Increased susceptibility to immunologically mediated glomerulonephritis inIFN-gamma-deficient mice

It is postulated that IFN-gamma confers susceptibility to immunologically m ediated tissue injury, To test this hypothesis, we compared the intensity o f accelerated anti-glomerular basement membrane glomerulonephritis between wild-type (IFN-gamma(+/+)) and IFN-gamma gene knockout (IFN-gamma(-/-)) mic e. This disease model is initiated by binding of heterologous (sheep) anti- glomerular basement membrane Abs to the glomeruli of mice preimmunized with sheep IgG. The secondary cellular and humoral immune responses to the plan ted Ag then lead to albuminuria and glomerular pathology. We found that IFN -gamma(-/-) mice or IFN-gamma(+/+) mice injected with IFN-gamma-neutralizin g Ab develop worse albuminuria and glomerular pathology than IFN-gamma(+/+) mice. The humoral response to sheep IgG (serum mouse anti-sheep IgG titers and intraglomerular mouse IgG deposits) was comparable in the IFN-gamma(+/ +) and IFN-gamma(-/-) groups. In contrast, IFN-gamma(-/-) mice mounted a st ronger cellular immune response (cutaneous delayed-type hypersensitivity re action) to sheep IgG than IFN-gamma(+/+) mice. These findings provide evide nce that endogenous IFN-gamma has a protective role in immunologically medi ated glomerulonephritis initiated by foreign Ags.