Rejection of pancreatic islet allografts remains a major problem to be solved before clinical application. Islet allotransplantation in congenic mice strains offers the opportunity to study mechanisms of both islet immunogenicity and susceptibility to rejection effector mechanisms, because isolated differences at the major histocompatibility complex can be controlled. In addition, the availability of monoclonal antibodies to alleles of the various H-2 loci and to lymphocyte subpopulations, as well as the availability of T lymphocyte clones allows one to either delete or add specific populations that may be important either in the immunogenicity of the islet graft or as effectors of rejection. Using congenic mice strains, we found that disparities for Class I (H-2 K or D) antigens alone, are sufficient to induce acute rejection, and indeed are a specific requirement. Islets from donors disparate only for Class II antigens are not rejected, even in recipients presensitized to the donor strain, as well as passively or actively immunized after transplantation. Furthermore, we have found that pretreatment of islet allografts with monoclonal anti-Ia antibody (Class II) prevented rejection even when the donors and recipients differed for Class I antigens alone and were identical for Class II antigens.2 These findings suggests that Ia positive cells can initiate an immune response leading to acute islet rejection even when Class II antigens are identical between the donor and recipient. Established islet allografts with Class I disparities could be rejected after active immunization with donor strain splenocytes, but the ability of donor splenocytes to induce rejection of the established islet allografts, remained intact after the elimination of Ia positive cells but not of T lymphocytes.3 Passive immunization with recipient strain lymphocytes sensitized to donor antigens in MLC also resulted in rapid rejection of long established anti-Ia treated Class I disparate islet allografts. To further investigate these findings, we will determine the fate of Ia positive cells within islets after monoclonal anti-Ia antibody treatment. We will also use cloned lymphocytes to determine which population of T-cells (helper, cytolytic or helper independent cytolytic) are responsible for rejection of established islet grafts. We will also test the effect of anti-Ia treatment on the survival of islet allografts in presensitized recipients. The results will not only provide clues on how to prevent islet allograft rejection, but also will provide information in general on the role of Class I and II antigens and of specific cell populations within the graft to induce an immune response.