NZW)F, LUPUS-LIKE NEPHRITIS WITH MONOCLONAL ANTIBODY TO -y INTERFERON

The F, hybrids of the autoimmune New Zealand Black (NZB) mice and the phenotypically normal New Zealand White (NZW) mouse strain, develop severe systemic autoimmune disease, more fulminant than that found in the parental NZB strain . These mice manifest several immune abnormalities including antibodies to nuclear antigens and subsequent development of a fatal, immune complex-mediated glomerulonephritis with female predominance, remarkably similar to systemic lupus erythematosus (SLE) in humans. As a reflection of their autoimmune nature, both the humanand murine forms of the disease show a strong association with MHC gene products . HLA DR2 and HLA DR3 individuals are at a higher risk than the general population to develop SLE (1), while in NZB/W F, mice (H-2d/°) a gene linked to the H-2u haplotype derived from the NZW parent contributes to the development of the lupus-like nephritis (2). The role of MHC genes in SLE and murine lupus is unknown. Similarly, it has been difficult to clarify the regulatory and functional abnormalities in the immune system that allow the tissue damage to occur in autoimmune disease . No doubt, with the large range of cellular interactions required for normal immunological function and tolerance, defects in the control or modulation of these interactions could occur at several levels and at any or all of these might result in reactivity to self antigens . In this study we pursue the hypothesis that IFN--t plays a crucial role in the pathogenesis of autoimmune processes . Earlier reports from this laboratory (3) and from others (4-5) have indicated that treatment of NZB/W F, mice with partially purified type I or type II interferon, resulted in an increased incidence of glomerulonephritis and death. If this hypothesis is correct, administration of IFN-y may upregulate the autoimmune process, while blocking the effect of IFN-y might downregulate such a process . We have tested this hypothesis in vivo, in the NZB X NZW/F, lupus nephritis murine model.