Regulated on activation, normal T cell expressed and secreted (RANTES) antagonist (Met-RANTES) controls the early phase of Trypanosoma cruzi-elicited myocarditis

Background-Comprehension of the pathogenesis of Trypanosoma cruzi-elicited myocarditis is crucial to delineate strategies aimed at ameliorating the inflammation associated with heart dysfunction. The augmented expression of CC chemokines, especially CCL5/RANTES and CCL3/MIP-1alpha, in the hearts of infected mice suggests a role for CC chemokines and their receptors in the pathogenesis of T cruzi-elicited myocarditis. Methods and Results-We report that during the early phase of infection in C3H/HeJ mice infected with 100 blood trypomastigotes of T cruzi, most of the inflammatory cells invading the heart tissue were CD8(+) cells and expressed CCR5, a CCL5/RANTES, and CCL3/MIP1-alpha receptor. Furthermore, peripheral blood CD8(+) T lymphocytes displayed increased expression of CCR5. These findings led us to use Met-RANTES, a selective CCR1 and CCR5 antagonist, to modulate the acute T cruzi-elicited myocarditis. Met-RANTES treatment did not interfere with parasitism but significantly decreased the numbers of CD4(+) and CD8(+) T cells, CCR5(+), and interleukin-4(+) cells invading the heart, paralleling the diminished deposition of fibronectin. Moreover, Met-RANTES treatment resulted in increased survival of infected animals, compared with saline treatment. Conclusions-These results indicate that the massive influx of CCR5(+) cells into cardiac tissue is not crucial for cell-mediated anti-T cruzi immunity but appears to be critical for pathogenesis of T cruzi-elicited myocarditis. Thus, CC chemokine receptors might become an attractive therapeutic target for further evaluation during T cruzi infection.