Costimulation blockade and regulatory T-cells in a non-human primate model of kidney allograft transplantation

Successful tolerance induction therapies in rodents are for the most part unsuccessful in larger primates. Costimulation blockade by anti-CD40 or anti-CD40 + anti-CD86 in the life-supporting kidney allograft model in the rhesus monkey prevented graft rejection during treatment but did not induce tolerance. Costimulation blockade has to be integrated in conventional immunosuppressive therapies. However, conventional immunosuppressive drugs may antagonize the immunoregulatory effects of costimulation blockade. We describe how costimulation blockade prevented graft rejection in the immediate post transplantation period. CsA treatment was initiated only after 42 days post transplantation and this had a beneficial effect on graft survival, resulting in two of 4 monkeys surviving long-term without additional immunosuppressive treatment. Furthermore we found no beneficial effect of ATG induction therapy on costimulation blockade treatment. ATG induced rapid reappearance of CD8+ memory T-cells in the peripheral blood, possibly responsible for the observed accelerated rejection. Infiltrating cells in kidney graft biopsies and tissues revealed high expression of FOXP3 and other regulatory T-cell markers during rejection. We also have described the phenotypic and functional characteristics of naturally occurring regulatory T-cells in rhesus monkeys.Dutch Kidney Foundation (Nierstichting) Dutch Transplantation Society (NTV) PanGenetics BV BPRCUBL - phd migration 201