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Considering recent clinical and experimental evidence, expectations for using DCDderived intestines have increased considerably. However, more knowledge about DCD procedure and long-term results after intestinal transplantation (ITx) is needed. We aimed to describe in detail a DCD procedure for ITx using normothermic regional perfusion (NRP) in a preclinical model. Small bowel was obtained from pigs donors after 1 h of NRP and transplanted to the recipients. Graft Intestinal samples were obtained during the procedure and after transplantation. Ischemia-reperfusion injury (Park-Chiu score), graft rejection and transplanted intestines absorptive function were evaluated. Seven of 8 DCD procedures with NRP and ITx were successful (87.5%), with a good graft reperfusion and an excellent recovery of the recipient. The architecture of grafts was well conserved during NRP. After an initial damage of Park-chiu score of 4, all grafts recovered from ischemia-reperfusion, with no or very subtle alterations 2 days after ITx. Most recipients (71.5%) did not show signs of rejection. Only two cases demonstrated histologic signs of mild rejection 7 days after ITx. Interestingly intestinal grafts showed good absorptive capacity. The study's results support the viability of intestinal grafts from DCD using NRP, contributing more evidence for the use of DCD for ITx. [ABSTRACT FROM AUTHOR]

Summary: To review our experience using sirolimus in a single centre paediatric intestinal transplantation cohort. Intestinal transplant patients with more than 3 months follow‐up were divided into two groups according to their immunosuppression regimen: tacrolimus, (TAC group, n = 45 grafts) or sirolimus (SRL group, n = 38 grafts), which included those partially or completely converted from tacrolimus to sirolimus. The indications to switch were tacrolimus side effects and immunological complications. Survival and complications were retrospectively analysed comparing both groups. SRL was introduced 9 months (0 months–16.9 years) after transplant. The main cause for conversion was worsening renal function (45%), followed by haemolytic anaemia (21%) and graft‐versus‐host‐disease (16%). Both groups showed a similar overall patient/graft survival (P = 0.76/0.08) and occurrence of rejection (24%/17%, P = 0.36). Immunological complications did not recur after conversion. Renal function significantly improved in most SRL patients. After a median follow‐up of 65.17 months, 28/46 survivors were on SRL, 26 with monotherapy, with good graft function. Over one‐third of our patients eventually required SRL conversion that allowed to improve their kidney function and immunological events, without entailing additional complications or survival impairment. Further trials are warranted to clarify the potential improvement of the standard tacrolimus maintenance by sirolimus conversion or addition. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stromal cells (MSC) have been proposed as a promising complement to standard immunosuppression in solid organ transplantation because of their immunomodulatory properties. The present work addresses the role of adipose‐derived MSC (Ad‐MSC) in an experimental model of acute rejection in small bowel transplantation (SBT). Material/Methods: Heterotopic allogeneic SBT was performed. A single dose of 1.5x106 Ad‐MSC was intra‐arterially delivered just before graft reperfusion. Animals were divided into CONTROL (CTRL), CONTROL+Ad‐MSC (CTRL_MSC), tacrolimus (TAC), and TAC+Ad‐MSC (TAC_MSC) groups. Each Ad‐MSC groups was subdivided in autologous and allogeneic third‐party groups. Results: Rejection rate and severity were similar in MSC‐treated and untreated animals. CTRL_MSC animals showed a decrease in macrophages, T‐cell (CD4, CD8, and Foxp3 subsets) and B‐cell counts in the graft compared with CTRL, this decrease was attenuated in TAC_MSC animals. Pro‐ and anti‐inflammatory cytokines and some chemokines and growth factors increased in CTRL_MSC animals, especially in the allogeneic group, whereas milder changes were seen in the TAC groups. Conclusion: Ad‐MSC did not prevent rejection when administered just before reperfusion. However, they showed immunomodulatory effects that could be relevant for a longer‐term outcome. Interference between tacrolimus and the MSC effects should be addressed in further studies. [ABSTRACT FROM AUTHOR]

