title: 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.
  
  
  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.affiliation: Department of Immunology, IOC-Fiocruz, Rio de Janeiro, Brazil.
authors.forename: Ana Paula M P
authors.initials: AP
authors.lastname: Marino
authors.forename: Andréa
authors.initials: A
authors.lastname: da Silva
authors.forename: Paula
authors.initials: P
authors.lastname: dos Santos
authors.forename: Luzia Maria de Oliveira
authors.initials: LM
authors.lastname: Pinto
authors.forename: Ricardo Tostes
authors.initials: RT
authors.lastname: Gazzinelli
authors.forename: Mauro Martins
authors.initials: MM
authors.lastname: Teixeira
authors.forename: Joseli
authors.initials: J
authors.lastname: Lannes-Vieira
mesh_terms: D000818:Animals; D065100:CCR5 Receptor Antagonists; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002598:Chagas Cardiomyopathy / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000627:therapeutic use*; D019742:Chemokines, CC / Q000096:biosynthesis / Q000235:genetics; D002634:Chemotaxis, Leukocyte; D005260:Female; D005353:Fibronectins / Q000032:analysis; D015847:Interleukin-4 / Q000032:analysis; D008213:Lymphocyte Activation; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D009205:Myocarditis / Q000097:blood / Q000188:drug therapy* / Q000469:parasitology / Q000503:physiopathology; D012333:RNA, Messenger / Q000096:biosynthesis; D054389:Receptors, CCR1; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D065100:CCR5 Receptor Antagonists; C491768:Ccl2 protein, mouse; C496534:Ccl3 protein, mouse; C496535:Ccl4 protein, mouse; C515301:Ccr1 protein, mouse; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC; D005353:Fibronectins; D019402:Macrophage Inflammatory Proteins; C108335:RANTES, Met-; D012333:RNA, Messenger; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D015847:Interleukin-4