Expertos Invitados





O TRATAMENTO COM BENZNIDAZOL PROMOVE MUDANÇAS NO COMPARTIMENTO LINFOIDE DE CAMUNDONGOS INFECTADOS PELO TRYPANOSOMA CRUZI

(especial para SIIC © Derechos reservados)
O tratamento com benznidazol interrompeu não apenas a replicação parasitária, mas também originou novos mecanismos regulatórios ocasionando mudanças na resposta imune.
perdigaooliveri9.jpg Autor:
Bianca Perdigão olivieri
Columnista Experto de SIIC

Institución:
Instituto Oswaldo Cruz Fundação Oswaldo Cruz

Artículos publicados por Bianca Perdigão olivieri
Coautores
Vinícius Cotta de Almeida*  Tania Araújo Jorge** 
Doutor em Ciências. Instituto Oswaldo Cruz/FIOCRUZ*
Doutora em Ciências. Instituto Oswaldo Cruz/FIOCRUZ**
Recepción del artículo
17 de Mayo, 2005 		Aprobación
7 de Junio, 2005
Primera edición
30 de Marzo, 2006 		Segunda edición, ampliada y corregida
7 de Junio, 2021

O TRATAMENTO COM BENZNIDAZOL PROMOVE MUDANÇAS NO COMPARTIMENTO LINFOIDE DE CAMUNDONGOS INFECTADOS PELO TRYPANOSOMA CRUZI

Resumen
A doença de Chagas é considerada uma doença endêmica em muitos países da América Latina. O benznidazol (N-benzil-2-nitroimidazol acetamida) é utilizado para a terapia desta doença, e o conceito de que o sucesso da terapia envolva a participação do sistema imune foi proposto. Neste texto, será feita a revisão dos principais resultados obtidos por nosso grupo no que diz respeito ao impacto da terapia com benznidazol sobre as principais populações linfocitárias presentes em órgãos linfóides durante a infecção experimental por T. cruzi. O tratamento com benznidazol atenuou as principais alterações observadas no timo, havendo redução da atrofia tímica e da eliminação de timócitos, concomitante ao restabelecimento do fenótipo normal com maioria de células imaturas CD4+CD8+, além da prevenção de depósitos de moléculas de matriz extracelular. Estes dados sugerem a preservação do compartimento linfóide central. De forma surpreendente, detectamos aumento na massa e celularidade do baço de camundongos infectados e tratados por benznidazol, relacionado à expansão preferencial de linfócitos T CD8+ com fenótipo efetor/memória. Além disso, houve modificação na relação CD4:CD8 e redução na frequência de apoptose. Em resumo, o tratamento com benznidazol interrompeu não apenas a replicação parasitária, mas também originou novos mecanismos regulatórios ocasionando mudanças na resposta imune.

Palabras clave
Benznidazol, Trypanosoma cruzi, camundongos, órgãos linfóides, linfócitos


Artículo completo
(castellano)
Extensión:  +/-6.83 páginas impresas en papel A4
Exclusivo para suscriptores/assinantes

BENZNIDAZOLE THERAPY PROMOTES CHANGES ON THE LYMPHOID COMPARTMENT OF TRYPANOSOMA CRUZI INFECTED MICE

Abstract
Chagas’ disease is endemic in most Latin American countries. The nitroderivative benznidazole (N-benzyl-2-nitroimidazole acetamide) is the most employed trypanocidal drug for Chagas’ disease and the concept that the success of anti-parasite treatment involves the immune system has been proposed. Here we review our work evaluating the impact of benznidazole therapy upon the main lymphocyte populations present in lymphoid organs in the course of experimental T. cruzi infection. Benznidazole treatment was able to lessen the severe abnormalities seen in the thymus following T. cruzi infection: it reduced thymus involution and thymocyte loss, restored the normal immature CD4+CD8+ phenotype, and prevented extracellular matrix deposits, substantiating the concept that the central lymphoid compartment is preserved. Surprisingly, in benznidazole-treated mice we detected higher spleen mass and viable cell numbers than in non-treated mice (higher splenomegaly), related to the preferential expansion of CD8+ T lymphocytes with high frequency of effector/memory cells, and a decrease in the apoptosis rate. As a consequence, a change in the CD4:CD8 ratio occurred as well. As a result, benznidazole treatment not only interrupted parasite replication but also induced new regulatory mechanisms, originating thus a different host immune response.

