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Blockade of the CD154-CD40 costimulatory pathway prevents the development of experimental autoimmune glomerulonephritis.

Authors: Reynolds, J  Khan, SB  Allen, AR  Benjamin, CD  Pusey, CD 
Citation: Reynolds J, etal., Kidney Int. 2004 Oct;66(4):1444-52.
Pubmed: (View Article at PubMed) PMID:15458437
DOI: Full-text: DOI:10.1111/j.1523-1755.2004.00907.x

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. CONCLUSION: 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.

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RGD Object Information
RGD ID: 5508170
Created: 2011-10-05
Species: All species
Last Modified: 2011-10-05
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.