title: CD80 and CD86 costimulatory molecules regulate crescentic glomerulonephritis by different mechanisms.
abstract: BACKGROUND
  CD80 and CD86 costimulatory molecules have been shown to affect the induction of Th1-mediated crescentic antiglomerular basement membrane (GBM) antibody-initiated glomerulonephritis (GN). The aim of the current studies was to define the mechanisms by which CD80 and CD86 regulate the development of this disease.
  
  
  METHODS
  Anti-GBM GN was induced in CD80-/-, CD86-/-, and CD80/86-/- mice, as well as in C57BL/6 controls. Renal injury and immune responses were assessed after 21 days. To examine whether costimulation by OX40-ligand compensates for the absence of CD80 and CD86 in inducing GN, OX40-ligand was blocked in wild-type and CD80/86-/- mice.
  
  
  RESULTS
  Crescentic GN and glomerular accumulation of CD4+ T cells and macrophages were attenuated in CD80-/- mice, correlating with significantly enhanced apoptosis and decreased proliferation of spleen CD4+ T cells. GN was exacerbated in CD86-/- mice, which was associated with attenuated IL-4 and enhanced IFN-gamma levels. In contrast, CD80/86-/- mice developed crescentic GN similar to that in controls. Inhibition of OX40-ligand exacerbated GN in wild-type mice by enhancing IFN-gamma production, and attenuated disease in CD80/86-/- mice by reducing glomerular CD4+ T-cell and macrophage accumulation.
  
  
  CONCLUSIONS
  CD80 is pathogenic in crescentic GN by enhancing survival and proliferation of CD4+ T cells, whereas CD86 is protective by enhancing Th2 and attenuating Th1 responses. Furthermore, in the presence of CD80 and CD86, OX40-ligand attenuates, whereas in their absence it enhances GN, suggesting that, in the absence of CD80 and CD86, the OX40/OX40-ligand pathway is an alternative costimulatory pathway in inducing crescentic GN.
authors: Centre for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
authors: Dragana
authors: D
authors: Odobasic
authors: A Richard
authors: AR
authors: Kitching
authors: Peter G
authors: PG
authors: Tipping
authors: Stephen R
authors: SR
authors: Holdsworth
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051940:B7-2 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D005921:Glomerulonephritis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D053278:OX40 Ligand; D013154:Spleen / Q000166:cytology / Q000276:immunology; D048069:Tumor Necrosis Factors
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors