PREVENTION OF MERCURIC CHLORIDE-INDUCED NEPHRITIS IN THE BROWN-NORWAYRAT BY TREATMENT WITH ANTIBODIES AGAINST THE ALPHA-4 INTEGRIN

HgCl2 induces the synthesis of anti-GBM Abs with the development of gl omerular and interstitial nephritis, as well as proteinuria, in the Br own Norway rat. The development of this autoimmune disease is a conseq uence of the appearance of an autoreactive T cell subset-inducing acti vation of B cells. The administration to mercury-treated rats of the m ouse anti-human VLA alpha 4 HP2/1 mAb, which cross-reacts with the rat homologue integrin, completely abrogated the interstitial cell infilt rates. As demonstrated by peripheral blood analysis, this effect is-no t a result of the depletion of circulating leukocytes or leukocyte sub sets. Interestingly, the administration of Abs specific for the alpha 4 integrin also highly reduced anti-GBM Ab synthesis, thus preventing detectable glomerular deposits and proteinuria. Our results confirm th at in vivo alpha 4 functions in adhesive interaction of circulating le ukocytes and vascular endothelium, and is centrally important in the e xtravasation and migration of T lymphocytes to sites of tissue injury. We also found a complete absence of interstitial cell infiltrates, to gether with a positive glomerular IgG lineal deposition pattern, when anti-GBM Abs were passively transferred to rats pretreated with anti-a lpha 4 mAb, thus indicating an independent role of alpha 4 integrin in both extravasation of immune cells and production of autoantibodies. Furthermore, these in vivo findings provide preliminary evidence for t he participation of the VLA-4 integrin in mediating the intercellular interaction of leukocytes regulating the production of Abs, most likel y through the existence of additional yet unknown ligand(s).