PROTECTION AGAINST DIABETES BY MHC HETEROZYGOSITY AND REVERSAL BY CYCLOPHOSPHAMIDE

In type I diabetes in both rodents and humans, genetic susceptibility to disease is strongly linked to MHC class II alleles. In some cases, however, certain class II alleles provide resistance to disease. To ex amine this effect in a well-defined system, we studied double transgen ic mice expressing influenza hemagglutinin (HA) on pancreatic islet be ta cells and an HA-specific TCR on CD4 T cells. On a susceptible B10.D 2 background, 70% of double transgenic mice develop an early-onset spo ntaneous autoimmune diabetes. MHC heterozygosity induced variable prot ection from diabetes, depending on the specific nonpermissive allele, but insulitis was invariably present. Autoreactive T cells retained th e ability to induce diabetes because cyclophosphamide treatment induce d diabetes in 81% of young MHC(d/b) transgenic mice, although the effe ct was diminished in older mice, Most importantly, treatment induced h igher IFN-gamma/IL-4 ratios among CD4 T cells, suggesting a strong shi ft toward Th1 development, perhaps through direct effects on patterns of gene expression in CD4 T cells. (C) 1998 Academic Press.