Key words
Benznidazole, Trypanosoma cruzi, mice, lymphoid organs, lymphocytes

Clasificación en siicsalud
Artículos originales > Expertos de Iberoamérica >
página   www.siicsalud.com/des/expertocompleto.php/

Especialidades
Principal: Infectología
Relacionadas: Bioquímica, Farmacología, Salud Pública



Comprar este artículo
Extensión: 6.83 páginas impresas en papel A4

file05.gif (1491 bytes) Artículos seleccionados para su compra



Enviar correspondencia a:
Araújo-Jorge T
Bibliografía del artículo
  1. Chagas C. Nova tripanosomíase humana. Estudos sobre a morfologia e o ciclo evolutivo de Schizotrypanum cruzi n.gen., n.sp., agente etiológico de nova entidade mórbida do homem. Mem Inst Oswaldo Cruz 1909; 1:159-218.
  2. World Health Organization. Chagas disease. Tropical Disease Research, 18th Program Report, UNDP/WB/TDR, Geneva, 2002.
  3. Dias JC. PAHO/WHO. Task force on the initiative of the South Cone for the elimination of vector transmission and interruption of transfusion transmission of Trypanosoma cruzi. Epidemiologic surveillance of Triatoma infestans. Rev Soc Bras Med Trop 1993; 26 Suppl 3:39-44.
  4. Dias JCP, Coura JR. Epidemiologia. In: Dias JCP, and Coura JR (ed.), Clínica e terapêutica da doença de Chagas, uma abordagem prática para o clínico geral, FIOCRUZ, Rio de Janeiro. 1997. p.33-65.
  5. Kierszenbaum F. Views on the autoimmunity hypothesis for Chagas disease pathogenesis. FEMS Immunol 2003; 37:1-11.
  6. Soares MBP, Pontes-de-Carvalho L, Ribeiro-dos-Santos R. The pathogenesis of Chagas’ disease: when autoimmune and parasite-specific immune response meet. An Acad Bras Cienc 2001; 73(4):547-59.
  7. Tarleton RL. Parasite persistence in the aetiology of Chagas disease. Int J Parasitol 2001; 31:550-4.
  8. Cançado JR, Brener Z. Terapêutica. In: Brener Z, Andrade Z (ed.) Trypanosoma cruzi e Doença de Chagas, Guanabara Koogan. 1979. p.362-424.
  9. Cerisola JA, Alvarez M, Rissio AM. Imunodiagnóstico da doença de Chagas. Evolução serológica de pacientes com doença de Chagas. Rev Inst Med Trop São Paulo 1970; 12:403-11.
  10. Schmuñis GA, Szarfman A, Coarasa L,. Guilleron C, Peralta JM. Anti-Trypanosoma cruzi agglutinins in acute human Chagas’ disease. Am Soc Trop Med Hyg 1980; 29:170-8.
  11. Galvão L, Nunes R, Cançado JR, Brener Z, Krettli A. Lytic antibodies titer as a means of assessing cure after treatment of Chagas’ disease: a 10 year follow-up study. Trans R Soc Trop Med Hyg 1993; 87:220-3.
  12. Viotti R, Vigliano C, Armenti H, Segura E. Treatment of chronic Chagas disease with benznidazole: clinical and serological evolution of patients with long-term follow-up. Am Heart J 1994; 127:151-62.
  13. Minoprio P, Coutinho A, Joskowicz M, D’Imperio-Lima MR, Eisen H. Polyclonal lymphocyte responses to murine Trypanosoma cruzi infection. II. Cytotoxic T lymphocytes. Scand J Immunol 1986; 24:669-79.
  14. Minoprio P, Eisen H, Forni L, D’Imperio-Lima MR, Joskowicz M, Coutinho A. Polyclonal lymphocyte responses to murine Trypanosoma cruzi infection. I. Quantitation of both T- and B-cell responses. Scand J Immunol 1986; 24:661-68.
  15. Minoprio P, Burlen O, Pereira P et al. Most B cells in acute Trypanosoma cruzi infection lacks parasite specificity. Scand J Immunol 1988; 28:553–61.
