Blockade of the CD154-CD40 costimulatory pathway prevents the development of experimental autoimmune glomerulonephritis.
BACKGROUND
Experimental autoimmune glomerulonephritis (EAG) was induced in Wistar-Kyoto (WKY) rats by immunization with rat glomerular basement membrane (GBM) in adjuvant. This model is characterized by anti-GBM antibody production, accompanied by focal necrotizing glomerulonephritis with crescent formation. There is also glomerular infiltration by T cells and macrophages. Our hypothesis was that blocking the interaction between CD154 (CD40L) on Th cells and CD40 on antigen-presenting cells should inhibit T-cell activation, and thus the development of EAG.


METHODS
The in vivo effects of a hamster anti-rat monoclonal antibody to CD154 (AH.F5) were examined in EAG starting at day -1 prior to immunization, day +7 after immunization, or day +14 after immunization.


RESULTS
When administered from day -1 at a dose of 10 mg/kg intraperitoneally three times per week for the duration of the study (4 weeks), AH.F5 resulted in a marked reduction in circulating anti-alpha3(IV)NC1 antibodies, deposits of IgG on the GBM, albuminuria, deposits of fibrin in the glomeruli, severity of glomerular abnormalities, and numbers of glomerular T cells and macrophages. When administered from day +7 at the same dose, AH.F5 resulted in a moderate reduction in the severity of disease, while administration from day +14 had no significant effect.


CONCLUSIONS
These studies demonstrate for the first time that early blockade of the CD154-CD40 T-cell costimulatory pathway can prevent the development of crescentic nephritis, and that delayed treatment can reduce the severity of disease. This confirms the importance of T cell mediated immunity in the pathogenesis of EAG, and suggests that strategies targeting T-cell costimulation may provide a novel approach in the treatment of human glomerulonephritis.
Renal Section, Division of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom. john.reynolds@imperial.ac.uk
John
J
Reynolds
Sarah B
SB
Khan
Andrew R
AR
Allen
Christopher D
CD
Benjamin
Charles D
CD
Pusey
D000419:Albuminuria / Q000276:immunology / Q000628:therapy; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology* / Q000628:therapy*; D000906:Antibodies / Q000097:blood; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001323:Autoantibodies; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000276:immunology* / Q000378:metabolism; D003404:Creatinine / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D019085:Fluorescent Antibody Technique, Direct; D007074:Immunoglobulin G / Q000097:blood; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism; D008297:Male; D051381:Rats; D011921:Rats, Inbred WKY; D013601:T-Lymphocytes / Q000276:immunology
D000906:Antibodies; D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D019013:CD40 Antigens; D007074:Immunoglobulin G; C051951:antiglomerular basement membrane antibody; D023201:CD40 Ligand; D005337:Fibrin; D003404:Creatinine