THE EFFECT OF H-2 COMPATIBILITY ON PANCREATIC BETA CELL SURVIVAL IN THE NONOBESE DIABETIC MOUSE

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Abstract
The effect of major histocompatibility (MHC) antigens on the survival of newborn pancreatic iso and allografts was assessed in the nonobese diabetic (NOD) mouse, which develops a spontaneous autoimmune diabetes. The NOD mouse (H-2Kd,Db) rejects skin allografts from CBA (H-2k) within a 12-day period, indicating normal immune function toward alloantigens. A pancreatic allograft into the NOD mouse represents a presumed first-set allogeneic response, as well as a possible second-set immune response to islets. To assess the effect of donor H-2 antigen and the influence of autoimmune disease on pancreatic graft survival, newborn pancreata from various strains of mice were transplanted into diabetic NOD mice treated with 40 mg/kg/day cyclosporine (CsA) that prevented skin allograft rejection. The grafts were then harvested at day 10 to histologically assess the graft viability. CBA pancreatic grafts, incompatible at all MHC loci, showed the least lymphocytic infiltration, and good donor beta cell survival. Furthermore, CBA newborn pancreata under appropriate conditions were able to cure or improve the diabetic condition in 3/6 NOD mice. In the graft sharing class I MHC antigens, lymphocytic infiltration was significantly increased, while the donor beta cell number clearly decreased. The intensity of the graft destruction was intermediate in C57BL/6 allografts sharing H-2Db antigen, and strongest in BALB/c allografts sharing H-2Kd and in NOD isografts. The results indicate that in diabetic NOD mice the CsA dose controlling allograft rejection is incapable of controlling antiislet immunity. This antiislet immunity appears to exert its effect in an H-2-restricted manner. These findings may have important implications for the transplantation of pancreatic tissue in treating type I diabetes in humans.