More experience needs to be accumulated in order to conclude whether transplanted patients represent or not a group of risk for SARS-CoV-2 infection and determine the best way to handle immunosuppression treatment. Novel coronavirus (SARS-CoV-2) infection in a patient with multivisceral transplant To the Editor, Coronavirus disease 2019 (COVID-19) pandemic has become one of the most challenging episodes in the history of modern public health, with particular emphasis in high-risk population.1 However, the evidence regarding their response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent responsible for COVID-19 is scant.2 Herein, we present the clinical and therapeutic course of a SARS-CoV-2 infection in a patient with multivisceral transplant and a recent tuberculosis infection. [Extracted from the article]

Summary: Intestinal grafts carry large donor lymphoid load that is replaced by recipient cells. The dynamics of this process may influence the tolerance, rejection or graft‐versus‐host disease. We analysed distribution and turnover of T and B (Lin+) lymphocytes, natural killer (NK) and helper innate lymphoid cells (hILC) in intestinal epithelium (IEp) and lamina propia (LP) from a long‐term cohort of eight intestinal recipients and from a single patient monitored deeply during the first 8 months post‐transplant (posTx). Long‐term intestinal grafts showed significantly higher %hILC than native bowels in IEp and LP until 10 years posTx and recovery to normal levels was observed afterwards. We also observed an imbalance between hILC subsets in IEp [increase of type 1 (ILC1) and decrease in type 3 (ILC3) innate lymphoid cells] that persisted along posTx time even when %hILC was similar to native bowels. Regarding hILC origin, we still detected the presence of donor cells at 13 years posTx. However, this chimerism was significantly lower than in Lin+ and NK populations. According to these findings, observation from the patient monitored in early posTx period showed that recipient hILC repopulate earlier and faster than Lin+ cells, with increase in ILC1 related to rejection and infection episodes. [ABSTRACT FROM AUTHOR]

Summary: In transplanted intestines, depletion of T cells together with long‐term persistence of ILC is observed, suggesting ILC insensitivity to immunosuppressive drugs. To further analyze helper ILC (hILC) apparent resistance to therapy, cytotoxic ILC (NK cells), hILC subsets (ILC1, ILC2, and ILC precursors (ILCP)), and their signature cytokines (IFNγ, IL4 + IL13, and IL22) were analyzed in peripheral blood of kidney and liver transplant recipients. Early after transplantation (posTx), transplanted patients showed significantly lower Lin + and NK cells, whereas total hILC, ILC1, ILC2, and ILCP numbers were similar in patients and controls. Between paired pre‐ and posTx samples, Lin + cell and NK cell counts significantly decreased, whereas all three hILC counts and their cytokine production remained similar. ILC1, ILC2, and ILCP numbers were also similar in patients under thymoglobulin or basiliximab (BAS), patients without induction (only maintenance therapy) and controls. hILC showed lower TMG binding comparing to Lin + cells, reduced expression of CD25 (BAS target), and diminished calcineurin activity with undetectable calcineurin and FKBP12 (tacrolimus target). hILC counts were not related to delayed graft function or biopsy‐proven acute rejection. Thus, hILC remain stable early after transplantation and seem unaffected by immunosuppressors, which may be related to reduced targets expression and low calcineurin activity. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) has rapidly become a global pandemic. Because the severity of the disease is highly variable, predictive models to stratify patients according to their mortality risk are needed. Our aim was to develop a model able to predict the risk of fatal outcome in patients with COVID-19 that could be used easily at the time of patients' arrival at the hospital. We constructed a prospective cohort with 611 adult patients in whom COVID-19 was diagnosed between March 10 and April 12, 2020, in a tertiary hospital in Madrid, Spain. The analysis included 501 patients who had been discharged or had died by April 20, 2020. The capacity of several biomarkers, measured at the beginning of hospitalization, to predict mortality was assessed individually. Those biomarkers that independently contributed to improve mortality prediction were included in a multivariable risk model. High IL-6 level, C-reactive protein level, lactate dehydrogenase (LDH) level, ferritin level, d -dimer level, neutrophil count, and neutrophil-to-lymphocyte ratio were all predictive of mortality (area under the curve >0.70), as were low albumin level, lymphocyte count, monocyte count, and ratio of peripheral blood oxygen saturation to fraction of inspired oxygen (SpO 2 /FiO 2). A multivariable mortality risk model including the SpO 2 /FiO 2 ratio, neutrophil-to-lymphocyte ratio, LDH level, IL-6 level, and age was developed and showed high accuracy for the prediction of fatal outcome (area under the curve 0.94). The optimal cutoff reliably classified patients (including patients with no initial respiratory distress) as survivors and nonsurvivors with 0.88 sensitivity and 0.89 specificity. This mortality risk model allows early risk stratification of hospitalized patients with COVID-19 before the appearance of obvious signs of clinical deterioration, and it can be used as a tool to guide clinical decision making. [ABSTRACT FROM AUTHOR]

