Hironari Nakano

β2-Adrenergic Agonists Suppress Rat Autoimmune Myocarditis Potential Role of β2-Adrenergic Stimulants as New Therapeutic Agents for Myocarditis

Background— The therapeutic potential of β2-adrenergic receptor (AR) agonists in the treatment of autoimmune diseases has been reported. However, the role of these drugs in the myocardial structure–induced autoimmune process, which is thought to play a crucial role in the progression of myocarditis to subsequent complications, has not been elucidated. Methods and Results— Experimental autoimmune myocarditis (EAM) was induced in rats by immunization with cardiac myosin. On daily administration from day 0 after immunization, the β2-selective AR agonists formoterol or salbutamol ameliorated EAM on day 21 and increased myocardial interleukin-10/interferon-γ mRNA levels. Propranolol, a nonselective β-AR antagonist, aggravated EAM on day 21 and decreased mRNA levels, whereas metoprolol, a β1-selective AR antagonist, showed no effect. These results were reflected in vivo by the proliferation of cardiac myosin–primed lymph node cells from drug-treated rats. In vitro addition of β2-selective AR agonists inhibited the activation of cardiac myosin fragment–specific myocarditogenic T lymphocytes, and this effect was reversed by ICI118,551, a β2-selective AR antagonist. Furthermore, treatment with 2 different β2-selective AR agonists starting on day 14 also ameliorated EAM on day 21. Conclusions— β2-AR stimulation suppressed the development of EAM by inhibiting cardiac myosin–specific T-lymphocyte activation in lymphoid organs and by shifting the imbalance in Th1/Th2 cytokine toward Th2 cytokine. Furthermore, it also ameliorated established myocardial inflammation. β2-AR–stimulating agents may represent important immunomodulators of the cardiac myosin–induced autoimmune process and have potential as a new therapy for myocarditis.

Myosin Autoreactive T Cells And Autoimmune Myocarditis. Lessons from the Disease Caused by Cardiac Myosin Peptide CM2

We have proposed a unique animal model of experimental autoimmune myocarditis (EAM). This rat myocarditis is systematically provoked by immunization with cardiac myosin, and evolves toward dilated cardiomyopathy through repetitive immunizations. In this process, myosin epitopes, dendritic cells and myosin autoreactive T cells are the three major elements initiating and promoting this disease. Despite many attempts, we have failed, thus far, to identify myosin autoreactive and myocarditogenic T cells in vitro. However, recently, T cell lines specifically reactive to the cardiac myosin peptide, CM 2 (AA: 1539-1555), and showing myocarditogenecity have been identified. Line characterization of harvested T cells from EAM rats rendered ill by whole cardiac myosin was repetitively and systematically tested. Thus, T cell lines autoreactive to CM 2 and inducing transfer myocarditis were isolated out of many candidates. Acute myocarditis transferred by means of these T cell lines became more severe, and disease transfer with these cell lines caused chronic myocarditis in syngenic Lewis rat. Importantly, the myosin autoreactive and myocarditogenic T cells were also able to transfer the myocarditis into SCID mice beyond the MHC restriction.