REDUCED SUSCEPTIBILITY TO COLLAGEN-INDUCED ARTHRITIS IN MICE DEFICIENT IN INTERCELLULAR-ADHESION MOLECULE-1

Intercellular adhesion molecule-1 (ICAM-1) plays an important role in the firm adhesion of leukocytes to venular endothelium and facilitates leukocyte extravasation from the vasculature into inflamed tissue, In addition, ICAM-1 is an important costimulatory molecule during Ag pre sentation to lymphocytes, Using mice deficient in ICAM-1, we have inve stigated the role of this molecule in the development of collagen-indu ced arthritis, After immunization with type II collagen, 71% of wild-t ype mice developed arthritis compared with 50% of ICAM-1 heterozygote mutants and 18% of ICAM-1 homozygous mutants. In those ICAM-1 mutants that developed arthritis, the mean day of onset, the mean number of in volved paws, and the severity of paw inflammation were not significant ly different from those in wild-type mice, The reduced incidence of ar thritis in the ICAM-1 homozygous mutant mice was not due to lack of im munity to type II collagen, since these mice developed similar levels of anti-type II collagen IgC compared with wild-type mice and had a po sitive delayed-type hypersensitivity reaction to type II collagen, The reduction of arthritis in heterozygous as well as homozygous deficien t mice indicates that expression of ICAM-1 can be a pivotal variable i n the pathogenesis of collagen-induced arthritis in mice. The results suggest that naturally occurring genetic variation in the expression o f ICAM-1 or related inflammatory cell adhesion molecules might influen ce susceptibility to the complex disease of rheumatoid arthritis in hu mans and support the concept that pharmacologic approaches to chronic reduction in the expression or the function of ICAM-1 may be of therap eutic value.