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-gamma R-IgG). We constructed this immunoadhesin by linking the extracellular portion of the mouse IFN-gamma R to the hinge and Fc region of an IgG1 heavy chain. Murine IFN-gamma R-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-gamma R-IgG can block mIFN-gamma-induced antiviral activity and expression of the class I MHC antigen H-2Kk in cultured cells. In vivo, mIFN-gamma R-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-gamma R-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.
Haak-Frendscho
M
M
Department of Molecular Biology, Genentech, Inc., South San Francisco, California 94080-4990.
Marsters
S A
SA
Chamow
S M
SM
Peers
D H
DH
Simpson
N J
NJ
Ashkenazi
A
A
D000818:Animals; D002448:Cell Adhesion / Q000276:immunology; D002478:Cells, Cultured; D004270:DNA, Circular / Q000276:immunology; D003877:Dermatitis, Contact / Q000276:immunology; D004686:Encephalomyocarditis virus / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008089:Listeria monocytogenes; D008088:Listeriosis / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D017471:Receptors, Interferon / Q000276:immunology*
D004270:DNA, Circular; D007074:Immunoglobulin G; D017471:Receptors, Interferon; D007371:Interferon-gamma