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Experimental Autoimmune Myocarditis in A/J mice Is an Interleukin-4-Dependent Disease with a Th2 Phenotype

https://doi.org/10.1016/S0002-9440(10)61685-9Get rights and content

Myocarditis in humans is often associated with an autoimmune process in which cardiac myosin (CM) is a major autoantigen. Experimental autoimmune myocarditis (EAM) is induced in mice by immunization with CM. We found that EAM in A/J mice exhibits a Th2-like phenotype demonstrated by the histological picture of the heart lesions (eosinophils and giant cells) and by the humoral response (association of IgG1 response with disease and up-regulation of total IgE). Blocking interleukin (IL)-4 with anti-IL-4 monoclonal antibody (mAb) reduced the severity of EAM. This reduction in severity was associated with a shift from a Th2-like to a Th1-like phenotype represented by a reduction in CM-specific IgG1; an increase in CM-specific IgG2a; an abrogation of total IgE response; a decrease in IL-4, IL-5, and IL-13; as well as a dramatic increase in interferon (IFN)-γ production in vitro. Based on the latter finding, we hypothesized that IFN-γ limits disease. Indeed, IFN-γ blockade with a mAb exacerbated disease. The ameliorating effect of IL-4 blockade was abrogated by co-administration of anti-IFN-γ mAb. Thus, EAM represents a model of an organ-specific autoimmune disease associated with a Th2 phenotype, in which IL-4 promotes the disease and IFN-γ limits it. Suppression of IFN-γ represents at least one of the mechanisms by which IL-4 promotes EAM.

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Supported by National Institutes of Health grants ES07141, HL33878, and HL65100; National Institute of Environmental Health Sciences grant ES03819; and Z.K. was supported by a fellowship of the Deutsche Herzstiftung e.V.

Current address for S. L. H.: Merck Research Laboratories, West Point, PA.

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