Anti-C4d chimeric antigen receptor regulatory T cells suppressed allograft rejection in ABO-incompatible heart transplantation.
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ABSTRACT:
SUBMITTER: Lee SK
PROVIDER: S-EPMC8720693 | biostudies-literature | 2022 Jan
REPOSITORIES: biostudies-literature
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Anti-C4d chimeric antigen receptor regulatory T cells suppressed allograft rejection in ABO-incompatible heart transplantation.
Lee Sun-Kyung SK Han Jerome J Piao Honglin H Shin Nara N Jang Joon Young JY Yan Ji-Jing JJ Kim Hyori H Chung Junho J Yang Jaeseok J
Genes & diseases 20210728 1
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Project description:Isohemagglutinin assays employing red blood cells (RBCs) are the most common assays used to measure antibody titer in ABO-incompatible kidney transplantation (ABOi KTx). However, ABO antigens expressed on RBCs are not identical to those of kidney and antibody titers do not always correlate with clinical outcome. We previously reported that CD31 was the main protein linked to ABO antigens on kidney endothelial cells (KECs), which was different from those on RBCs. We developed a new method to measure antibody titer using a microarray of recombinant CD31 (rCD31) linked to ABO antigens (CD31-ABO microarray). Mass spectrometry analysis suggested that rCD31 and native CD31 purified from human kidney had similar ABO glycan. To confirm clinical use of CD31-ABO microarray, a total of 252 plasma samples including volunteers, hemodialysis patients, and transplant recipients were examined. In transplant recipients, any initial IgG or IgM antibody intensity >30,000 against the donor blood type in the CD31-ABO microarray showed higher sensitivity, specificity, positive predictive value, and negative predictive value of AABMR, compared to isohemagglutinin assays. Use of a CD31-ABO microarray to determine antibody titer specifically against ABO antigens expressed on KECs will contribute to precisely predicting AABMR or preventing over immunosuppression following ABOi KTx.
| S-EPMC8985549 | biostudies-literature
Project description:ABO-incompatible (ABOi) kidney transplantation has long been considered a contraindication to successful kidney transplantation. During the last 25 years, increasing organ shortage enforced the development of strategies to overcome the ABO antibody barrier. In the meantime, ABOi kidney transplantation has become a routine procedure with death-censored graft survival rates comparable to the rates in compatible transplantations. Desensitization is usually achieved by apheresis and B cell-depleting therapies that are accompanied by powerful immunosuppression. Anti-A/B antibodies are aimed to be below a certain threshold at the time of ABOi kidney transplantation and during the first 2 weeks after surgery. Thereafter, even a rebound of anti-A/B antibodies does not appear to harm the kidney transplant, a phenomenon that is called accommodation, but is poorly understood. There is still concern, however, that infectious complications such as viral disease, Pneumocystis jirovecii pneumonia, and severe urinary tract infections are increased after ABOi transplantations. Recent data from the Collaborative Transplant Study show that during the first year after kidney transplantation, one additional patient death from an infectious complication occurs in 100 ABOi kidney transplant recipients. Herein, we review the recent evidence on ABOi kidney transplantation with a focus on desensitization strategies and respective outcomes.
| S-EPMC5338156 | biostudies-literature
Project description:ABO-incompatible transplantation has been successfully performed in the kidney and liver. However, lungs are subject to strong rejection and are vulnerable to infection because they are directly exposed to air. Therefore, lung transplantation from organs with incompatible blood types has been considered a significant challenge. Due to the severe shortage of donors, ABO-incompatible lung transplantation might be a viable method to save critically ill patients with end-stage respiratory diseases. Herein, we review the worldwide published reports about both minor and major ABO-incompatible lung transplantations. In North America, major ABO-incompatible lung transplants have been performed in cases with clerical errors in blood typing. But they were successful with additional treatments following the protocol for ABO-incompatible transplants in other organs (multiple plasma exchanges and additional immunosuppressive therapy such as anti-thymocyte globulin administration). In Japan, major ABO-incompatible living-donor lobar lung transplantations have also been performed successfully when the recipient does not have an ABO antibody against the donor. This unique situation sometimes occurs when the recipient undergoes hematopoietic stem cell transplantation before lung transplantation, in which the recipient's blood type changes after hematopoietic stem cell transplantation. One infant and one adult had successful intentional major ABO-incompatible lung transplantation with both induction therapy and aggressive maintenance antibody-depletion therapy. Furthermore, an experimental antibody-depletion study has also been conducted to overcome ABO incompatibility. Even though intentional major ABO-incompatible lung transplantation has rarely been performed, several significant pieces of evidence have been accumulated to prepare for ABO-incompatible lung transplantation in selected cases. In the future, this challenge can potentially expand the donor organ pool and lead to improvements in the fairness of organ allocation.
