[Background] Pre-formed donor-specific anti-HLA antibodies (DSA) from prior transplantation, transfusion, or pregnancy affects a significant portion (35%) of patients awaiting a kidney transplant. Highly sensitized patients have very low rates of eventual transplantation, and, when transplanted, have worse short- and long-term graft survival.

[Method] All rhesus macaques were sensitized by a full MHC mismatched skin graft (~ 2cm diameter). Grafts all rejected within 2 weeks without treatment. After sensitization, animals received, Belatacept (N=3), Belatacept/Anti-CD40 mAb(2C10) (N=3), or Belatacept/2C10/Bortezomib (N=3) for a month. Renal transplants from the skin donor were then performed with basiliximab, tacrolimus, MMF, and steroid immunosupression.

[Results] Bortezomib treatment reduced bone marrow plasma cells but follicular helper T cells (Tfh) were significantly increased. Belatacept alone or Belatacept with 2C10 treated animals showed reduction of Tfh cells but showed no effect on BM plasma cells in the sensitized setting. DSA was not significantly reduced by either proteasome or costimulation blockade (COB). The combination of COB and bortezomib (dual targeting) significantly reduced BM plasma cells, serum DSA levels, and LN Tfh cells compared to Bortezomib or COB alone. Interestingly, pre-transplant memory CD4 T (Tcm) cells were greatly reduced compared to untreated controls. To assess the desensitization effect, kidney transplantation was performed. Renal allografts without desensitization showed accelerated rejection (N=5, MST=3.6d) with basiliximab. In contrast, desensitization with Bortezomib/Belatacept/2C10 treatment dramatically prolonged graft survival (N=3, MST>23.6d; p=0.013) with no signs of rejection.

[Conclusion] Desensitization with proteasome inhibitor or costimulation blockade showed limited effect on desensitization. However, targeting costimulation signals in conjunction with Bortezomib profoundly reduced Tfh cell populations, plasma cell number, and serum DSA. These data suggest that combined bortezomib and COB (dual targeting) may be worthy of further investigation as a desensitization regimen for highly sensitized living donor renal transplant recipients.

CITATION INFORMATION: Kwun J, Burghuber C, Manook M, Ezekian B, Park J, Freishlag K, Yoon J, Iwakoshi N, Farris A, Knechtle S. Dual Targeting of Costimulation and Proteasome to Desensitize and Prolong Graft Survival of Sensitized Nonhuman Primates. Am J Transplant. 2017;17 (suppl 3).

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