We investigated whether the development of spontaneous T-cell-mediated type I diabetes in NOD mice is influenced by B cells and immunoglobulin (Ig). During the first 4 weeks of life, B-cell development was suppressed by repeated administration of rabbit anti-mouse IgM (RaIgM), while controls received polyclonal rabbit Ig (NRIg). A reduction in the incidence of diabetes, as well as in development of insulitis, was observed after either of these treatments. However, the effect on insulitis was more pronounced in mice treated with RaIgM compared with those treated with NRIg. Furthermore, while the optimal effect of NRIg was obtained after a single injection at birth, the additional effect of RaIgM on development of insulitis was observed only after continued treatment for the first 4 weeks of life. Taken together these data suggest a possible role of Ig/B cells in the development of autoimmunity in the NOD mouse. The additional effect observed after continued suppression of the neonatal B-cell development suggests that this population may contribute significantly to the establishment of an auto-aggressive lymphocyte repertoire in the NOD mouse.

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The mechanisms contributing to the development of autoimmune insulin-dependent diabetes mellitus have been analyzed in allophenic mouse chimeras of the NOD +* C57BL/6 strain combination (where NOD is nonobese diabetic). Occurrence of lymphoid cell infiltration (insulitis) in pancreatic islets was observed in the majority of such chimeras. The development of insulitis was found to correlate with major histocompatibility complex chimerism in lymphoid cells and in thymus cortical regions. Chimeras with more than 50% of C57BL/6 lymphoid cells rarely developed insulitis. Our data suggest that the correlation with the thymic cortical region is absolute. Thus, all individuals displaying NOD or NOD/ C57BL/6 thymic cortical regions developed insulitis, whereas we have not observed insulitis in chimeras with only C57BL/6 thymic cortical regions. Thus the positive selection of T cells appears to play a crucial role in the development of insulindependent diabetes mellitus.One of the best animal models of human insulin-dependent diabetes mellitus is represented by the nonobese diabetic (NOD) mouse (1). In these mice overt diabetes develops spontaneously in a majority of female mice and less frequently in male mice. As in human insulin-dependent diabetes mellitus, development of overt diabetes in NOD mice is preceded by infiltration of lymphoid cells into the pancreatic islets and is observed only after massive destruction of insulin-producing f3 cells (2).Predisposition to the disease is under polygenic control, one of the genes having been identified as the major histocompatibility complex (MHC) class II locus both in man and in the NOD mouse strain (3, 4). The involvement of MHC genes in the development of autoimmunity in NOD mice indicates that T cells play a crucial role in this process. Indeed, the disease can be transferred with cells from diabetic animals (5) requiring both CD4+ and CD8+ cells (6, 7). NOD mice express a unique I-A molecule (I-ANOi) where aspartic acid in position 57 ofthe 13 chain is replaced by serine (8). This is observed also in the HLA-DQ ,8 chain of many Caucasians with insulin-dependent diabetes mellitus (9-11). The I-E antigen is absent in the NOD strain due to a defect in I-E a chain expression (3). Recent reports showing that insulitis in NOD mice can be prevented by the introduction of I-E a chain or non-NOD I-A transgenes have supported the hypothesis that I-A and I-E expression affects development of insulitis (12-15).I-E expression is known to mediate intrathymic clonal deletion of sets of T-cell antigen receptors carrying specific 13-chain variable regions (16, 17). Based on these observations, the protective effect of I-E has been suggested to reflect negative selection through intrathymic clonal deletion of potentially hazardous T-cell clones (12, 18). However, the observation that NOD mice expressing promoter-mutated I-E a chain genes mediating intrathymic deletion of I-Ereactive T cells still develop insulitis has cast doubt about this hypothesis (19).To further investigate t...