We have previously reported that islets present in cultured fetal pig pancreas (FPP) are resistant to destruction by Galalpha(1,3)Gal antibodies and compliment, but are susceptible to the 'secondary' antibody response which occurs on transplanting pig islet tissue to Galo/o murine recipients. In a model of antibody-mediated graft rejection, we tested the resistance of porcine islets to antibody. Using FPP from human CD46 transgenic pigs, we now report that the complement regulator, CD46, affords protection from antibody-mediated rejection when mouse anti-pig serum (MAPS) was administered to scid mice bearing PFF grafts from either CD46 transgenic or normal pigs. Indeed, whereas normal pig islets were destroyed by an intraperitoneal (i.p.) injection of 0.1 to 0.2 ml of MAPS antibody, destruction of CD46-expressing transgenic islets required 0.5 ml, i.e. up to five times the amount. In contrast, there was no prolongation of the survival of CD46 transgenic mouse skin or heart major histocompatibility complex-compatible or -incompatible allografts--rejected by predominantly cellular immune mechanisms, as opposed to xenograft rejection. Although complement regulators have been examined for their protective role in hyperacute rejection of vascularized xenografts, it is clear that they also have protective effects in the later, antibody-mediated responses, but are unlikely to effect the inflammatory response in cell-mediated rejection.