Treatment of murine lupus with cDNA encoding IFN-γR/Fc (original) (raw)

2000, Journal of Clinical Investigation

Introduction Lupus, the prototypic systemic autoimmune disease, is characterized by a high female predominance, multiorgan pathology, and a broad spectrum of autoantibodies, of which those against nuclear antigens typically predominate (1). The etiology of this disease is still unknown, but a strong genetic predilection appears to be a dominant factor (reviewed in ref. 2). Despite considerable advances in the management of this disease, morbidity and mortality remain high, and intense efforts are ongoing to develop less toxic and more efficacious treatments. Among the many avenues pursued in experimental models, those related to immunointervention with blocking peptides (3), antibodies, and other agents that inhibit coreceptor or costimulatory molecules (4-6), and those using agonist and antagonists of cytokines (reviewed in ref. 7 and 8), appear to be promising. Many cytokine abnormalities have been identified in lupus-predisposed mice and humans (reviewed in ref. 7 and 8), the most prominent of which is increased levels of IFN-γ in serum, lymphoid organs, and afflicted tissues. The importance of this Th1 type inflammatory cytokine in lupus pathogenesis was suggested by the initial demonstration of Jacob et al. (9) that (NZBxW)F 1 lupus mice treated with IFN-γ or its inducers showed accelerated disease, whereas those treated with anti-IFN-γ Ab beginning at the early stage showed significant delay in disease onset. The most compelling evidence for the deleterious effects of IFN-γ in lupus was obtained recently by us (10) and