EXPRESSION OF INTERCELLULAR-ADHESION MOLECULE-1 ON PANCREATIC BETA-CELLS ACCELERATES BETA-CELL DESTRUCTION BY CYTOTOXIC T-CELLS IN MURINE AUTOIMMUNE DIABETES

Intercellular adhesion molecule 1 (ICAM-1) plays an important role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) by bein g involved in the extravasation of lymphocytes from the circulation in to the inflamed pancreas. However, the mechanism of beta-cell destruct ion by which expression of ICAM-1 on beta-cells may facilitate adhesio n of effector cells still remains to be elucidated Several Lines of ev idence suggest that this adhesion molecule is involved in the destruct ion of pancreatic beta-cells by killer lymphocytes in the NOD mouse, w hich shows an autoimmune diabetic syndrome similar to that of human ID DM. Immunohistochemical study under Light microscopy demonstrated that all of the mononuclear cells infiltrating the islets strongly express ed ICAM-1 and leukocyte function-associated antigen 1 (LFA-1), a count erreceptor of ICAM-1, whereas ICAM-1 expression on islet cells was not apparent. However, immunohistochemical staining under electron micros copy revealed that islet beta-cells adjacent to infiltrating lymphocyt es were clearly stained by an anti-ICAM-1 monoclonal-antibody (mAb). F low cytometric analysis showed that the ICAM-1 expression on NOD islet cells and NOD-derived insulinoma cells (MIN6N8a) was inducible by int erferon (IFN)-gamma or tumor necrosis factor-alpha. These cytokines' h ad an additive effect on the ICAM-I induction. Susceptibility of MIN6N 8a cells to lysis by a NOD islet-derived CD8(+) cytotoxic T-cell clone was greatly enhanced by IFN-gamma pretreatment, and this enhancement was abolished by anti-ICAM-1 and anti-LFA-1 mAbs. When both mAbs were administered into NOD mice with spontaneous or adoptively transferred diabetes, the development of diabetes was significantly prevented.