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Desensitizing highly sensitized heart transplant candidates with the combination of belatacept and proteasome inhibition.

ABSTRACT: HLA antibodies pose a significant barrier to transplantation and current strategies to reduce allosensitization are limited. We hypothesized that augmenting proteasome inhibitor (PI) based desensitization with costimulation blockade (belatacept) to mitigate germinal center (GC) responses might increase efficacy and prevent rebound. Four highly sensitized (calculated panel reactive antibody [cPRA] class I and/or II >99%, complement-dependent cytotoxicity panel reactive antibody [CDC PRA+], C1q+) heart transplant candidates were treated with the combination of belatacept and PI therapy, which significantly reduced both class I and II HLA antibodies and increased the likelihood of identifying an acceptable donor. Three negative CDC crossmatches were achieved against 3, 6, and 8 donor-specific antibodies (DSA), including those that were historically C1q+ binding. Posttransplant, sustained suppression of 3 of 3, 4 of 6, and 8 of 8 DSA (cases 1-3) was achieved. Analysis of peripheral blood mononuclear cells before and after desensitization in one case revealed a decrease in naïve and memory B cells and a reduction in T follicular helper cells with a phenotype suggesting recent GC activity (CD38, PD1, and ICOS). Furthermore, a shift in the natural killer cell phenotype was observed with features suggestive of activation. Our findings support synergism between PI based desensitization and belatacept facilitating transplantation with a negative CDC crossmatch against historically strong, C1q binding antibodies.

SUBMITTER: Alishetti S

PROVIDER: S-EPMC8366746 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Kidney transplantation is the most effective treatment for end-stage kidney disease. Sensitization, the formation of human leukocyte antigen (HLA) antibodies, remains a major barrier to successful kidney transplantation. Despite the implementation of desensitization strategies, many candidates fail to respond. Current progress is hindered by the lack of biomarkers to predict response and to guide therapy. Our objective was to determine whether differences in immune and gene profiles may help identify which candidates will respond to desensitization therapy.Single-cell mass cytometry by time-of-flight (CyTOF) phenotyping, gene arrays, and phosphoepitope flow cytometry were performed in a study of 20 highly sensitized kidney transplant candidates undergoing desensitization therapy. Responders to desensitization therapy were defined as 5% or greater decrease in cumulative calculated panel reactive antibody (cPRA) levels, and non-responders had 0% decrease in cPRA. Using a decision tree analysis, we found that a combination of transitional B cell and regulatory T cell (Treg) frequencies at baseline before initiation of desensitization therapy could distinguish responders from non-responders. Using a support vector machine (SVM) and longitudinal data, TRAF3IP3 transcripts and HLA-DR-CD38+CD4+ T cells could also distinguish responders from non-responders. Combining all assays in a multivariate analysis and elastic net regression model with 72 analytes, we identified seven that were highly interrelated and eleven that predicted response to desensitization therapy.Measuring baseline and longitudinal immune and gene profiles could provide a useful strategy to distinguish responders from non-responders to desensitization therapy. This study presents the integration of novel translational studies including CyTOF immunophenotyping in a multivariate analysis model that has potential applications to predict response to desensitization, select candidates, and personalize medicine to ultimately improve overall outcomes in highly sensitized kidney transplant candidates.

Project description:BackgroundPatients with broad HLA sensitization have poor access to donor organs, high mortality while waiting for kidney transplant, and inferior graft survival. Although desensitization strategies permit transplantation via lowering of donor-specific antibodies, the B cell-response axis from germinal center activation to plasma cell differentiation remains intact.MethodsTo investigate targeting the germinal center response and plasma cells as a desensitization strategy, we sensitized maximally MHC-mismatched rhesus pairs with two sequential skin transplants. We administered a proteasome inhibitor (carfilzomib) and costimulation blockade agent (belatacept) to six animals weekly for 1 month; four controls received no treatment. We analyzed blood, lymph node, bone marrow cells, and serum before desensitization, after desensitization, and after kidney transplantation.ResultsThe group receiving carfilzomib and belatacept exhibited significantly reduced levels of donor-specific antibodies (P=0.05) and bone marrow plasma cells (P=0.02) compared with controls, with a trend toward reduced lymph node T follicular helper cells (P=0.06). Compared with controls, carfilzomib- and belatacept-treated animals had significantly prolonged graft survival (P=0.02), and renal biopsy at 1 month showed significantly reduced antibody-mediated rejection scores (P=0.02). However, four of five animals with long-term graft survival showed gradual rebound of donor-specific antibodies and antibody-mediated rejection.ConclusionsDesensitization using proteasome inhibition and costimulation blockade reduces bone marrow plasma cells, disorganizes germinal center responses, reduces donor-specific antibody levels, and prolongs allograft survival in highly sensitized nonhuman primates. Most animals experienced antibody-mediated rejection with humoral-response rebound, suggesting desensitization must be maintained after transplantation using ongoing suppression of the B cell response.

Project description:BACKGROUND:The current U.S. priority ranking for heart candidates is based on treatment intensity, not objective markers of severity of illness. This system may encourage centers to overtreat candidates. OBJECTIVES:This study sought to describe national variation in the intensity of treatment of adult heart transplantation candidates and identify center-level predictors of potential overtreatment. METHODS:The registrations of all U.S. adult heart transplantation candidates from 2010 to 2015 were collected from the SRTR (Scientific Registry of Transplant Recipients). "Potential overtreatment" was defined as treatment of a candidate who did not meet American Heart Association cardiogenic shock criteria with either high-dose inotropes or an intra-aortic balloon pump. Multilevel logistic regression and propensity score models were used to adjust for candidate variability at each center. Center-level variables associated with potential overtreatment were identified. RESULTS:From 2010 to 2015, 108 centers listed 12,762 adult candidates who were not in cardiogenic shock for heart transplantation. Of these, 1,471 (11.6%) were potentially overtreated with high-dose inotropes or intra-aortic balloon pumps. In the bottom quartile of centers, only 2.1% of candidates were potentially overtreated compared with 27.6% at top quartile centers, an interquartile difference of 25.5% (95% confidence interval: 21% to 30%). Adjusting for candidate differences did not significantly alter the interquartile difference. Local competition with 2 or more centers increased the odds of potential overtreatment by 50% (adjusted odds ratio: 1.50; 95% confidence interval: 1.07 to 2.11). CONCLUSIONS:There is wide variation in the treatment practices of adult heart transplantation centers. Competition for transplantable donor hearts is associated with the potential overtreatment of hemodynamically stable candidates. Overtreatment may compromise the fair and efficient allocation of scarce deceased donor hearts.

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Desensitizing highly sensitized heart transplant candidates with the combination of belatacept and proteasome inhibition.

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