CD28-B7 blockade prevents the development of experimental autoimmune glomerulonephritis.
Experimental autoimmune glomerulonephritis (EAG), an animal model of Goodpasture's disease, can be induced in Wistar Kyoto (WKY) rats by a single injection of rat glomerular basement membrane (GBM) in adjuvant. EAG is characterized by circulating and deposited anti-GBM antibodies, accompanied by focal necrotizing glomerulonephritis with crescent formation. The role of T cells in the pathogenesis of EAG remains unclear. T-cell costimulation is provided by ligation of CD28 with either B7.1 (CD80) or B7.2 (CD86) on antigen-presenting cells, and can be inhibited by a soluble form of CTLA4 (CTLA4-Ig) that binds to both B7.1 and B7.2. We examined the effect of CD28-B7 blockade on the development of EAG using native CTLA4-Ig or mutant CTLA4-Ig (Y100F-Ig), which selectively blocks B7.1. Native CTLA4-Ig treatment ameliorated EAG by several measures, including the levels of circulating anti-GBM antibodies, albuminuria, the deposition of IgG and fibrin in the glomeruli, the severity of glomerular abnormalities, and the numbers of infiltrating T cells and macrophages. Y100F-Ig resulted in a similar reduction in the severity of nephritis, but produced no overall reduction in circulating anti-GBM antibodies, although there was a reduction in IgG2a antibodies. We concluded that CD28-B7 blockade reduced autoantibody production and cellular infiltration of glomeruli, and prevented target organ injury. Our results suggest a key role for B7. 1 in costimulation of Th1-like autoimmune responses in the rat, and show that glomerular injury in EAG is largely dependent on cell-mediated mechanisms.
Reynolds
J
J
Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London W12 ONN, United Kingdom. john.reynolds@ic.ac.uk
Tam
F W
FW
Chandraker
A
A
Smith
J
J
Karkar
A M
AM
Cross
J
J
Peach
R
R
Sayegh
M H
MH
Pusey
C D
CD
D000069594:Abatacept; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000494:pharmacology; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology*; D001485:Basement Membrane / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology*; D060908:CTLA-4 Antigen; D004195:Disease Models, Animal; D005337:Fibrin / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005921:Glomerulonephritis / Q000276:immunology*; D018796:Immunoconjugates; D007074:Immunoglobulin G / Q000097:blood; D007668:Kidney / Q000276:immunology / Q000473:pathology; D009154:Mutation; D051381:Rats; D011919:Rats, Inbred Strains; D013601:T-Lymphocytes / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D001323:Autoantibodies; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556708:Ctla4 protein, rat; D018796:Immunoconjugates; D007074:Immunoglobulin G; D000069594:Abatacept; D005337:Fibrin