DIFFERENTIAL-EFFECTS OF ANTIBODIES TO VASCULAR CELL-ADHESION MOLECULE-1 AND DISTINCT EPITOPES OF THE ALPHA-4 INTEGRIN IN HGCL2- INDUCED NEPHRITIS IN BROWN-NORWAY RATS

Four distinct epitopes (A, B1, B2, and C) have been functionally defin ed on the human alpha 4 integrin. In this study, two cross-reactive an tihuman alpha 4 monoclonal antibodies (mAb) (HP2/1 and HP2/4 specific for epitopes B1 and B2, respectively) were used to functionally charac terize the rat VLA-4 subunit and to define similar functional epitopes in this rodent species. It was found that B1 and B2 anti-alpha 4 mAb completely block adhesion to fibronectin, but the inhibition of adhesi on to vascular cell adhesion molecule-1 (VCAM-1) with HP2/1 mAb was lo wer than with HP2/4 mAb. It was also observed that epitope B2 HP2/4 mA b induced homotypic aggregation in rat lymphocytes, whereas epitope B1 HP2/1 mAb did not. Using the HgCl2 model of nephritis, this study sho ws the protective effect of both anti-alpha 4 mAb against infiltration of the renal interstitium by leukocytes. Nevertheless, HP2/1 mAb, but not HP2/4 mAb, virtually abolished the anti-glomerular basement membr ane antibody synthesis and glomerular deposits. These findings indicat e the dual but independent role played by alpha 4 integrins in both ex travasation of leukocytes and in the production of antibodies. Finally , this study demonstrates that anti-rat VCAM-1 mAb showed a positive r eactivity of the renal vascular endothelium and, most importantly, tha t administration of anti-VCAM-1 antibodies completely abrogated the in terstitial cell infiltrates without affecting anti-glomerular basement membrane antibody production. These results confirm the important rol e played by VLA-4/VCAM-1 pathway in leukocyte infiltration, and furthe r support the dual and independent role of a4 integrins in both renal infiltration and autoantibody synthesis in this model of renal disease .