan A, van Unen V, Beyrend G, Laban S, van der Keur C, Kapsenberg HJM, Höllt T, Chuva de Sousa Lopes SM, van der Hoorn MP, Koning F, Claas FHJ, Eikmans M, and Heidt S
- Subjects
- Adult, Cells, Cultured, Cellular Microenvironment, Female, Flow Cytometry, Humans, Immune Tolerance, Immunophenotyping, Decidua immunology, Leukocytes immunology, Lymphocytes immunology, Perinatology methods, Placenta immunology, Pregnancy, Pregnancy Complications immunology
- Abstract
During healthy pregnancy, a balanced microenvironment at the maternal-fetal interface with coordinated interaction between various immune cells is necessary to maintain immunological tolerance. While specific decidual immune cell subsets have been investigated, a system-wide unbiased approach is lacking. Here, mass cytometry was applied for data-driven, in-depth immune profiling of the total leukocyte population isolated from first, second, and third trimester decidua, as well as maternal peripheral blood at time of delivery. The maternal-fetal interface showed a unique composition of immune cells, different from peripheral blood, with significant differences between early and term pregnancy samples. Profiling revealed substantial heterogeneity in the decidual lymphoid and myeloid cell lineages that shape gestational-specific immune networks and putative differentiation trajectories over time during gestation. Uncovering the overall complexity at the maternal-fetal interface throughout pregnancy resulted in a human atlas that may serve as a foundation upon which comprehension of the immune microenvironment and alterations thereof in pregnancy complications can be built., (Copyright © 2020 van der Zwan, van Unen, Beyrend, Laban, van der Keur, Kapsenberg, Höllt, Chuva de Sousa Lopes, van der Hoorn, Koning, Claas, Eikmans and Heidt.)
- Published
- 2020
- Full Text
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11. Regulatory T Cells in Pregnancy: It Is Not All About FoxP3.
- Author
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Krop J, Heidt S, Claas FHJ, and Eikmans M
- Subjects
- Animals, Female, Humans, Forkhead Transcription Factors immunology, Immune Tolerance immunology, Pregnancy immunology, T-Lymphocyte Subsets immunology, T-Lymphocytes, Regulatory immunology
- Abstract
In pregnancy, the semi-allogeneic fetus needs to be tolerated by the mother's immune system. Regulatory T cells (Tregs) play a prominent role in this process. Novel technologies allow for in-depth phenotyping of previously unidentified immune cell subsets, which has resulted in the appreciation of a vast heterogeneity of Treg subsets. Similar to other immunological events, there appears to be great diversity within the Treg population during pregnancy, both at the maternal-fetal interface as in the peripheral blood. Different Treg subsets have distinct phenotypes and various ways of functioning. Furthermore, the frequency of individual Treg subsets varies throughout gestation and is altered in aberrant pregnancies. This suggests that distinct Treg subsets play a role at different time points of gestation and that their role in maintaining healthy pregnancy is crucial, as reflected for instance by their reduced frequency in women with recurrent pregnancy loss. Since pregnancy is essential for the existence of mankind, multiple immune regulatory mechanisms and cell types are likely at play to assure successful pregnancy. Therefore, it is important to understand the complete microenvironment of the decidua, preferably in the context of the whole immune cell repertoire of the pregnant woman. So far, most studies have focused on a single mechanism or cell type, which often is the FoxP3 positive regulatory T cell when studying immune regulation. In this review, we instead focus on the contribution of FoxP3 negative Treg subsets to the decidual microenvironment and their possible role in pregnancy complications. Their phenotype, function, and effect in pregnancy are discussed., (Copyright © 2020 Krop, Heidt, Claas and Eikmans.)
- Published
- 2020
- Full Text
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12. Development and Validation of a Multiplex Non-HLA Antibody Assay for the Screening of Kidney Transplant Recipients.
