Diverse adhesion molecules participate in many important responses and thus would be implicated in the pathogenesis of various autoimmune diseases. However, there is little evidence for the role of these molecules in autoimmune insulin-dependent diabetes mellitus. Here we present several lines of evidence suggesting that leukocyte function-associated antigen-1 (LFA-1) and its counter-receptor intercellular adhesion molecules (ICAM-1), one of the most important pairs among these adhesion molecules, are involved in the development of autoimmune diabetes in the non-obese diabetic (NOD) mouse. Immunohistochemical study showed the hyperexpression of ICAM-1 on islet-infiltrating mononuclear cells and vascular endothelium in NOD pancreas. In vivo administration of anti-LFA-1 or anti-ICAM-1 mAb from 5 to 30 (or 12) weeks of age exerted a very strong preventative effect on the development of spontaneous diabetes with a marked reduction of insulitis, whereas both antibodies, even combined to use simultaneously, could not prevent cyclophosphamide-induced diabetes. Adoptive transfer of insulitis and diabetes to young NOD mice following the injection of islet-derived mononuclear cells from diabetic donors was completely blocked by administration of both antibodies to recipients. The present study, therefore, provides the first evidence that immunointervention to LFA-1-ICAM-1 interaction has a strong prophylactic effect on autoimmune diabetes in NOD mice.

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 beta-cell destruction by which expression of ICAM-1 on beta-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 beta-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 beta-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)-gamma or tumor necrosis factor-alpha. 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-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.(ABSTRACT TRUNCATED AT 250 WORDS)

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Nonobese diabetic (NOD) mice spontaneously develop an autoimmune diabetes resembling human insulin-dependent diabetes mellitus (IDDM). Several lines of evidence suggest that T cells are responsible for mononuclear cell infiltration into the islets (insulitis) and destruction of beta cells in NOD mice. Disease transfer studies have shown that both splenic CD4 and CD8 T cells from diabetic NOD mice are necessary to transfer diabetes to newborn or sublethally irradiated NOD mice [1, 2] and islet-specific CD4 and CD8 T-cell clones are both required before significant insulitis develops in irradiated NOD mice [3]. However, islet-specific CD4 T-cell clones have been found to cause diabetes when injected into unmanipulated young NOD mice [4] or NOD F1 mice [5]. In addition, CD4 T cells from diabetic NOD donors have also been shown to transfer disease into NOD-severe combined immunodeficient (scid) mice