Soluble forms of intercellular adhesion molecule-1 inhibit insulitis and onset of autoimmune diabetes

Increased concentration of circulating adhesion molecules in human serum have been described in different immune-mediated diseases. Recently, we proposed an immunomodulatory function of soluble forms of the intercellular adhesion molecule-1 (ICAM-1) during the pathogenesis of human Type I (insulin-dependent) diabetes mellitus. To test this hypothesis in nonobese diabetic (NOD) mice, a spontaneous animal model for human Type I diabetes, two recombinant forms of soluble murine ICAM-1 were generated, one monomeric soluble ICAM-1 containing all five extracellular Ig-like domains of ICAM-1 (rICAM-1) and one dimeric protein with the N-terminal extracellular domains fused to the constant regions of murine IgG2a (rICAM-1-Ig). Beginning at age 35 days prediabetic NOD mice received i. p. injections of 5 microg recombinant ICAM-1-proteins three times a week for 4.5 months. At day 170 diabetes development was reduced (p < 0.001) in NOD mice receiving rICAM-1 (8%) or rICAM-1-Ig (8%) treatment in comparison with sham treated animals (45%). After termination of therapy animals treated with multimeric rICAM-1-Ig were protected longer than animals treated with rICAM-1. Prevention of diabetes was associated with decreased infiltration of pancreatic islets by mononuclear cells. A selective downregulation of Th1-type cytokine expression was observed in a second set of experiments in which diabetes development was synchronised by cyclophosphamide. These data support the hypothesis that circulating forms of adhesion molecules have an immunomodulatory function and can intervene in islet inflammation.