  16. Minoprio P, Itohara S, Heusser C,. Tonegawa S, Coutinho A. Immunobiology of murine Trypanosoma cruzi infection: the predominance of parasite-nonspecific responses and the activation of TCRI T cells. Immunol Ver 1989; 112:183-207.
  17. Leite-de-Moraes MC, Hontebeyrie-Joskowicz M, Leboulenger F, Savino W, Dardenne M, Lepault F. Studies on the thymus in Chagas’ disease. II. Thymocyte subset fluctuations in Trypanosoma cruzi-infected mice: relationship to stress. Scand J Immunol 1991; 33:267-75.
  18. Savino W, Leite-de-Moraes MC, Hontebeyrie-Joskowicz M, Leboulenger F, Dardenne M. Studies on the thymus in Chagas’disease. I. Changes in the thymic microenvironment in mice acutely infected with Trypanosoma cruzi. Eur J Immunol 1989; 19:1727-33.
  19. Kierszenbaum F. What are T-cell subpopulations really doing in Chagas’ disease Parasitol Today 1995;11:6-7.
  20. Tarleton RL. The role of T cells in Trypanosoma cruzi infection. Parasitol Today 1995; 1:7-9.
  21. Tarleton RL, Koller BH, Latour A, Postan M. Susceptibility of beta 2-microglobulin-deficient mice to Trypanosoma cruzi infection. Nature 1992; 356:338-40.
  22. Tarleton RL, Sun J, Zhang L, Postan M. Depletion of T-cell subpopulations results in exacerbation of myocarditis and parasitism in experimental Chagas’ disease. Infect Immun 1994; 62(5):1820-9.
  23. Rottenberg ME, Bakhiet M, Olsson T et al. Differential susceptibilities of mice genomically deleted of CD4 and CD8 to infections with Trypanosoma cruzi or Trypanosoma brucei. Infect Immun 1993; 61:5129-33.
  24. Michailowsky V, Murta SMF, Carvalho-Oliveira L et al. Interleukin-12 enhances in vivo parasiticidal effect of benznidazole during acute experimental infection with a naturally drug-resistant strain of Trypanosoma cruzi. Antimicrob Agents Chemother 1998; 42:2549-56.
  25. Murta SM, Ropert C, Alves RO, Gazzinelli RT, Romanha AJ. In-vivo treatment with benznidazole enhances phagocytosis, parasite destruction and cytokine release by macrophages during infection with a drug-susceptible but not with a derived drug-resistant Trypansoma cruzi population. Parasite Immunol 1999; 21(10):535-44.
  26. Romanha AJ, Alves RO, Murta SM, Silva JS, Ropert C, Gazzinelli RT. Experimental chemotherapy against Trypanosoma cruzi infection: essential role of endogenous interferon-gamma in mediating parasitologic cure. J Infect Dis 2002; 186(6): 823-8.
  27. Piaggio E, Roggero E, Pitashny M,. Wietzerbin J, Bottasso OA, Revelli SS. Treatment with benznidazole and its immunomodulating effects on Trypanosoma cruzi-infected rats. Parasitol Res 2001; 87(7):539-47.
  28. Antunez MI, Feinstein RE, Cardoni RL, Gronvik KO. Trypanosoma cruzi: T cell subpopulations in the Peyer's patches of BALB/c infected mice. Exp Parasitol 1996; 87:58-64.
  29. Cotta-de-Almeida V, Bonomo A, Mendes-da-Cruz DA et al. Trypanosoma cruzi infection modulates intrathymic contents of extracellular matrix ligants and receptors and alters thymocyte migration. Eur J Immunol 2003; 33(9):2439-48.
  30. Cotta-de-Almeida V, Bertho AL, Villa-Verde DMS, Savino W. Phenotypic and functional alterations of thymic nurse cells following acute Trypanosoma cruzi infection. Clin Immunol Immunopathol 1997; 82:125-32.
