Escape from self-tolerance leads to neonatal insulin-dependent diabetes mellitus

Double transgenic (dTg) mice expressing the hemagglutinin (HA) of influenza virus under the insulin promoter and the TCR specific for the immunodomina nt CD4 T cell epitope of HA (HA110-120) develop insulin-dependent diabetes mellitus (IDDM). In order to gain information on the breaking down of neona tal self-tolerance we studied the occurrence of IDDM after birth. Our resul ts showed that newborn mice develop fulminant IDDM characterized by occurre nce of insulitis as early as 3 days after birth, followed by hyperglycemia by 7 days, and significant hypoinsulinemia by 28 days. The neonatal breakdown of self-tolerance of T cells positively selected in the thymus is supported by the facts that: (i) peripheral HA110-120 specifi c T cells from neonates are fully functional and proliferated upon stimulat ion with the nominal peptide, and (ii) peptide-specific T cells were accumu lated in the pancreas of dTg mice as early as 3 days after birth. Our results demonstrate that diabetes occurring in young dTg mice is due to early activation of self-reactive T cells immediately after birth. Accumul ation of specific T cells in the target organ leads to destruction of pancr eatic beta-cells and IDDM. These mice may provide a useful model to evaluat e new strategies for the prevention of diabetes.