IFN-γ Mediates Crescent Formation and Cell-Mediated Immune Injury in Murine Glomerulonephritis

Abstract. Features of crescentic glomerulonephritis suggest that it results from a T helper 1 (Th1) nephritogenic immune response. Interferon-γ (IFN-γ), produced by Th1 cells, is involved in T cell-directed macrophage activation in effector Th1 responses. The hypothesis that endogenous IFN-γ contributes to the development of crescentic glomerulonephritis was tested by comparing the development of glomerulonephritis (induced by a planted antigen) and immune responses in normal C57BL/6 mice (IFN-γ +/+) and in mice genetically deficient in IFN-γ (IFN-γ -/-). Ten days after the initiation of glomerulonephritis, IFN-γ -/- mice developed fewer glomerular crescents (5 ± 1% versus 26 ± 3%, P < 0.005), less severe glomerular injury, and less renal impairment. Effectors of delayed-type hypersensitivity (CD4+ T cells, macrophages, and fibrin) in glomeruli were reduced in IFN-γ -/- mice. Skin delayed-type hypersensitivity to sheep globulin was reduced. Total antigen-specific Ig and splenocyte interleukin-2 production were unchanged, but antigen-specific serum IgG2a was reduced. Markers of an antigen-specific Th2 response (serum IgG1, splenocyte interleukin-4) were unchanged. Studies 22 d after the initiation of glomerulonephritis showed that IFN-γ -/- mice still had fewer crescents (11 ± 2% versus 22 ± 3%, P = 0.02) and glomerular CD4+ T cells and macrophages than IFN-γ +/+ mice. These studies demonstrate that endogenous IFN-γ mediates crescentic glomerulonephritis by promoting cell-mediated immune injury. They support the hypothesis that crescentic glomerulonephritis is a manifestation of a Th1 nephritogenic immune response.