*Purpose: Costimulation blockade strategies targeting the CD40/CD154 pathway are highly effective in preventing xenograft rejection in pig-to-nonhuman primate (NHP) transplantation models. The aim of this study was to assess the relative therapeutic efficacy of tacrolimus, a clinically applicable immunosuppressive agent, compared to either anti-CD40 or anti-CD154 therapies.

*Methods: Rhesus macaques (n=17) with low pre-transplant xenoreactive antibody titers were selected following recipient screening. Selected recipients underwent bilateral nephrectomy and life-sustaining porcine renal xenotransplantation using GGTA1 KO/CD55 transgenic donor pigs (NSRRC, Columbia, MO). Animals underwent T cell depletion and were randomized to one of three maintenance treatment regimens: tacrolimus (target trough 8-12ng/mL), anti-CD40 (clone 2C10R4), or anti-CD154 (clone 5C8), plus mycophenolic acid and steroids.

*Results: Recipients treated with anti-CD154 therapy (n=6) experienced the longest survival (MST=235 days, p=0.0031), including three rhesus macaques with survival over 300 days (406, 400, 310 days). Recipients treated with anti-CD40 therapy (n=4) exhibited a moderate prolongation in survival (MST=29.5 days) whereas tacrolimus-treated recipients (n=6) experienced the shortest survival (MST = 11.5 days). Graft failure was associated with an increase in serum creatinine.

*Conclusions: Here we demonstrate that immunosuppression with anti-CD154 or anti-CD40 therapy is associated with prolonged survival of kidney xenografts relative to tacrolimus in a porcine-to-NHP xenotransplantation model. These data provide further rationale for clinical translation of these costimulation blockade reagents which demonstrate the strongest survival benefit for xenotransplant recipients.

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