| S-EPMC10323570 | biostudies-literature
Project description:BackgroundABO incompatible kidney transplantation (ABOi-KT) is an important approach for overcoming donor shortages. We evaluated the effect of ABOi-KT on living donor KT.MethodsTwo nationwide transplantation databases were used. We evaluated the impact of ABOi-KT on overall living donor transplant activity and spousal donation as subgroup analysis. In addition, we compared the clinical outcome between ABOi-KT and ABO compatible KT (ABOc-KT) from spousal donor, and performed a Cox proportional hazards regression analysis to define the risk factors affecting the allograft outcomes.ResultThe introduction of ABOi-KT increased overall living donor KT by 12.2% and its portion was increased from 0.3% to 21.7% during study period. The ABOi-KT in living unrelated KT was two times higher than that of living related donor KT (17.8 vs.9.8%). Spousal donor was a major portion of living unrelated KT (77.6%) and ABOi-KT increased spousal donation from 10% to 31.5% in living donor KT. In addition, increasing rate ABOi-KT from spousal donor was 10 times higher than that of living related donor. The clinical outcome (incidence of acute rejection, allograft function, and allograft and patient survival rates) of ABOi-KT from spousal donor was comparable to that of ABOc-KT. Neither ABO incompatibility nor spousal donor was associated with acute rejection or allograft failure on multivariate analysis.ConclusionsABOi-KT increased overall living donor KT, and ABOi-KT from spousal donor is rapidly increasing with favorable clinical outcomes.
| S-EPMC5360260 | biostudies-literature
Project description:IntroductionThe aim of this study was to analyze the results after pediatric heart transplantation (pHTx) at our single center differentiating between ABO-incompatible (ABOi) and -compatible (ABOc) procedures.Methods and patientsWe retrospectively analyzed outcomes of ABO-incompatible HTx procedures performed at our center and compared the data to ABO-compatible HTx of the same era. Eighteen children (<17 months) underwent pediatric HTx and seven of them underwent ABO-incompatible HTx between 2003 and 2015.ResultsMechanical circulatory support as bridge to transplant was necessary in 3/7 patients before ABO-incompatible HTx and in 3/11 patients before ABO-compatible HTx. Mean waiting time on the list was 36 ± 30 days for ABO-incompatible HTx and 86 ± 65 days for ABO-compatible HTx. The 5-years re-transplant free survival was 86% following ABO-incompatible and 91% after ABO-compatible. In the cohort undergoing ABO-incompatible HTx, 2 patients showed an acute cellular rejection, while early graft failure was not observed. In the cohort undergoing ABOcompatible HTx, acute cellular rejection was observed in 9/11 patients, with early graft failure occurring in nine and CVP in two. A total of ten children were listed for ABO-incompatible HTx after 2015; however, all ten underwent an ABO-compatible transplantation.DiscussionThis study adds much needed information to the literature on ABOi-HTx by showing with a retrospective single center analysis that it is safe and leads to shorter waiting times. We conclude that strategies for ABOi-HTx should be elaborated further, potentially allowing more timely transplantation and thereby preventing waiting list complications such as the need for mechanical circulatory support and even death.
| S-EPMC11499225 | biostudies-literature
Project description:BackgroundEndothelial cells are vital in the transplant immune system as semiprofessional antigen-presenting cells. Few studies have investigated the importance of anti-endothelin subtype A receptor (ETAR) antibodies in kidney transplantation. Here, we aimed to analyze the association between anti-angiotensin II type I receptor (AT1R) and anti-ETAR antibodies and the association between the presence of anti-endothelial antibodies and the risk of allograft rejection in kidney transplantation.MethodsIn total, 252 patients who underwent kidney transplantation were enrolled in this study. Antibodies for human leukocyte antigens (HLAs) and non-HLAs were analyzed immediately before transplantation. Patients were categorized based on the occurrence of antibody-mediated rejection (AMR) or T-cell-mediated rejection (TCMR) by 2017 Banff classification. All p-values were two-tailed, and statistical significance was set at p < 0.05.ResultsPatients with anti-AT1R antibodies had a 3.49-fold higher risk of TCMR than those without anti-AT1R antibodies. Patients with anti-ETAR antibodies had a 5.84-fold higher risk of AMR than those without anti-ETAR antibodies. The hazard ratio of AMR in patients with both HLA DSAs and anti-ETAR antibodies, relative to patients without anti-ETAR antibodies and HLA DSAs, was 32.85 (95% CI = 1.82-592.91).ConclusionOur findings indicated that anti-ETAR antibodies are associated with AMR, and patients with both anti-ETAR antibodies and de novo HLA DSAs were at a high risk of AMR.
