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 role in development of experimental autoimmune myocarditis (EAM), as IL-12p40 and IL-12Rbeta1 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.
Sonderegger
Ivo
I
Institute of Integrative Biology, Molecular Biomedicine, ETH Zürich, Switzerland.
Röhn
Till A
TA
Kurrer
Michael O
MO
Iezzi
Giandomenica
G
Zou
Yu
Y
Kastelein
Robert A
RA
Bachmann
Martin F
MF
Kopf
Manfred
M
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D016233:Immunotherapy, Active; D018664:Interleukin-12 / Q000235:genetics / Q000502:physiology; D053765:Interleukin-12 Subunit p35 / Q000235:genetics; D053762:Interleukin-12 Subunit p40 / Q000235:genetics; D020381:Interleukin-17 / Q000037:antagonists & inhibitors*; D053759:Interleukin-23 / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009205:Myocarditis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D022721:Vaccines, Virosome / Q000627:therapeutic use
D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D020381:Interleukin-17; D053759:Interleukin-23; D022721:Vaccines, Virosome; D018664:Interleukin-12