Dominant role of intercellular adhesion molecule-1 in the pathogenesis of autoimmune diabetes in non-obese diabetic mice

Intercellular adhesion molecule (ICAM)-1 is involved in forming the immunol ogical synapse. The contribution of ICAM-1 to immune responses is not criti cal because mice with a disrupted ICAM-1 gene do not have grossly abnormal immune reactivity. Here we report on the surprising finding that diabetes-p rone NOD mice with a disrupted ICAM-1 gene (ICAM-1(- / -)) are completely p rotected from disease development. While 64% of ICAM-1(+ / +) and 44% of IC AM-1(+ / -) female NOD mice developed overt diabetes until 310 days old, no ICAM-1(- / -) NOD mice became hyperglycaemic. Histological examinations re vealed minor infiltration around pancreatic islets of ICAM-1(- / -) NOD mic e. 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-gamma, interleukin (IL)-12p40 and IL-12p35 pancre atic mRNA levels, leading to an increased ratio of IFN-gamma: IL-4 and IL-1 2p40: IL-12p35 expression. In contrast, ICAM-1(- / -) NOD mice did not upre gulate IFN-gamma or IL-12p40 gene expression but maintained IL-4 and increa sed IL-12p35 gene expression. These results identify a dominant ICAM-1, kno ckout, and non-redundant role of ICAM-1 in the development of autoimmune (C ) 2001 Academic Press.