Intracerebrally (IC) transplanted outbred Wistar and inbred Lewis (AgB1/1) strain rat islets and pancreatic endocrine cells (PEC) were able to function for a prolonged period in nonimmunosuppressed diabetic inbred ACI (AgB4/4) rats across a major histocompatibility barrier. All recipients were sensitized to various degrees to the donor antigens, as demonstrated by circulating cytotoxic antibody, irrespective of the survival of the IC graft. Nevertheless, the antidonor antibody titers in the IC islet and PEC graft recipients were lower and peaked later when compared with ACI recipients that received an intraportal islet allograft. PEC were also transplanted IC in immunized ACI recipients. In recipients hyperimmunized by repeated splenocyte injections, accelerated PEC graft rejection was observed. In recipients with weaker immunization by intraportal whole islet allograft 2 months prior to the IC allograft, the IC PEC allografts were also rejected. To assess if ACI rats with long-term-functioning IC islet/PEC allograft developed tolerance to the donor antigens, these animals were transplanted with a donor-strain skin graft. The skin grafts were all rejected in a first-set fashion similar to normal control ACI rats. Also, 7/12 and 7/9 recipients rejected their functional IC islet or PEC allograft, respectively, following transplantation of a donor-strain skin allograft, thus indicating that the transplanted PEC maintained their antigenicity even after long-term survival of over 1 year in allogeneic recipients. The data indicate that the brain does possess immunoprotective properties for the islet/PEC allograft. The protection, however, is relatively weak and is possibly due to the paucity of the effector mechanism in the brain relative to that normally present systemically.