The aim of this study was to find noninvasive T-cell markers able to predict rejection or infection risk after kidney transplantation. We prospectively examined T-lymphocyte subsets after cell culture stimulation (according to CD38, CD69, CD95, CD40L, and CD25 expression) in 79 first graft recipients from four centers, before and after transplantation. Patients were followed up for one year. Patients who rejected within month-1 (n = 10) showed high pre-transplantation and week-1 post-transplantation percentages of CD95 + , in CD4 + and CD8 + T-cells ( P < 0.001 for all comparisons). These biomarkers conferred independent risk for early rejection (HR:5.05, P = 0.061 and HR:75.31, P = 0.004; respectively). The cut-off values were able to accurately discriminate between rejectors and non-rejectors and Kaplan–Meier curves showed significantly different free-of-rejection time rates ( P < 0.005). Patients who rejected after the month-1 (n = 4) had a higher percentage of post-transplantation CD69 + in CD8 + T-cells than non-rejectors ( P = 0.002). Finally, patients with infection (n = 41) previously showed higher percentage of CD38 + in CD8 + T-cells at all post-transplantation times evaluated, being this increase more marked in viral infections. A cut-off of 59% CD38 + in CD8 + T-cells at week-1, week-2 and month-2 reached 100% sensitivity for the detection of subsequent viral infections. In conclusion, predictive biomarkers of rejection and infection risk after transplantation were detected that could be useful for the personalized care of kidney recipients. [ABSTRACT FROM AUTHOR]

Background: Donor-specific anti-HLA antibodies (DSA) impact negatively on the outcome of intestinal grafts. Although the use of antibody-removal therapies (ART) is becoming more frequent in the last few years, issues regarding their timing and effectiveness remain under discussion., Methods: In the present study, we report our experience with eight ART procedures (based on plasmapheresis, intravenous immunoglobulin, and rituximab) in eight pediatric intestinal and multivisceral transplants with de novo DSA (dnDSA)., Results: ART were performed when dnDSA appeared in two contexts: (1) concomitant with rejection (acute or chronic) or (2) without rejection or any other clinical symptom. Complete DSA removal was observed in seven out of eight patients, showing an effectiveness of 88%. In the group treated for dnDSA without clinical symptoms, the success rate was 100%, with complete DSA removal and without rejection afterward. A shorter time between DSA detection and ART performance appeared as a significant factor for the success of the therapy ( p  = 0.0002). DSA against HLA-A and DQ alleles were the most resistant to ART, whereas anti-DR DSA were the most sensitive. In addition, the 8-year allograft survival rate in recipients undergoing ART was similar to that in those without DSA, being significantly lower in non-treated DSA-positive recipients ( p  = 0.013)., Conclusion: The results confirm the effectiveness of ART in terms of DSA removal and allograft survival and encourage its early use even in the absence of clinical symptoms., 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., (© 2023 Lasa-Lázaro, Ramos-Boluda, Mancebo, Castro-Panete, González-Sacristán, Serradilla, Andrés-Moreno, Hernández Oliveros, Paz-Artal and Talayero.)

