title: Effect of CTLA-4 chimeric protein on rat autoimmune anti-glomerular basement membrane glomerulonephritis.
abstract: The interaction of the T cell receptor with the antigen/major histocompatibility class II complex is insufficient to induce optimal T cell activation. Co-stimulatory signals, including those provided by CD28/CTLA-4 on T cells and B7 molecules (B7-1, -2, and -3) on antigen-presenting cells, are also required. CD28-B7 interactions can be blocked by a soluble human CTLA-4 chimeric protein (CTLA4Ig). We tested the effect of administration of CTLA4Ig on experimental anti-glomerular basement membrane (GBM) autoimmune glomerulonephritis in Wistar-Kyoto rats induced by immunization with bovine GBM. The disease is characterized by development of antibody to the alpha 3 chain of type IV collagen (Goodpasture's antigen), deposition of rat IgG in GBM, infiltration of the kidney by T cells and macrophages, severe crescent formation and renal failure leading to death in 5-6 weeks. Animals injected with human CTLA4Ig from day 0 to day 14 or to day 35 had reduced disease severity. Beneficial effects were observed even when injections were begun after the onset of glomerulonephritis on day 14. However, the rats developed antibody to the human CTLA4Ig, associated with reduction in levels of circulating CTLA4Ig. The results provide evidence for CD28/CTLA-4 signaling in rat autoimmune glomerulonephritis, and suggest that more effective inhibition of B7-dependent T cell activation, such as might be achieved with homologous CTLA4Ig, could be useful in the treatment of autoimmune diseases.
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston.
authors.forename: K
authors.initials: K
authors.lastname: Nishikawa
authors.forename: P S
authors.initials: PS
authors.lastname: Linsley
authors.forename: A B
authors.initials: AB
authors.lastname: Collins
authors.forename: I
authors.initials: I
authors.lastname: Stamenkovic
authors.forename: R T
authors.initials: RT
authors.lastname: McCluskey
authors.forename: G
authors.initials: G
authors.lastname: Andres
mesh_terms: D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D000954:Antigens, Surface / Q000276:immunology; D001485:Basement Membrane / Q000276:immunology; D060908:CTLA-4 Antigen; D002417:Cattle; D003094:Collagen / Q000276:immunology; D005455:Fluorescent Antibody Technique; D015433:Glomerulonephritis, Membranous / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D018796:Immunoconjugates; D007124:Immunoenzyme Techniques; D007678:Kidney Glomerulus / Q000276:immunology; D009363:Neoplasm Proteins / Q000276:immunology; D051381:Rats; D011921:Rats, Inbred WKY; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D000954:Antigens, Surface; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556708:Ctla4 protein, rat; D018796:Immunoconjugates; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; C074075:TM4SF1 protein, human; D000069594:Abatacept; D003094:Collagen