| S-EPMC10561590 | biostudies-literature
Project description:Recent large meta-analyses suggested a poorer long-term patients' and grafts' outcomes after ABO incompatible (ABOi) living-donor kidney transplantation (LDKT) compared to ABO compatible LDKT. However, little is known about the long-term histological pattern after ABOi LDKT. We compared the histological features observed on protocol biopsies from 03/11 to 11/19 in 94 ABOi LDKT (including 14 with preformed Donor Specific Antibodies, pDSAs), 27 LDKT ABO compatible (ABOc) with pDSAs, and 21 ABOc without pDSAs) during the first five years post transplantation. During the first 5 years post-transplantation, a progression of chronic lesions (patients with a ci >0 raised from 11% to 65%, p<0.0001, patients with a ct >0 raised from 29% to 78%, p<0.0001) was observed in ABOi LDKT without pDSAs. Histological patterns of evolution were comparable to those observed in ABOc kidney transplant patients. Microvascular inflammation was lower in ABOi LDKT without pDSAs compared to those with pDSAs (ABOi or ABOc). At last follow-up, 28 months, IQR (15-48) post-transplantation, 29 patients (36%) had a severe graft dysfunction (defined by a CKD-epi eGFR < 30 mL/min/1.73m²). The donor age was a predictive factor for the development of severe kidney allograft dysfunction at last follow-up (HR= 1.05, 95% CI [1.05-1.10], p= 0.03). Hence, long-term histological analysis of ABOi LDKT shows only an increase of chronic interstitial and tubular atrophy changes, without active lesions. These data confirm that ABOi LDKT programs can be securely developed.
| S-EPMC9582152 | biostudies-literature
Project description:We performed a single-center retrospective cohort study of 66 consecutive ABO incompatible kidney transplants (ABOiKT) performed without B-cell depleting therapy. Outcomes were compared to an earlier era performed with rituximab (n = 18) and a contemporaneous cohort of ABO compatible live donor transplants (ABOcKT). Acute rejection within 3 months of transplant was significantly more common after rituximab-free ABOiKT compared to ABOiKT with rituximab (OR 8.8, p = 0.04) and ABOcKT (OR 2.9, p = 0.005) in adjusted analyses. Six recipients of rituximab-free ABOiKT experienced refractory antibody mediated rejection requiring splenectomy, and a further two incurred early graft loss with no such episodes amongst ABOiKT with rituximab or ABOcKT cohorts. Patient and graft survival were similar between groups over a median follow-up of 3.1 years. This observational evidence lends strong support to the continued inclusion of rituximab in desensitization protocols for ABOiKT.
| S-EPMC10547868 | biostudies-literature
Project description:BackgroundABO blood group antigens in the liver are expressed mainly on endothelial cells or biliary epithelial cells but not on hepatocytes. This suggests that ABO-incompatible hepatocyte transplantation (ABOi-HTx) is theoretically feasible. However, the effects of stress on ABO blood group antigen expression caused by isolation and intraportal infusion require thorough investigation before ABOi-HTx can be implemented in clinical settings.MethodsHuman hepatocytes were isolated from liver tissue obtained from liver resection or deceased donor livers. The expression of blood group antigens on cryopreserved human liver tissues and isolated hepatocyte smear specimens were examined by immunofluorescent staining. The effect of proinflammatory cytokines on blood group antigen expression of hepatocytes was evaluated by flow cytometry. Instant blood-mediated inflammatory reaction after hepatocyte incubation with ABO-incompatible whole blood was examined using the tubing loop model.ResultsBlood group antigens were mainly expressed on vessels in the portal area. In hepatocyte smear specimens, isolated hepatocytes did not express blood group antigens. In contrast, a subset of cells in the smear specimens of nonparenchymal liver cells stained positive. In the flow cytometry analysis, isolated hepatocytes were negative for blood group antigens, even after 4-h incubation with cytokines. Platelet counts and complement activation were not significantly different in ABO-identical versus ABO-incompatible settings in the tubing loop model.ConclusionOur study showed that blood group antigens were not expressed on hepatocytes, even after isolation procedures or subsequent incubation with cytokines. This finding is an important step toward removing the restriction of ABO matching in hepatocyte transplantation. Our results suggest that ABOi-HTx is a feasible therapeutic option, especially in patients who require urgent treatment with freshly isolated hepatocytes, such as those with acute liver failure.
| S-EPMC7068001 | biostudies-literature
Project description:We report a case of antibody-mediated rejection treated with the human CD38 monoclonal antibody daratumumab in a 58-year-old female patient with end-stage kidney disease due to autosomal dominant polycystic kidney disease who received an ABO- and human leukocyte antigen antibody-incompatible living donor kidney transplant. The patient experienced an episode of severe antibody-mediated rejection within the first week of transplantation. Blood-group-antibody selective immunoadsorption in combination with administration of four doses of daratumumab (each 1800 mg s.c.) led to a persistent decrease of ABO- and more interestingly donor-specific human leukocyte antigen antibody reactivity and resulted in clinical and histopathological remission with full recovery of graft function, which has remained stable until post-transplant day 212. This case illustrates the potential of targeting CD38 in antibody-mediated rejection.
| S-EPMC10631334 | biostudies-literature