Pretransplant desensitization with costimulation blockade and proteasome inhibitor reduces DSA and delays antibody-mediated rejection in highly sensitized nonhuman primate kidney transplant recipients

Background: Patients with broad HLA sensitization have poor access to donor organs, highmortality 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. Methods: To 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, bonemarrowcells, and serum before desensitization, after desensitization, and after kidney transplantation. Results: The group receiving carfilzomib and belatacept exhibited significantly reduced levels of donorspecific 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 1month 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 antibodymediated rejection. Conclusions: Desensitization 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 antibodymediated rejection with humoral-response rebound, suggesting desensitization must bemaintained after transplantation using ongoing suppression of the B cell response.