PROLONGED ACCEPTANCE OF CONCORDANT AND DISCORDANT XENOGRAFTS WITH COMBINED CD40 AND CD28 PATHWAY BLOCKADE

Background. The prompt and vigorous immune response to xenogenic tissu e remains a significant barrier to clinical xenotransplantation, Simul taneous blockade of the CD28 and CD40 costimulatory pathways has been shown to dramatically inhibit the immune response to alloantigen. Meth ods. In this study, we investigated the ability of simultaneous blocka de of the CD28 and CD40 pathways to inhibit the immune response to xen oantigen in the rat-to-mouse and pig-to-mouse models. Results. Simulta neous blockade of the CD28 and CD40 pathways produced marked inhibitio n of the cellular response to xenoantigen in vivo and produced long-te rm acceptance of xenogeneic cardiac and skin grafts (rat-to-mouse), an d markedly suppressed an evoked antibody response to xenoantigen, In a ddition, this strategy significantly prolonged the survival of pig ski n on recipient mice. Conclusions. Long-term hyporesponsiveness to xeno antigen across both a concordant and discordant species barrier, measu red by the stringent criterion of skin grafting, can be achieved using a noncytoablative treatment regimen.