  31. Leite-de-Moraes MC, Hontebeyrie-Joskowicz M, Dardenne M, Savino W. Modulation of thymocyte subsets during acute and chronic phases of experimental Trypanosoma cruzi infection. Immunol 1992; 77(1):95-8.
  32. Mendes-da-Cruz DA, DeMeis J, Cotta-de-Almeida V, Savino W. Experimental Trypanosoma cruzi infection alters the shaping of the central and peripheral T-cell repertoire. Microbes Infect 2003; 5(10):825-32.
  33. Schmunis GA, Cappa SMG, Traversa OC, Jaanovsky JF. The effects of immuno-depression due to neonatal thymectomy on infections with Trypanosoma cruzi in mice. Trans R Soc Trop Med Hyg 1971; 65:89-94.
  34. Gonçalves-da-Costa SC, Lagrange PH, Hurtrel B, Keer I, Alencar A. Role of T lymphocytes in the resistance and immunopathology of experimental Chagas’disease. 1. Histopathological studies. Ann Inst Pasteur (Immunol.) 1984; 135:317-32.
  35. Kierszenbaum F, Pienkowski MM. Thymus-dependent control of host defense mechanisms against Trypanosoma cruzi infection. Infect Immun 1979; 24:117-20.
  36. Bottasso OA, Revelli SS, Davila H et al. Enhanced myocardial lesions in chronically Trypanosoma cruzi-infected rats subjected to adult thymectomy. Immunol Lett 1993; 37:175-80.
  37. Roggero E, Perez A, Tamae-Kakazu M et al. Differential susceptibility to acute Trypanosoma cruzi infection in BALB/c and C57BL/6 mice is not associated with distinct parasite load but cytokine abnormalities. Clin Exp Immunol 2002; 128:421-8.
  38. Olivieri BP, Farias-De-Oliveira DA, Araujo-Jorge T, Cotta-De-Almeida V. Benznidazole Therapy in Trypanosoma cruzi-Infected Mice Blocks Thymic Involution and Apoptosis of CD4+CD8+ Double-Positive Thymocytes Antimicrob Agents Chemother. 2005; 49(5):1981-1987.
  39. Mantuano-Barradas M, Henriques-Pons A, Araújo-Jorge TC, Di Virgilio F, Coutinho-Silva R, Persechini PM. Extracellular ATP induces cell death in CD4+/CD8+ double-positive thymocytes in mice infected with Trypanosoma cruzi. Microbes Infect 2003; 5(15):1363-71.
  40. Henriques-Pons A, DeMeis J, Cotta-De-Almeida V, Savino W, Araujo-Jorge TC. Fas and perforin are not required for thymus atrophy induced by Trypanosoma cruzi infection. Exp Parasitol 2004; 107(1-2):1-4.
  41. Mucci J, Hidalgo A, Mocetti E, Argibay PF, Leguizamón MS, Campetella O. Thymocyte depletion in Trypanosoma cruzi infection is mediated by trans-sialidase-induced apoptosis on nurse cells complex. PNAS 2002; 99(6):3896-901.
  42. Risso MG, Garbarino GB, Mocetti E et al. Differential expression of a virulence factor, the trans-sialidase, by the main Trypanosoma cruzi phylogenetic lineages. J Infect Dis 2004; 189(12):2250-9.
  43. Savino W, Mendes-da-Cruz DA, Silva JS, Dardenne M, Cotta-de-Almeida V. Intrathymic T-cell migration: a combinatorial interplay of extracellular matrix and chemokines. Trends Immunol 2002; 23(6):305-13.
  44. Dos Reis GA. Cell-mediated immunity in experimental Trypanosoma cruzi-infection. Parasitol Today 1997; 13:335-42.
  45. Kierszenbaum F, de Diego JL, Fresno M, Sztein MB. Inhibitory effects of the Trypanosoma cruzi membrane glycoprotein AGC10 on the expression of IL-2 receptor chains and secretion of cytokines by subpopulations of activated human T lymphocytes. Eur J Immunol 1999; 29:1684–91.
  46. Reina-San-Martin B, Degrave W, Rougeot C et al. A B-cell mitogen from a pathogenic trypanosome is a novel eukaryotic proline racemase. Nature Med 2000; 6:890-7.
