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

Abstract

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.

• Authors: Ana Paula M P Marino, Andréa da Silva, Paula dos Santos, Luzia Maria de Oliveira Pinto, Ricardo Tostes Gazzinelli, Mauro Martins Teixeira, Joseli Lannes-Vieira
• Journal: Circulation (Circulation) Vol. 110 Issue 11 Pg. 1443-9 (Sep 14 2004) ISSN: 1524-4539 [Electronic] United States
• PMID: 15337689 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCR5 Receptor Antagonists
• Ccl2 protein, mouse
• Ccl3 protein, mouse
• Ccl4 protein, mouse
• Ccr1 protein, mouse
• Chemokine CCL2
• Chemokine CCL3
• Chemokine CCL4
• Chemokine CCL5
• Chemokines, CC
• Fibronectins
• Macrophage Inflammatory Proteins
• RANTES, Met-
• RNA, Messenger
• Receptors, CCR1
• Receptors, CCR5
• Receptors, Chemokine
• Interleukin-4

Topics

• Animals
• CCR5 Receptor Antagonists
• CD4-Positive T-Lymphocytes (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Chagas Cardiomyopathy (blood, drug therapy, physiopathology)
• Chemokine CCL2 (biosynthesis, genetics)
• Chemokine CCL3
• Chemokine CCL4
• Chemokine CCL5 (analogs & derivatives, antagonists & inhibitors, metabolism, therapeutic use)
• Chemokines, CC (biosynthesis, genetics)
• Chemotaxis, Leukocyte
• Female
• Fibronectins (analysis)
• Interleukin-4 (analysis)
• Lymphocyte Activation
• Macrophage Inflammatory Proteins (biosynthesis, genetics, metabolism)
• Mice
• Mice, Inbred C3H
• Myocarditis (blood, drug therapy, parasitology, physiopathology)
• RNA, Messenger (biosynthesis)
• Receptors, CCR1
• Receptors, CCR5 (biosynthesis, genetics, physiology)
• Receptors, Chemokine (antagonists & inhibitors, physiology)