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. 1993 Aug;79(4):594–599.

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

M Haak-Frendscho 1, S A Marsters 1, S M Chamow 1, D H Peers 1, N J Simpson 1, A Ashkenazi 1
PMCID: PMC1421939  PMID: 8406584

Abstract

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.

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Selected References

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  1. Ashkenazi A., Marsters S. A., Capon D. J., Chamow S. M., Figari I. S., Pennica D., Goeddel D. V., Palladino M. A., Smith D. H. Protection against endotoxic shock by a tumor necrosis factor receptor immunoadhesin. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10535–10539. doi: 10.1073/pnas.88.23.10535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Billiau A. Gamma-interferon: the match that lights the fire? Immunol Today. 1988 Feb;9(2):37–40. doi: 10.1016/0167-5699(88)91256-X. [DOI] [PubMed] [Google Scholar]
  3. Buchmeier N. A., Schreiber R. D. Requirement of endogenous interferon-gamma production for resolution of Listeria monocytogenes infection. Proc Natl Acad Sci U S A. 1985 Nov;82(21):7404–7408. doi: 10.1073/pnas.82.21.7404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Byrn R. A., Mordenti J., Lucas C., Smith D., Marsters S. A., Johnson J. S., Cossum P., Chamow S. M., Wurm F. M., Gregory T. Biological properties of a CD4 immunoadhesin. Nature. 1990 Apr 12;344(6267):667–670. doi: 10.1038/344667a0. [DOI] [PubMed] [Google Scholar]
  5. Didlake R. H., Kim E. K., Sheehan K., Schreiber R. D., Kahan B. D. Effect of combined anti-gamma interferon antibody and cyclosporine therapy on cardiac allograft survival in the rat. Transplantation. 1988 Jan;45(1):222–223. [PubMed] [Google Scholar]
  6. Enk A. H., Katz S. I. Early molecular events in the induction phase of contact sensitivity. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1398–1402. doi: 10.1073/pnas.89.4.1398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Farrar M. A., Schreiber R. D. The molecular cell biology of interferon-gamma and its receptor. Annu Rev Immunol. 1993;11:571–611. doi: 10.1146/annurev.iy.11.040193.003035. [DOI] [PubMed] [Google Scholar]
  8. Fountoulakis M., Juranville J. F., Stüber D., Weibel E. K., Garotta G. Purification and biochemical characterization of a soluble human interferon gamma receptor expressed in Escherichia coli. J Biol Chem. 1990 Aug 5;265(22):13268–13275. [PubMed] [Google Scholar]
  9. Gentz R., Hayes A., Grau N., Fountoulakis M., Lahm H. W., Ozmen L., Garotta G. Analysis of soluble human and mouse interferon-gamma receptors expressed in eukaryotic cells. Eur J Biochem. 1992 Dec 1;210(2):545–554. doi: 10.1111/j.1432-1033.1992.tb17453.x. [DOI] [PubMed] [Google Scholar]
  10. Haak-Frendscho M., Young K. M., Czuprynski C. J. Treatment of mice with human recombinant interleukin-2 augments resistance to the facultative intracellular pathogen Listeria monocytogenes. Infect Immun. 1989 Oct;57(10):3014–3021. doi: 10.1128/iai.57.10.3014-3021.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Heremans H., Van Damme J., Dillen C., Dijkmans R., Billiau A. Interferon gamma, a mediator of lethal lipopolysaccharide-induced Shwartzman-like shock reactions in mice. J Exp Med. 1990 Jun 1;171(6):1853–1869. doi: 10.1084/jem.171.6.1853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Jacob C. O., van der Meide P. H., McDevitt H. O. In vivo treatment of (NZB X NZW)F1 lupus-like nephritis with monoclonal antibody to gamma interferon. J Exp Med. 1987 Sep 1;166(3):798–803. doi: 10.1084/jem.166.3.798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kürschner C., Garotta G., Dembić Z. Construction, purification, and characterization of new interferon gamma (IFN gamma) inhibitor proteins. Three IFN gamma receptor-immunoglobulin hybrid molecules. J Biol Chem. 1992 May 5;267(13):9354–9360. [PubMed] [Google Scholar]
  14. Kürschner C., Ozmen L., Garotta G., Dembic Z. IFN-gamma receptor-Ig fusion proteins. Half-life, immunogenicity, and in vivo activity. J Immunol. 1992 Dec 15;149(12):4096–4100. [PubMed] [Google Scholar]
  15. Landolfo S., Cofano F., Giovarelli M., Prat M., Cavallo G., Forni G. Inhibition of interferon-gamma may suppress allograft reactivity by T lymphocytes in vitro and in vivo. Science. 1985 Jul 12;229(4709):176–179. doi: 10.1126/science.3160110. [DOI] [PubMed] [Google Scholar]
  16. Lesslauer W., Tabuchi H., Gentz R., Brockhaus M., Schlaeger E. J., Grau G., Piguet P. F., Pointaire P., Vassalli P., Loetscher H. Recombinant soluble tumor necrosis factor receptor proteins protect mice from lipopolysaccharide-induced lethality. Eur J Immunol. 1991 Nov;21(11):2883–2886. doi: 10.1002/eji.1830211134. [DOI] [PubMed] [Google Scholar]
  17. Marsters S. A., Frutkin A. D., Simpson N. J., Fendly B. M., Ashkenazi A. Identification of cysteine-rich domains of the type 1 tumor necrosis factor receptor involved in ligand binding. J Biol Chem. 1992 Mar 25;267(9):5747–5750. [PubMed] [Google Scholar]
  18. Novick D., Engelmann H., Wallach D., Rubinstein M. Soluble cytokine receptors are present in normal human urine. J Exp Med. 1989 Oct 1;170(4):1409–1414. doi: 10.1084/jem.170.4.1409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Peppel K., Crawford D., Beutler B. A tumor necrosis factor (TNF) receptor-IgG heavy chain chimeric protein as a bivalent antagonist of TNF activity. J Exp Med. 1991 Dec 1;174(6):1483–1489. doi: 10.1084/jem.174.6.1483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Piguet P. F., Grau G. E., Hauser C., Vassalli P. Tumor necrosis factor is a critical mediator in hapten induced irritant and contact hypersensitivity reactions. J Exp Med. 1991 Mar 1;173(3):673–679. doi: 10.1084/jem.173.3.673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Raymond C. A. Diverse approaches to new therapies may hold promise in multiple sclerosis. JAMA. 1986 Aug 8;256(6):685–687. [PubMed] [Google Scholar]
  22. Rubinstein S., Familletti P. C., Pestka S. Convenient assay for interferons. J Virol. 1981 Feb;37(2):755–758. doi: 10.1128/jvi.37.2.755-758.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Yong V. W., Moumdjian R., Yong F. P., Ruijs T. C., Freedman M. S., Cashman N., Antel J. P. Gamma-interferon promotes proliferation of adult human astrocytes in vitro and reactive gliosis in the adult mouse brain in vivo. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7016–7020. doi: 10.1073/pnas.88.16.7016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Zoller M. J., Smith M. Oligonucleotide-directed mutagenesis using M13-derived vectors: an efficient and general procedure for the production of point mutations in any fragment of DNA. Nucleic Acids Res. 1982 Oct 25;10(20):6487–6500. doi: 10.1093/nar/10.20.6487. [DOI] [PMC free article] [PubMed] [Google Scholar]

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