Adoptive Transfer of Regulatory T Cells Protects against Coxsackievirus B3-Induced Cardiac Fibrosis

Abstract

BackgroundCardiac fibrogenesis in the late stage of viral myocarditis causing contractile dysfunction and ventricular dilatation, is a major pathogenic factor for the progression of myocarditis to serious cardiovascular diseases including dilated cardiomyopathy (DCM) and congestive heart failure (HF). Recent studies indicate that regulatory T cells (Tregs) are involved in the fibrotic process of liver and lung fibosis. However, the role of Tregs in the development of viral myocarditis-caused cardiac fibrosis and their therapeutic potential remains unclear.Methodology/Principal FindingsMyocardial fibrosis was induced in BALB/c mice by intraperitoneal injection of Coxsackievirus B3 (CVB3) assessed by picrosirius red staining and detection of expression levels of collagen I, matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-3 (MMP-3) and tissue inhibitor of metalloproteinase-1 (TIMP-1). Myocardial Treg frequency was down-regulated during the course of viral myocarditis and a negative correlation with the severity of cardiac fibrosis was found. To explore the role of Tregs in CVB-induced cardiac fibrosis, Treg was in vivo depleted by injecting anti-CD25 mAb which resulted in aggravation of cardiac fibrosis. In consistent with that, after adoptive transfer of isolated Tregs into mice, significant amelioration of CVB3-induced cardiac fibrosis was confirmed. Interleukin-10 (IL-10) neutralizing antibodies were used in vivo and in vitro to explore the molecular mechanism of the therapeutic effect of Treg. It was found that administration of anti-IL-10 mAb after Treg transfer abrogated Treg’s treating effect and the inhibition of Treg on collagen production by cardiac fibroblasts was mediated mainly through IL-10.Conclusion/SignificanceOur data suggested that Tregs have a protective role in the fibrotic process of CVB3-induced cardiac fibrosis via secreting IL-10 and might provide an alternative option for the future treatment of cardiac fibrosis.

Activated Circulating Myeloid-Derived Suppressor Cells in Patients with Dilated Cardiomyopathy

“…Therefore, the cross-talk between MDSCs and Tregs remains incompletely defined. In addition, accumulating evidence confirms the involvement of Tregs in the development and progression of DCM [39][40][41]. In this study, we found that the frequencies of CD4 + CD25…”

The role of lymphocytes in the development and treatment of alopecia areata

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Emerging pharmacologic targets and treatments for myocarditis

“…In two separate studies Tregs cultured from syngeneic mice were transferred into irradiated mice (Cao, et al, 2013;Shi, et al, 2010). Using the same principle a blood draw-culture and reconstitution strategy could push the balance of the immune response from autoimmunity toward reparation and resolution of the myocarditis.…”