Prevention of mercuric chloride-induced nephritis in the brown Norway rat by treatment with antibodies against the alpha 4 integrin.
HgCl2 induces the synthesis of anti-GBM Abs with the development of glomerular and interstitial nephritis, as well as proteinuria, in the Brown Norway rat. The development of this autoimmune disease is a consequence of the appearance of an autoreactive T cell subset-inducing activation of B cells. The administration to mercury-treated rats of the mouse anti-human VLA alpha 4 HP2/1 mAb, which cross-reacts with the rat homologue integrin, completely abrogated the interstitial cell infiltrates. As demonstrated by peripheral blood analysis, this effect is not a result of the depletion of circulating leukocytes or leukocyte subsets. 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 that in vivo alpha 4 functions in adhesive interaction of circulating leukocytes and vascular endothelium, and is centrally important in the extravasation and migration of T lymphocytes to sites of tissue injury. We also found a complete absence of interstitial cell infiltrates, together with a positive glomerular IgG lineal deposition pattern, when anti-GBM Abs were passively transferred to rats pretreated with anti-alpha 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 the participation of the VLA-4 integrin in mediating the intercellular interaction of leukocytes regulating the production of Abs, most likely through the existence of additional yet unknown ligand(s).
Molina
A
A
Department of Pathology, Ramón and Cajal Hospital, Madrid, Spain.
Sánchez-Madrid
F
F
Bricio
T
T
Martín
A
A
Barat
A
A
Alvarez
V
V
Mampaso
F
F
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D002448:Cell Adhesion; D004277:DNA, Single-Stranded / Q000276:immunology; D007116:Immunization, Passive; D016023:Integrins / Q000502:physiology*; D007678:Kidney Glomerulus / Q000276:immunology; D007958:Leukocyte Count; D008297:Male; D008627:Mercuric Chloride / Q000037:antagonists & inhibitors*; D009393:Nephritis / Q000139:chemically induced*; D011507:Proteinuria / Q000139:chemically induced; D051381:Rats; D011914:Rats, Inbred BN; D016029:Receptors, Very Late Antigen / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000276:immunology
D000911:Antibodies, Monoclonal; D004277:DNA, Single-Stranded; D016023:Integrins; D016029:Receptors, Very Late Antigen; D008627:Mercuric Chloride