There is an urgent need to address the shortage of potential multivisceral grafts in order to reduce the average time in waiting list. Since donation after circulatory death (DCD) has been successfully employed for other solid organs, a thorough evaluation of the use of intestinal grafts from DCD is warranted. Here, we have generated a model of Maastricht III DCD in rodents, focusing on the viability of intestinal and multivisceral grafts at five (DCD5) and twenty (DCD20) minutes of cardiac arrest compared to living and brain death donors. DCD groups exhibited time-dependent damage. DCD20 generated substantial intestinal mucosal injury and decreased number of Goblet cells whereas grafts from DCD5 closely resemble those of brain death and living donors groups in terms intestinal morphology, expression of tight junction proteins and number of Paneth and Globet cells. Upon transplantation, intestines from DCD5 showed increased ischemia/reperfusion damage compared to living donor grafts, however mucosal integrity was recovered 48 h after transplantation. No differences in terms of graft rejection, gene expression and absorptive function between DCD5 and living donor were observed at 7 post-transplant days. Collectively, our results highlight DCD as a possible strategy to increase multivisceral donation and transplantation procedures., 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 Stringa, Vecchio Dezillio, Talayero, Serradilla, Errea, Machuca, Papa-Gobbi, Camps Ortega, Pucci Molineris, Lausada, Andres Moreno, Rumbo and Hernández Oliveros.)

Background: Prognostic biomarkers of acute rejection (AR) in solid organ transplantation have been addressed in multiple small retrospective studies, and there is a critical need for multicenter studies. Because of their tolerogenic properties, regulatory T cells (Tregs) play an important role in transplant outcome., Methods: In the present multicenter study, we have retrospectively examined different Treg subpopulations in an independent cohort of kidney transplant patients within first year after kidney transplantation. All participating centers used identical flow cytometry standard operating procedures., Results: Seventy-five renal transplant patients were included, and six of them experienced an AR episode. The activated Treg (aTreg) subpopulation (CD4CD25CD62LCD45RO) was increased in the AR group before transplantation, and an aTreg percentage higher than 1.46% before kidney transplantation conferred an increased risk of AR. The univariate logistic regression model achieved an area under the curve of 81.6%. By including recipient age and thymoglobulin induction as variables in a multivariate logistic regression model, the prediction of AR improved to 92.4%., Conclusion: The evaluation of CD4CD25CD62LCD45RO aTreg cells may be useful as pretransplantation predictive biomarker of AR in kidney transplant patients. Definitive confirmation of our results awaits tests in validation groups.

Background: Human CD8 immunodeficiency is characterized by undetectable CD8(+) lymphocytes and an increased population of CD4(-)CD8(-) (double negative) T lymphocytes., Design and Methods: We hypothesized that the double negative subset corresponds to the cellular population that should express CD8 and is committed to the cytotoxic T lymphocyte lineage. To assess this, we determined the phenotype and function of peripheral blood mononuclear cells and/or magnetically isolated double negative T lymphocytes from two CD8-deficient patients. To analyze the expression and co-localization with different organelles, 293T cells were transfected with plasmids bearing wild-type or mutated CD8α., Results: CD8α mutated protein was retained in the cytoplasm of transfected cells. The percentages of double negative cells in patients were lower than the percentages of CD8(+) T cells in healthy controls. Double negative cells mostly had an effector or effector memory phenotype whereas naïve T cells were under-represented. A low concentration of T-cell receptor excision circles together with a skewed T-cell receptor-V repertoire were observed in the double negative population. These data suggest that, in the absence of CD8 co-receptor, the thymic positive selection functions suboptimally and a limited number of mature T-cell clones would emerge from the thymus. In vitro, the double negative cells showed a mild defect in cytotoxic function and decreased proliferative capacity., Conclusions: It is possible that the double negative cells are major histocompatibility complex class-I restricted T cells with cytolytic function. These results show for the first time in humans that the presence of the CD8 co-receptor is dispensable for cytotoxic ability, but that it affects the generation of thymic precursors committed to the cytotoxic T lymphocyte lineage and the proliferation of mature cytotoxic T cells.