Inhibition of interferon-γ by an interferon-γ receptor immunoadhesin.

Interferon-γ (IFN-γ) is an important cytokine which regulates inflammatory and immune response mechanisms. IFN-γ 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-γ has been implicated in the pathogenesis of several autoimmune and inflammatory diseases and in graft rejection. Here, we describe, a recombinant inhibitor of IFN-γ, termed murine IFN-γ receptor immunoadhesin (mIFN-γR-IgG). We constructed this immunoadhesin by linking the extracellular portion of the mouse IFN-γR to the hinge and Fc region of an IgG1 heavy chain. Murine IFN-γR-IgG is secreted by transfected cells as a disulphide-bonded homodimer which binds IFN-γ bivalently, with high affinity and in a species-specific manner. In vitro, mIFN-γRIgG can block mIFN-γ-induced antiviral activity and expression of the class I MHC antigen H-2K^k in cultured cells. In vivo, mIFN-γ,R-IgG can block the function of endogenous mIFN-γ in mouse models of infection with Listeria monocytogenes and of contact sensitivity. These results show that mIFNγR-IgG is an effective and specific inhibitor of mIFN-γ both in vitro and in vivo. Thus, in general, IFN-γ receptor immunoadhesins may be useful for investigating the biological functions of IFN-γ as well as for preventing deleterious effects of IFN-γ in human disease. [ABSTRACT FROM AUTHOR]