Intercellular adhesion molecule 1 (ICAM-1) plays an important role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) by being involved in the extravasation of lymphocytes from the circulation into the inflamed pancreas. However, the mechanism of β-cell destruction by which expression of ICAM-1 on β-cells may facilitate adhesion of effector cells still remains to be elucidated. Several lines of evidence suggest that this adhesion molecule is involved in the destruction of pancreatic β-cells by killer lymphocytes in the NOD mouse, which shows an autoimmune diabetic syndrome similar to that of human IDDM. Immunohistochemical study under light microscopy demonstrated that all of the mononuclear cells infiltrating the islets strongly expressed ICAM-1 and leukocyte function-associated antigen 1 (LFA-1), a counterreceptor of ICAM-1, whereas ICAM-1 expression on islet cells was not apparent. However, immunohistochemical staining under electron microscopy revealed that islet β-cells adjacent to infiltrating lymphocytes were clearly stained by an anti-ICAM-1 monoclonal antibody (mAb). Flow cytometric analysis showed that the ICAM-1 expression on NOD islet cells and NOD-derived insulinoma cells (MIN6N8a) was inducible by interferon (IFN)-γ or tumor necrosis factor-α. These cytokines had an additive effect on the ICAM-1 induction. Susceptibility of MIN6N8a cells to lysis by a NOD islet-derived CD8+ cytotoxic T-cell clone was greatly enhanced by IFN-γ 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. These results suggest that cytokines secreted by isletinfiltrating mononuclear cells could induce the ICAM-1 expression on γ-cells, which accelerates the γ-cell destruction by cytotoxic T-cells. Therefore, immunointervention of the ICAM-l/LFA-1 pathway would be an excellent strategy to prevent human IDDM.
Expression of Intercellular Adhesion Molecule 1 on Pancreatic β-Cells Accelerates β-Cell Destruction by Cytotoxic T-Cells in Murine Autoimmune Diabetes
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Nrorio Yagi, Koichi Yokono, Kazuhiko Amano, Masao Nagata, Kazuya Tsukamoto, Yutaka Hasegawa, Ryoji Yoneda, Naoko Okamoto, Hiroaki Moriyama, Masatoshi Miki, Yoichi Tominaga, Jun-ich Miyazaki, Hideo Yagita, Ko Okumura, Akira Mizoguchi, Akinori Miki, Chizuka Ide, Sakan Maeda, Masato Kasuga; Expression of Intercellular Adhesion Molecule 1 on Pancreatic β-Cells Accelerates β-Cell Destruction by Cytotoxic T-Cells in Murine Autoimmune Diabetes. Diabetes 1 July 1995; 44 (7): 744–752. https://doi.org/10.2337/diab.44.7.744
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