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

Abstract

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-12Rb1 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. IntroductionDilated cardiomyopathy has been associated with infection by certain viruses (specific strains of coxsackie virus and cytomegalovirus), bacteria (Streptococci, Borrelia, Cornybacterium diphtheriae) or protozoa (Trypansosoma cruzi) [1]. Infection causes an acute heart muscle inflammation (myocarditis) followed in susceptible individuals by an autoimmune response primarily directed against heart muscle myosin, leading to myocardial dilation and heart failure.In experimental animal models, myocarditis can be induced in the absence of infection by immunization of susceptible mice (and rats) with cardiac myosin [2] or a pathogenic peptide located in the head portion of [4,6,7]. Based on studies in mice deficient for IL-12p40 or IL-12Rb1, we and others have suggested that IL-12 is critical for disease development [8,9]. However, more recently it became clear that the heterodimers IL-12 (p40/35) and IL-23 (p40/p19) share the p40 subunit and the b1 chain of their receptor and that IL-23, rather than IL-12, is essential for inflammatory responses in the central nervous system and joints [10,11]. IL-23 has been implicated in the development of a recently described subset of CD4 T cells characterized by the production of IL-17, . Notably, these cells have been shown to exert a pathogenic role in several autoimmune and inflammatory diseases including EAE, collagen-induced arthritis and T cell-mediated colitis [15][16][17]. Development of this subset is promoted by IL-23, TGF-b and IL-6 and inhibited by [18][19][20][21][22]. We report here that IL-23 and IL-17 are pathogenic mediators of cardiac inflammation, which could be successfully targeted by immunothe...

CD11b+ Monocytes Abrogate Th17 CD4+ T Cell-Mediated Experimental Autoimmune Myocarditis

“…In this context, it has been shown recently, that IL-6, which is essential for the induction of Th17 T cells (8), and IL-23-promoting Th17 expansion are both critical for EAM development (12,13). Our data prove the direct pathogenic role of IL-17 in EAM development, because IL-17 depletion prevents EAM development.…”

“…Autoimmune myocarditis is a Th17 T cell-mediated disease (12,13). In wild-type mice, MyHC-␣/CFA immunization results in the generation of heart-specific Th17 as well as Th1 T cell responses.…”

“…Historically, two major CD4 ϩ T cell subsets have been defined according to their cytokine production pattern: IFN-␥-producing Th1 cells, and Th2 cells releasing IL-4. Recent data, however, suggest that EAM development critically depends on the IL-23-STAT4 axis (11) promoting the expansion of another autoreactive CD4 ϩ T cell subset characterized by IL-17 production (12)(13)(14). These observations argue against a disease-promoting role of autoreactive Th1 cells in EAM.…”

Anti‐cytokine vaccines and the immunotherapy of autoimmune diseases

“…Three papers [19][20][21] in this issue of the European Journal of Immunology extend these previous findings and describe the use of IL-17 itself as a vaccine against autoimmunity. Sonderegger et al [19] studied the role …”

Absence of nonhematopoietic MHC class II expression protects mice from experimental autoimmune myocarditis

“…Hence in the WT setting, IFN-γ may have an important part in the establishment of acute EAM while IL-17A has an essential role in profibrotic remodeling, chronicity, and progression to DCM. The protective effect of IFN-γ observed in mice deficient in IFN-γ or its receptor [6,22] is thus likely to be due mainly to the facts that (i) IFN-γ confines activated CD4 + T-cell expansion via nitric oxide [34], (ii) IFN-γ is involved in regulating CD4 + T-cell activation and apoptosis [31], and (iii) IFN-γ suppresses exacerbating Th17 responses [41][42][43], and thus to be unrelated to the IFN-γ-induced MHCII expression addressed in our study. Remarkably, two reports applying distinct models of spontaneous EAM, which are not based on immunization with α-MyHC, proposed that IFN-γ is driving the initial inflammatory phase of EAM [19,20].…”