- Author
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Kamburova EG, Kardol-Hoefnagel T, Wisse BW, Joosten I, Allebes WA, van der Meer A, Hilbrands LB, Baas MC, Spierings E, Hack CE, van Reekum FE, van Zuilen AD, Verhaar MC, Bots ML, Drop ACAD, Plaisier L, Meeldijk J, Bovenschen N, Seelen MAJ, Sanders JS, Hepkema BG, Lambeck AJA, Bungener LB, Roozendaal C, Tilanus MGJ, Voorter CE, Wieten L, van Duijnhoven EM, Gelens MACJ, Christiaans MHL, van Ittersum FJ, Nurmohamed SA, Lardy NM, Swelsen W, van der Pant KAMI, van der Weerd NC, Ten Berge IJM, Bemelman FJ, van der Boog PJM, de Fijter JW, Betjes MGH, Heidt S, Roelen DL, Claas FH, and Otten HG
- Subjects
- Allografts immunology, Graft Rejection blood, Graft Rejection immunology, Graft Survival immunology, Humans, Isoantibodies immunology, Isoantigens immunology, Kidney immunology, Kidney Failure, Chronic surgery, Transplant Recipients, Graft Rejection diagnosis, High-Throughput Screening Assays methods, Histocompatibility Testing methods, Isoantibodies blood, Kidney Transplantation adverse effects
- Abstract
The best treatment for patients with end-stage renal disease is kidney transplantation. Although graft survival rates have improved in the last decades, patients still may lose their grafts partly due to the detrimental effects of donor-specific antibodies (DSA) against human leukocyte antigens (HLA) and to a lesser extent also by antibodies directed against non-HLA antigens expressed on the donor endothelium. Assays to detect anti-HLA antibodies are already in use for many years and have been proven useful for transplant risk stratification. Currently, there is a need for assays to additionally detect multiple non-HLA antibodies simultaneously in order to study their clinical relevance in solid organ transplantation. This study describes the development, technical details and validation of a high-throughput multiplex assay for the detection of antibodies against 14 non-HLA antigens coupled directly to MagPlex microspheres or indirectly via a HaloTag. The non-HLA antigens have been selected based on a literature search in patients with kidney disease or following transplantation. Due to the flexibility of the assay, this approach can be used to include alternative antigens and can also be used for screening of other organ transplant recipients, such as heart and lung.
- Published
- 2018
- Full Text
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13. Cross-Reactivity of Virus-Specific CD8+ T Cells Against Allogeneic HLA-C: Possible Implications for Pregnancy Outcome.
- Author
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van der Zwan A, van der Meer-Prins EMW, van Miert PPMC, van den Heuvel H, Anholts JDH, Roelen DL, Claas FHJ, and Heidt S
- Subjects
- CD8-Positive T-Lymphocytes metabolism, Cell Line, Cross Reactions, Decidua cytology, Female, HLA-C Antigens metabolism, Humans, Immunoglobulin G immunology, Immunoglobulin G metabolism, Isoantibodies immunology, Isoantibodies metabolism, Pregnancy, Pregnancy Outcome, Trophoblasts immunology, Trophoblasts metabolism, Viruses immunology, CD8-Positive T-Lymphocytes immunology, Decidua immunology, HLA-C Antigens immunology, Isoantigens immunology, Maternal-Fetal Exchange immunology
- Abstract
Heterologous immunity of virus-specific T cells poses a potential barrier to transplantation tolerance. Cross-reactivity to HLA-A and -B molecules has broadly been described, whereas responses to allo-HLA-C have remained ill defined. In contrast to the transplant setting, HLA-C is the only polymorphic HLA molecule expressed by extravillous trophoblasts at the maternal-fetal interface during pregnancy. Uncontrolled placental viral infections, accompanied by a pro-inflammatory milieu, can alter the activation status and stability of effector T cells. Potential cross-reactivity of maternal decidual virus-specific T cells to fetal allo-HLA-C may thereby have detrimental consequences for the success of pregnancy. To explore the presence of cross-reactivity to HLA-C and the other non-classical HLA antigens expressed by trophoblasts, HLA-A and -B-restricted CD8+ T cells specific for Epstein-Barr virus, Cytomegalovirus, Varicella-Zoster virus, and Influenza virus were tested against target cells expressing HLA-C, -E, and -G molecules. An HLA-B
* 08:01-restricted EBV-specific T cell clone displayed cross-reactivity against HLA-C* 01:02. Furthermore, cross-reactivity of HLA-C-restricted virus-specific CD8+ T cells was observed for HCMV HLA-C* 06:02/TRA CD8+ T cell lines and clones against HLA-C* 03:02. Collectively, these results demonstrate that cross-reactivity against HLA-C can occur and thereby may affect pregnancy outcome.- Published
- 2018
- Full Text
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14. PIRCHE-II Is Related to Graft Failure after Kidney Transplantation.
