INHIBITION OF INTERFERON-GAMMA BY AN INTERFERON-GAMMA RECEPTOR IMMUNOADHESIN

Interferon-gamma (IFN-gamma) is an important cytokine which regulates inflammatory and immune response mechanisms. IFN-gamma enhances the presentation and recognition of antigens by inducing the expression of major histocompatibility complex (MHC) proteins, by activating effector T cells and mononuclear phagocytes, and by modulating immunoglobulin production and class selection in B cells. Inappropriate production of IFN-gamma has been implicated in the pathogenesis of several autoimmune and inflammatory diseases and in graft rejection. Here, we describe a recombinant inhibitor of IFN-gamma, termed murine IFN-gamma receptor immunoadhesin (mIFN-gammaR-IgG). We constructed this immunoadhesin by linking the extracellular portion of the mouse IFN-gammaR to the hinge and Fc region of an IgG1 heavy chain. Murine IFN-gammaR-IgG is secreted by transfected cells as a disulphide-bonded homodimer which binds IFN-gamma bivalently, with high affinity and in a species-specific manner. In vitro, mIFN-gammaR-IgG can block mIFN-gamma-induced antiviral activity and expression of the class I MHC antigen H-2K(k) in cultured cells. In vivo, mIFN-gammaR-IgG can block the function of endogenous mIFN-gamma in mouse models of infection with Listeria monocytogenes and of contact sensitivity. These results show that mIFN-gammaR-IgG is an effective and specific inhibitor of mIFN-gamma both in vitro and in vivo. Thus, in general, IFN-gamma receptor immunoadhesins may be useful for investigating the biological functions of IFN-gamma as well as for preventing deleterious effects of IFN-gamma in human disease.