title: Anti-CD8 monoclonal antibody therapy is effective in the prevention and treatment of experimental autoimmune glomerulonephritis.
abstract: Experimental autoimmune glomerulonephritis (EAG), which is an animal model of Goodpasture's disease, can be induced in Wistar Kyoto rats by a single injection of rat glomerular basement membrane (GBM) in adjuvant. EAG is characterized by circulating and deposited anti-GBM antibodies, focal necrotizing glomerulonephritis with crescent formation, and glomerular infiltration by T cells and macrophages. Our hypothesis was that T cell-mediated immunity, in addition to humoral immunity, was necessary for the development of crescentic nephritis in this model. To investigate the role of CD8+ T cells in the pathogenesis of EAG, the in vivo effects of an anti-CD8 monoclonal antibody (OX8) were examined, with administration starting at the time of immunization (prevention) or 2 wk after immunization, when glomerular abnormalities were first detected (treatment). When administered intraperitoneally at 5 mg/kg, three times per week, from week 0 to week 4 (prevention), OX8 completely inhibited the development of albuminuria, deposits of fibrin in the glomeruli, glomerular and interstitial abnormalities, the influx of CD8+ T cells and macrophages, and glomerular expression of granzyme B and inducible nitric oxide synthase. Circulating anti-GBM antibody levels were not reduced, but there was a reduction in the intensity of antibody deposition on the GBM. When administered at the same dose from week 2 to week 4 (treatment), OX8 greatly reduced the severity of EAG; in particular, the formation of crescents was prevented. These studies demonstrate that anti-CD8 monoclonal antibody therapy is effective in both the prevention and treatment of EAG. They confirm the importance of T cell-mediated immunity in the pathogenesis of this model of Goodpasture's disease. Similar therapeutic approaches may be worth investigating in human crescentic glomerulonephritis.
authors.affiliation: *Renal Section, Division of Medicine, and Department of Histopathology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Reynolds
authors.affiliation: *Renal Section, Division of Medicine, and Department of Histopathology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, United Kingdom.
authors.forename: Vicki A
authors.initials: VA
authors.lastname: Norgan
authors.affiliation: *Renal Section, Division of Medicine, and Department of Histopathology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, United Kingdom.
authors.forename: Upinder
authors.initials: U
authors.lastname: Bhambra
authors.affiliation: *Renal Section, Division of Medicine, and Department of Histopathology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, United Kingdom.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Smith
authors.affiliation: *Renal Section, Division of Medicine, and Department of Histopathology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, United Kingdom.
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
authors.affiliation: *Renal Section, Division of Medicine, and Department of Histopathology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, United Kingdom.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Pusey
mesh_terms: D000419:Albuminuria / Q000209:etiology; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000097:blood / Q000378:metabolism / Q000517:prevention & control* / Q000652:urine; D000906:Antibodies / Q000097:blood; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D016827:CD8 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D003404:Creatinine / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007074:Immunoglobulin G / Q000378:metabolism; D007150:Immunohistochemistry; D018655:Lymphocyte Count; D008297:Male; D051381:Rats; D011921:Rats, Inbred WKY
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D016827:CD8 Antigens; D007074:Immunoglobulin G; D005337:Fibrin; D003404:Creatinine