Determinants of donor-specific B cell tolerance in kidney transplantation in sensitized recipients

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ABSTRACT – Project 2 Kidney transplantation is the preferred treatment for end-stage renal failure due to improved patient survival, quality of life, and healthcare costs compared to dialysis. However, sensitized patients with preformed human leukocyte antigen (HLA) antibodies due to prior exposure to allogeneic HLA via transfusion, pregnancy, and previous transplantation face lower rates of transplantation that result in higher waitlist mortality. Furthermore, even if these patients are transplanted after desensitization, they frequently have worse short- and long-term graft survival compared to non-sensitized patients due to increased risk of rejection. We have shown that a combination of plasma cell targeting with proteasome inhibitor (carfilzomib) and co-stimulation blockade with belatacept reduces preformed antibody prior to kidney transplantation in sensitized nonhuman primates (NHP). Together with cytolytic induction, this pharmacological desensitization prevented early antibody-mediated rejection (AMR) and significantly prolonged graft survival in sensitized recipients. However, the peri-transplant desensitization was not able to control late AMR. Interestingly, post-transplant belatacept was able to suppress donor-specific antibody (DSA), disrupt germinal centers, and prevent plasma cell increase in NHP following depletion. This approachachievedprolonged graft survival with less AMR but promoted significant complications including viral reactivation and post-transplant lymphoproliferative disorders (PTLD). We hypothesize that the more specific (and even donor-specific) targeting of humoral responses including B cells, plasma cells, and complement may better control post-transplant AMR in sensitized hosts and create a therapeutic window to induce donor-specific tolerance. We will evaluate guided homeostatic repopulation with apoptotic donor cells for re-establishing an immune repertoire that favors transplantation tolerance. To explore this hypothesis, we propose 3 specific aims: 1) To evaluate adjuvant therapies targeting down-stream post-transplant humoral responses following desensitization. 2) To determine efficacy of antigen-specific pro-tolerant approaches in highly sensitized NHPs recipients. 3) To identify the functional phenotype of allo-specific T and B cell repertoires required to establish tolerance in sensitized recipients.