Monoclonal antibodies to the integrin alpha-4 subunit inhibit the murine contact hypersensitivity response.
Lymphocyte-endothelial cell recognition is an active multistep process central to the pathophysiology of inflammation. In vitro models of lymphocyte adhesion predict that the beta 1 integrin very late antigen-4 (VLA-4), an activation-dependent adhesion receptor, can mediate the firm sustained attachment required for the extravasation of memory lymphocytes. We have used murine contact hypersensitivity as an in vivo model in which to evaluate the role of alpha-4 integrins in an evolving inflammatory response. We demonstrate that the intravenous administration of 75 micrograms of the anti-alpha-4 specific monoclonal antibodies R1-2 or PS/2 4-6 h prior to challenge significantly inhibits the efferent response of 2,4 dinitrofluorobenzene, or oxazolone-sensitized mice. The disease-modifying effect of anti-alpha 4 treatment was evident as a 50-60% reduction in the ear swelling response. By histological analysis treated animals scored lower for edema, number of epidermal lesions and degree of leukocyte infiltration. Antibody-treated animals have elevated numbers of circulating mononuclear leukocytes present in the same relative ratio as untreated control animals, suggesting that the inhibitory effect was not due to antibody-dependent cellular depletion of effector lymphocytes. These data are consistent with a central role for VLA-4 in the pathophysiologic process of inflammation.
Chisholm
P L
PL
Biogen, Inc., Cambridge Center, MA 02142.
Williams
C A
CA
Lobb
R R
RR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D003877:Dermatitis, Contact / Q000276:immunology* / Q000473:pathology; D005260:Female; D006241:Haptens; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000473:pathology; D007111:Immunity, Cellular; D051379:Mice; D008807:Mice, Inbred BALB C; D016029:Receptors, Very Late Antigen / Q000276:immunology*; D013997:Time Factors
D000911:Antibodies, Monoclonal; D006241:Haptens; D016029:Receptors, Very Late Antigen