Localized effect for CD28/B7 regulation of autoimmune diabetes in the Nonobese Diabetic (NOD) mouse

CD28/B7 costimulation regulates diabetes in the NOD mouse since treatment of mice with human CTLA4Ig (hCTLA4Ig) between ages 2-8 weeks prevented disease. However, preventing CD28/B7 interactions in CD28^-/- or CTLA4Ig transgenic NOD mice resulted in dramatic exacerbation of diabetes, suggesting that the role of costimulation may change over time. We found that hCTLA4Ig treatment between ages 5-7 weeks prevented diabetes whereas treatment either before or after this time did not. Protection was not due to a loss of β cell antigen-reactive or diabetogenic cells. Splenocytes from 12 week old, hCTLA4Ig-treated mice showed glutamic acid decarboxylase (GAD)₆₅-stimulated proliferation and IFNγ levels similar to controls. Treated mice developed diabetes after cyclophosphamide treatment. Moreover, spleen cells from treated mice were capable of adoptively transferring diabetes. Yet hCTLA4Ig-treated mice had increased levels of GAD₆₇ IgG₁, suggesting an increased presence of Th2 cells. Protection appeared to be due to a Th1 to Th2 phenotype shift that was only apparent in the pancreas. Pancreatic levels of IFNγ were comparable between hCTLA4Ig-treated and control mice, but IL-4 was detectable only in treated mice. Thus, blockade of B7 during early pancreatic inflammation with hCTLA4Ig diverts islet antigen-reactive T cells to a Th2 phenotype that is restricted to the pancreas. Therefore, progression to diabetes at this stage is dependent on costimulation provided by CTLA-4 ligands.