*Purpose: Blockade of the CD28/B7 costimulation pathway has shown great promise as part of desensitization and maintenance immunosuppression regimens in our sensitized nonhuman primate model. We hypothesized that blocking the CD40/CD40L axis would effectively desensitize highly sensitized nonhuman primates, and also that CD40 blockade-based maintenance immunosuppression would prolong graft survival in sensitized recipients after kidney transplantation.

*Methods: Rhesus macaques (n=4) were sensitized to maximally MHC-mismatched donors with two sequential skin transplants, then desensitized with an anti-CD40 agent (2C10R4, 20mg/kg weekly for 4 weeks) concurrent with a proteasome inhibitor (carfilzomib, 27mg/m2 weekly for four weeks). Two weeks after desensitization, animals underwent life-sustaining kidney transplants from their MHC-mismatched skin donors. Rhesus-specific antithymocyte globulin was used for induction. Maintenance immunosuppression consisted of an anti-CD40 agent (2C10R4), rapamycin, and methylprednisolone. Peripheral lymph nodes, peripheral blood, and bone marrow were analyzed throughout the study period.

*Results: Desensitization with anti-CD40 therapy and proteasome inhibition reduced donor-specific antibody (DSA, Figure 1A) and significantly reduced replicating B cells within lymph nodes (Figure 1B). Two primates have undergone kidney transplantation, with normal graft function 14 days after transplantation. The remaining primates will undergo scheduled kidney transplantation.

*Conclusions: Desensitization with CD40 blockade and proteasome inhibition effectively reduces DSA levels and lymph node B cell replication over a four-week period. Sensitized recipients to date have experienced normal graft function on anti-CD40-based maintenance immunosuppression. The CD40/CD40L axis deserves further study in the setting of sensitized recipients.

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