CC chemokine receptor-1 antagonist improves development of experimental autoimmune myocarditis through induction of T cell anergy

Abstract

Objective: CC chemokine receptor-1 (CCR-1) is bound to CC chemokine and is expressed on T lymphocytes. We examined the role of CCR1 in myocarditis using CCR1 antagonist, BX471. Methods: Lewis rats were immunized with cardiac myosin to establish experimental autoimmune myocarditis (EAM) on day 0. Rats were administered subcutaneously with CCR-1 antagonist from day 0 (group BX0) or from day 14 (group BX14) daily and were sacrificed on day 21 (each group: n = 6). Results: We confirmed the expression of CCR1 in heart inflammatory cells using immunohistochemical study. Myocarditis-affected areas in the treated groups were lower than controls. Cardiac function in the treated group improved. (group BX0 or group BX14 vs controls: area ratio; 1.0 ± 1.1%vs51.8 ± 8.3% or 11.8 ± 2.9%vs52.4 ± 9.3%, FS; 46.7 ± 3.6%vs20.8 ± 2.6% or 39.4 ± 4.1%vs22.0 ± 5.9%, respectively P < 0.05). CCR1 antagonist suppressed the cytokine expression of IL-6, IL-1beta and TNFalpha mRNA. T cell proliferation assay was performed with CD4+T cells isolated from control rats stimulated with cardiac myosin. T cell proliferation was suppressed by CCR1 antagonist and IL-2 restored T cell activation. Western blotting revealed that CCR1 antagonist suppressed ERK activity of T cells after myosin stimulation. Conclusions: CCR1 antagonist reduced the severity of EAM via inhibition of cytokine expression with induction of T cell anergy. CCR1 antagonist, BX471, have potential as a novel therapy for myocarditis.