- Author
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Geneugelijk K, Niemann M, Drylewicz J, van Zuilen AD, Joosten I, Allebes WA, van der Meer A, Hilbrands LB, Baas MC, Hack CE, van Reekum FE, Verhaar MC, Kamburova EG, Bots ML, Seelen MAJ, Sanders JS, Hepkema BG, Lambeck AJ, Bungener LB, Roozendaal C, Tilanus MGJ, Vanderlocht J, Voorter CE, Wieten L, van Duijnhoven EM, Gelens M, Christiaans MHL, van Ittersum FJ, Nurmohamed A, Lardy JNM, Swelsen W, van der Pant KA, van der Weerd NC, Ten Berge IJM, Bemelman FJ, Hoitsma A, van der Boog PJM, de Fijter JW, Betjes MGH, Heidt S, Roelen DL, Claas FH, Otten HG, and Spierings E
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Donor Selection, Female, Graft Rejection immunology, Graft Rejection pathology, Humans, Male, Middle Aged, Netherlands epidemiology, Retrospective Studies, Risk Factors, Tissue Donors, Graft Rejection epidemiology, Graft Survival immunology, HLA Antigens immunology, Histocompatibility Testing, Kidney Transplantation
- Abstract
Individual HLA mismatches may differentially impact graft survival after kidney transplantation. Therefore, there is a need for a reliable tool to define permissible HLA mismatches in kidney transplantation. We previously demonstrated that donor-derived Predicted Indirectly ReCognizable HLA Epitopes presented by recipient HLA class II (PIRCHE-II) play a role in de novo donor-specific HLA antibodies formation after kidney transplantation. In the present Dutch multi-center study, we evaluated the possible association between PIRCHE-II and kidney graft failure in 2,918 donor-recipient couples that were transplanted between 1995 and 2005. For these donors-recipients couples, PIRCHE-II numbers were related to graft survival in univariate and multivariable analyses. Adjusted for confounders, the natural logarithm of PIRCHE-II was associated with a higher risk for graft failure [hazard ratio (HR): 1.13, 95% CI: 1.04-1.23, p = 0.003]. When analyzing a subgroup of patients who had their first transplantation, the HR of graft failure for ln(PIRCHE-II) was higher compared with the overall cohort (HR: 1.22, 95% CI: 1.10-1.34, p < 0.001). PIRCHE-II demonstrated both early and late effects on graft failure in this subgroup. These data suggest that the PIRCHE-II may impact graft survival after kidney transplantation. Inclusion of PIRCHE-II in donor-selection criteria may eventually lead to an improved kidney graft survival.
- Published
- 2018
- Full Text
- View/download PDF
15. B Cell Immunity in Solid Organ Transplantation.
- Author
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Karahan GE, Claas FH, and Heidt S
- Abstract
The contribution of B cells to alloimmune responses is gradually being understood in more detail. We now know that B cells can perpetuate alloimmune responses in multiple ways: (i) differentiation into antibody-producing plasma cells; (ii) sustaining long-term humoral immune memory; (iii) serving as antigen-presenting cells; (iv) organizing the formation of tertiary lymphoid organs; and (v) secreting pro- as well as anti-inflammatory cytokines. The cross-talk between B cells and T cells in the course of immune responses forms the basis of these diverse functions. In the setting of organ transplantation, focus has gradually shifted from T cells to B cells, with an increased notion that B cells are more than mere precursors of antibody-producing plasma cells. In this review, we discuss the various roles of B cells in the generation of alloimmune responses beyond antibody production, as well as possibilities to specifically interfere with B cell activation.
- Published
- 2017
- Full Text
- View/download PDF
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