PROGRAMMED CELL-DEATH IN THE PATHOGENESIS OF MURINE IDDM - RESISTANCETO APOPTOSIS INDUCED IN LYMPHOCYTES BY CYCLOPHOSPHAMIDE

The non-obese diabetic (NOD) mouse displays several immune related def ects, each of which could potentially contribute to the immunopathogen esis of diabetes that spontaneously develops in these mice. The report ed resistance of NOD-lymphocytes to several apoptosis-inducing signals constitutes one such factor. Apoptosis plays a key role in the homeos tasis of the immune system, as a means of selecting lymphocyte reperto ires both in primary lymphoid organs and in the periphery; distortions in the apoptotic machinery may therefore be hypothesized to be implic ated in the pathogenesis of autoimmune disorders. We now report that c yclophosphamide constitutes an apoptosis signal to peripheral lymphocy tes and we provide evidence that NOD B cells as well as both CD4 and C D8 T cells display resistance to cyclophosphamide-induced apoptosis. T hese observations support the notion that apoptosis resistance in NOD mice exists at various levels, and suggest that the CY-sensitive lymph oid population, believed to play an important role in inhibiting the d isease in diabetes resistant NOD mice (particularly males), may be con trolled by mechanisms that are mediated by apoptosis. (C) 1996 Academi c Press Limited