Protective effects of monoclonal antibody to VLA-4 on leukocyte adhesion and course of disease in adjuvant arthritis in rats.
OBJECTIVE
Leukocyte adhesion to the endothelium of postcapillary venules is considered an important step in the inflammatory response. Cell adhesion molecules have been found to play a role in virtually every cellular interaction from inflammation to reperfusion injury. The purpose of this study was to determine the extent of leukocyte adhesion during the development of adjuvant arthritis in rats, and the putative inhibitory effect of a monoclonal antibody (Mab) to very late activation antigen-4 (VLA-4) on leukocyte adhesion and on arthritic disease.


METHODS
Adjuvant arthritis was induced in rats by subdermal injection of Freund's adjuvant and arthritis index quantified on the 18th day of disease. Number of rolling, adherent leukocytes/100 microns venule and blood cell velocity were quantified in mesenteric venules (20-30 microns diameter and 100 microns length) of Wistar-Lewis rats, using intravital microscopy.


RESULTS
We administered a Mab to rat VLA-4, alpha 4-subunit, at a dose of 1 mg/kg intravenously on Days 1, 9, and 17 to the arthritic rats. Both variables measured in mesenteric venules were reduced. Leukocyte rolling was partially inhibited (by 57%), whereas leukocyte adhesion was totally inhibited (by 94%). In addition, the arthritis index decreased by 54%. Nonbinding isotype mouse IgG1 control antibody did not affect either of the variables.


CONCLUSIONS
Leukocyte adhesion in mesenteric venules of adjuvant arthritic rats involves VLA-4 interaction with an unknown endothelial ligand, which is completely inhibited by Mab to rat VLA-4, indicating a promising effect on clinical symptoms.
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Microcirculatory Laboratory, Hoechst AG, Wiesbaden, Germany.
D000818:Animals; D018926:Anti-Allergic Agents / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000503:physiopathology*; D002448:Cell Adhesion / Q000187:drug effects; D007074:Immunoglobulin G / Q000494:pharmacology; D039041:Integrin alpha4beta1; D016023:Integrins / Q000276:immunology*; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D016201:Receptors, Lymphocyte Homing / Q000276:immunology*
D018926:Anti-Allergic Agents; D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D039041:Integrin alpha4beta1; D016023:Integrins; D016201:Receptors, Lymphocyte Homing