Neutralization of IL‐17 by active vaccination inhibits IL‐23‐dependent autoimmune myocarditis

The most common reason for heart failure in young adults is dilated cardiomyopathy often resulting from myocarditis. Clinical studies and animal models provide evidence that an autoimmune response against heart myosin is the underlying reason for the disease. IL‐12 has been suggested to play a key r...

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Bibliographic Details
Published in:European Journal of Immunology 2006-11, Vol.36 (11), p.2849-2856
Main Authors: Sonderegger, Ivo, Röhn, Till A., Kurrer, Michael O., Iezzi, Giandomenica, Zou, Yu, Kastelein, Robert A., Bachmann, Martin F., Kopf, Manfred
Format: Article
Language:English
Subjects:
Animals
Autoimmune Diseases - immunology
Autoimmune Diseases - pathology
Autoimmune Diseases - prevention & control
Autoimmunity
Auto‐vaccination
Cell Proliferation
Disease Models, Animal
IL‐17
IL‐23
Immunotherapy, Active
Interleukin-12 - genetics
Interleukin-12 - physiology
Interleukin-12 Subunit p35 - genetics
Interleukin-12 Subunit p40 - genetics
Interleukin-17 - antagonists & inhibitors
Interleukin-23 - antagonists & inhibitors
Interleukin-23 - physiology
Mice
Mice, Knockout
Myocarditis
Myocarditis - immunology
Myocarditis - pathology
Myocarditis - prevention & control
Vaccines, Virosome - therapeutic use
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Summary:The most common reason for heart failure in young adults is dilated cardiomyopathy often resulting from myocarditis. Clinical studies and animal models provide evidence that an autoimmune response against heart myosin is the underlying reason for the disease. IL‐12 has been suggested to play a key role in development of experimental autoimmune myocarditis (EAM), as IL‐12p40 and IL‐12Rβ1 knockouts are protected from disease. In this study, we have compared IL‐12p40–/– mice, IL‐12p35–/– mice and mice treated with a neutralizing IL‐23 antibody in EAM and found that in fact IL‐23, not IL‐12, is responsible for inflammatory heart disease. However, these cytokines appear to have redundant activity for priming and expansion of autoreactive CD4 T cells, as specific T cell proliferation was only defective in the absence of both cytokines. IL‐23 has been suggested to promote a pathogenic IL‐17‐producing T cell population. We targeted IL‐17 by capitalizing on an active vaccination approach that effectively breaks B cell tolerance. Neutralization of IL‐17 reduced myocarditis and heart autoantibody responses, suggesting that IL‐17 is the critical effector cytokine responsible for EAM. Thus, targeting of IL‐23 and IL‐17 by passive and active vaccination strategies holds promise as a therapeutic approach to treat patients at risk for development of dilated cardiomyopathy. See accompanying commentary: http://dx.doi.org/10.1002/eji.200636760
ISSN:0014-2980
1521-4141
1365-2567
DOI:10.1002/eji.200636484