BREAKING SELF-TOLERANCE IN NONOBESE DIABETIC MICE

Unresponsiveness to self is maintained through two mechanisms of immun e regulation: thymic-negative selection and peripheral tolerance. Alth ough thymic-negative selection is a major mechanism to eliminate self- reactive T cells, normal mice have readily detectable populations of T cells reactive to self-proteins but do not exhibit autoimmune respons es. It has been postulated that autoimmune disease results from breakd own or loss of peripheral tolerance. We present data that demonstrate that peripheral tolerance or unresponsiveness to self call be broken i n nonobese diabetic (NOD) mice. Immunization of NOD mice (but not of c onventional mice) with self-peptides caused an immune response to the self-peptide with resultant autoproliferation of peripheral lymphocyte s. Autoproliferation of self-reactive T cells in NOD mice resulted fro m the recognition and proliferation of the activated T cells to endoge nously processed and presented self-antigens. This loss of self-tolera nce demonstrated in vitro may well be the basis of NOD autoimmune dise ase in vivo.