Dominant Role of Intercellular Adhesion Molecule-1 in the Pathogenesis of Autoimmune Diabetes in Non-obese Diabetic Mice

Abstract

Intercellular adhesion molecule (ICAM)-1 is involved in forming the immunological synapse. The contribution of ICAM-1 to immune responses is not critical because mice with a disrupted ICAM-1 gene do not have grossly abnormal immune reactivity. Here we report on the surprising finding that diabetes-prone NOD mice with a disrupted ICAM-1 gene (ICAM-1−/−) are completely protected from disease development. While 64% ofICAM-1+/+ and 44% of ICAM-1+/−female NOD mice developed overt diabetes until 310 days old, no ICAM-1−/−NOD mice became hyperglycaemic. Histological examinations revealed minor infiltration around pancreatic islets of ICAM1−/−NOD mice. Administration of cyclophosphamide caused a progression to severe islet destruction in ICAM-1+/+NOD mice within 10 days. In contrast, ICAM-1−/−mice showed only mild insulitis. Furthermore,ICAM-1+/+ NOD mice showed an increase of IFN-γ, interleukin (IL)-12p40 and IL-12p35 pancreatic mRNA levels, leading to an increased ratio of IFN-γ: IL-4 and IL-12p40: IL-12p35 expression. In contrast,ICAM-1−/− NOD mice did not upregulate IFN-γ or IL-12p40 gene expression but maintained IL-4 and increased IL-12p35 gene expression. These results identify a dominant and non-redundant role of ICAM-1 in the development of autoimmune diabetes.