CD80 and CD86 costimulatory molecules regulate crescentic glomerulonephritis by different mechanisms

Kidney Int. 2005 Aug;68(2):584-94. doi: 10.1111/j.1523-1755.2005.00436.x.

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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / blood
  • Antibodies / pharmacology
  • Antigens, CD / genetics
  • Antigens, CD / immunology*
  • Antigens, CD / metabolism
  • Apoptosis
  • B7-1 Antigen / genetics
  • B7-1 Antigen / immunology*
  • B7-1 Antigen / metabolism
  • B7-2 Antigen
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Division / immunology
  • Cells, Cultured
  • Glomerulonephritis / immunology*
  • Glomerulonephritis / metabolism*
  • Glomerulonephritis / pathology
  • Kidney Glomerulus / immunology
  • Kidney Glomerulus / metabolism
  • Kidney Glomerulus / pathology
  • Macrophages / immunology
  • Macrophages / pathology
  • Male
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology*
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Spleen / cytology
  • Spleen / immunology
  • Tumor Necrosis Factors

Substances

  • Antibodies
  • Antigens, CD
  • B7-1 Antigen
  • B7-2 Antigen
  • Cd86 protein, mouse
  • Membrane Glycoproteins
  • Tnfsf4 protein, mouse
  • Tumor Necrosis Factors