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Prevents Ovalbumin-Induced Anaphylaxis by an IFN-
-Dependent Mechanism1Division of Immunology, Institute of Infectious Disease and Molecular Medicine, Health Science Faculty, University of Cape Town, Cape Town, South Africa
IL-4R
-mediated STAT6 activation serves an essential role in various animal models of allergy and asthma at both the sensitization and effector phases. IL-4 and IL-13 signaling via the IL-4R chain exacerbates murine anaphylaxis, but the cell-specific requirements for IL-4R expression are unclear. The purpose of this study was to elucidate the mechanisms of systemic anaphylaxis to OVA in gene-targeted mice with a deletion of the IL-4R chain in the macrophage/neutrophil or CD4+ T lymphocyte population. Results demonstrated that anaphylaxis in this model was entirely dependent upon the Fc
RII/III and was associated with mast cell degranulation. Expression of the IL-4R on CD4+ T cells, but not macrophages or neutrophils, was critical for severe anaphylaxis, characterized by diarrhea, hypothermia, and death. Ab depletion experiments demonstrated that IFN- protected against mortality and severe intestinal pathology despite the presence of Ag and specific Ab. This protection was associated with reduced levels of mast cell protease, a marker of mast cell degranulation, suggesting that IFN- may inhibit mast cell degranulation in vivo. These data suggest that it may be possible to limit the severity of anaphylaxis using rational therapies designed to increase numbers of IFN--producing cells by targeting IL-4R signaling in CD4+ T lymphocytes.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the University of Cape Town, the National Research Foundation (South Africa), and the Medical Research Council of South Africa.
2 N.N. and D.R.H. contributed equally to this work.
3 Current address: University of Cincinnati School of Medicine, Department of Internal Medicine, Division of Immunology, Cincinnati, OH 45208.
4 Current address: Royal Melbourne University of Technology, School of Applied Science, Allergy Research Group, Melbourne, Australia.
5 Address correspondence and reprint requests to Dr. Frank Brombacher, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Health Science Faculty, University of Cape Town, Werner Beit South, Cape Town, South Africa. E-mail address: fbrombac{at}mweb.co.za
6 Abbreviations used in this paper: PAF, platelet-activating factor; MMCP, mouse mast cell protease.
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