CD28-B7 blockade prevents the development of experimental autoimmune glomerulonephritis

J Clin Invest. 2000 Mar;105(5):643-51. doi: 10.1172/JCI6710.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abatacept
  • Animals
  • Anti-Glomerular Basement Membrane Disease / immunology
  • Antigens, CD
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / pharmacology
  • Autoantibodies / immunology
  • Autoimmune Diseases / immunology*
  • B7-1 Antigen / immunology*
  • Basement Membrane / immunology
  • CD28 Antigens / immunology*
  • CTLA-4 Antigen
  • Disease Models, Animal
  • Fibrin / metabolism
  • Fluorescent Antibody Technique
  • Glomerulonephritis / immunology*
  • Immunoconjugates*
  • Immunoglobulin G / blood
  • Kidney / immunology
  • Kidney / pathology
  • Mutation
  • Rats
  • Rats, Inbred Strains
  • T-Lymphocytes / immunology


  • Antigens, CD
  • Antigens, Differentiation
  • Autoantibodies
  • B7-1 Antigen
  • CD28 Antigens
  • CTLA-4 Antigen
  • Ctla4 protein, rat
  • Immunoconjugates
  • Immunoglobulin G
  • Abatacept
  • Fibrin