Published Online
on August 30, 2004

A more recent version of this article appeared on September 14, 2004

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Submitted on February 4, 2004
Revised on May 13, 2004
Accepted on May 13, 2004

Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) Antagonist (Met-RANTES) Controls the Early Phase of Trypanosoma cruzi-Elicited Myocarditis

Ana Paula M.P. Marino MSc, Andréa da Silva MSc, Paula dos Santos MSc, Luzia Maria de Oliveira Pinto PhD, Ricardo Tostes Gazzinelli PhD, Mauro Martins Teixeira MD, PhD, and Joseli Lannes-Vieira PhD^*

From the Department of Immunology (A.P.M.P.M., A.d.S., P.d.S., L.M.d.O.P., J.L.-V.), IOC-Fiocruz, Rio de Janeiro; the Laboratory of Immunopathology (R.T.G.), CPqRR-Fiocruz, Belo Horizonte; and the Department of Biochemistry and Immunology (R.T.G., M.M.T.), UFMG, Belo Horizonte, Brazil.

^* To whom correspondence should be addressed. E-mail: lannes{at}ioc.fiocruz.br.

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-1, 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- 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.

Key words: heart disease • myocarditis • inflammation • infection • receptors

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Targeting the Chemokines in Myocardial Inflammation

Nikolaos G. Frangogiannis and Mark L. Entman
Circulation 2004 110: 1341-1342. [Extract] [Full Text]

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