  47. Lopes MF, Da Veiga VF, Santos AR, Fonseca MEF, DosReis GA. Activation-induced CD4+ T cell death by apoptosis in experimental Chagas’ disease. J Immunol. 1995; 154:744-52.
  48. Lopes MF, DosReis GA. Trypanosoma cruzi-induced immunossupression: selective triggering of CD4+ T cell death by the T-cell receptor CD3 pathway and not by the CD69 or Ly-6 activation pathway. Infect Immun 1996; 64:1559-64.
  49. Olivieri BP, Cotta-De-Almeida V, Araujo-Jorge T. Benznidazole treatment following acute Trypanosoma cruzi infection triggers CD8+ T-cell expansion and promotes resistance to reinfection. Antimicrob Agents Chemother. 2002; 46(12):3790-96.
  50. Coura JR, de Castro SL. A critical review on Chagas disease chemotherapy. Mem Inst Oswaldo Cruz 2002; 97(1):3-24.
  51. Urbina JA, Docampo R. Specific chemotherapy of Chagas disease: controversies and advances. Trends Parasitol 2003; 19(11):495-501.
  52. Apt W, Arribada A, Zulantay I, Sanchez G, Vargas SL, Rodriguez J. Itraconazole or allopurinol in the treatment of chronic American trypanosomiasis: the regression and prevention of electrocardiographic abnormalities during 9 years of follow-up. Ann Trop Med Parasitol 2003;97(1):23-9.
  53. Avila JL, Polegre MA, Robins RK. Biological action of pyrazolopyrimidine derivatives against Trypanosoma cruzi studies in vitro e in vivo. Comp Biochem Physiol 1987; 86C:49-54.
  54. Brener Z, Cancado JR, Galvão LM et al. An experimental and clinical assay with ketoconazole in the treatment of Chagas disease. Mem Inst Oswaldo Cruz 1993; 88(1):149-53.
  55. Meirovich CI, Montrull HL, Gallerano RH, Sosa RR. Allopurinol in the treatment of chronic Chagas' disease. Arq Bras Cardiol 1985; 45(3):217-23.
  56. Moreira AAB, De Souza HBWT, Amato Neto V et al. Avaliação da atividade terapêutica do itraconazol nas infecções crônicas, experimental e humana, pelo Trypanosoma cruzi. Rev Inst Med Trop São Paulo 1992; 34:177-80.
  57. Molina J, Martins-Filho O, Brener Z, Romanha AJ, Loebenberg D, Urbina JA. Activities of the triazole derivative SCH 56592 (posaconazole) against drug-resistant strains of the protozoan parasite Trypanosoma (Schizotrypanum) cruzi in immunocompetent and immunosuppressed murine hosts. Antimicrob Agents Chemother 2000; 44(1):150-5.
  58. Urbina JA, Payares G, Sanoja C et al. Parasitological cure of acute and chronic experimental Chagas disease using the long-acting experimental triazole TAK-187. Activity against drug-resistant Trypanosoma cruzi strains. Int J Antimicrob Agents 2003; 21(1):39-48.
  59. Urbina JA, Payares G, Molina J et al. Cure of short- and long-term experimental Chagas' disease using D0870. Science 1996; 273(5277):969-71.
  60. Urbina JA, Payares G, Contreras LM et al. Antiproliferative effects and mechanism of action of SCH 56592 against Trypanosoma (Schizotrypanum) cruzi: in vitro and in vivo studies. Antimicrob Agents Chemother 1998; 42(7):1771-7.
 
 
 
 
 
 
 
 
 
 
 
 
Está expresamente prohibida la redistribución y la redifusión de todo o parte de los contenidos de la Sociedad Iberoamericana de Información Científica (SIIC) S.A. sin previo y expreso consentimiento de SIIC.
ua31618
Home

Copyright siicsalud © 1997-2024 ISSN siicsalud: 1667-9008