CELL-MEDIATED INHIBITION OF THE TRANSFER OF AUTOIMMUNE DIABETES IN NOD MICE

The nonobese diabetic (NOD)' mouse provides a relevant model for insulin-dependent diabetes mellitus (IDDM). Spontaneous IDDM is usually observed after 12 wk of age and largely predominates in females (1). The role of autoimmune phenomena in the destruction of islet (3 cells in this model is indicated by islet infiltration by mononuclear cells, mainly T lymphocytes (2, 3), by prevention ofIDDM by neo-natal thymectomy (4), and by in vivo treatment with cyclosporine A (5), anti-CD4 + (6, 7), or anti-I-A mAbs (8). In addition, adoptive transfer of overt diabetes has recently been obtained both in healthy NOD neonates (9) and in pre-irradiated adult male recipients (10, 11) by injection of spleen cells collected from diabetic NOD mice. The need for irradiation in order to render nondiabetic adult NOD mice susceptible to diabetes transfer appears around 5 wk of age in females and around 3 wk of age in males (9). Diabetes transfer depends in both models on the simultaneous presence of CD4+ and CD8 + cells (9, 11). The role of T cells is further underlined by the predominance of Thy-1,2+ cells in islet infiltrates (3), the absence ofdiabetes in NOD nu/nu mice (12), and by efficient transfer of the disease in B cell-deprived recipients (13). Finally, it is worth noting that the NOD mouse disease shows a poly-genic susceptibility that includes clear genetic linkage with genes mapping within the MHC (14-17). The role of regulatory T cells in the development ofantipancreatic autoimmunity remains unclear. Induction of early diabetes in young male as well as female NOD mice by injections ofcyclophosphamide (18) and the requirement for the pre-irradiation mentioned above to transfer IDDM into adult recipients (10), suggested a role of suppressive immune phenomena whose nature has remained elusive in other systems. The adoptive transfer model provides a sensitive assay for further establishing the existence of such suppressive phenomena and studying their mechanisms. In this study, we bring direct evidence for suppressor cells that inhibit the transfer of diabetes in 8-wk-old pre-irradiated NOD recipients. We show that suppressor cells in this model are age and sex dependent, are CD4+ cells, and are abrogated by thymectomy at 3 wk of age. t Abbreviations used in this paper: IDDM, insulin-dependent diabetes mellitus ; NOD, nonobese diabetic mice .