- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- Pentoxifylline associated with Sbv treatment reduces the frequency of CD68+ macrophages in ML patients, without changing the frequency of T cells.
- Pentoxifylline associated with Sbv reduces the number of CD68+ TNF-alpha+ cells in lesions from ML patients without reducing the number of CD68+ cells expressing IL-10.
- Treatment with PTX associated with Sbv treatment does not alter the frequency of granzyme A expression, and high expression of granzyme A is correlated with longer healing time.
- DISCUSSION
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-
1.
Desjeux P, 2004. Leishmaniasis: current situation and new perspectives. Comp Immunol Microbiol Infect Dis 27: 305–318.
-
2.
Oliveira WN, Ribeiro LE, Schrieffer A, Machado P, Carvalho EM, Bacellar O, 2014. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of human tegumentary leishmaniasis. Cytokine 66: 127–132.
-
3.
Souza AS, Giudice A, Pereira JM, Guimarães LH, de Jesus AR, de Moura TR, Wilson ME, Carvalho EM, Almeida RP, 2010. Resistance of Leishmania (Viannia) braziliensis to nitric oxide: correlation with antimony therapy and TNF-α production. BMC Infect Dis 10: 209.
-
4.
Gollob KJ, Viana AG, Dutra WO, 2014. Immunoregulation in human American leishmaniasis: balancing pathology and protection. Parasite Immunol 36: 367–376.
-
5.
Faria DR et al. 2005. Decreased in situ expression of interleukin-10 receptor is correlated with the exacerbated inflammatory and cytotoxic responses observed in mucosal leishmaniasis. Infect Immun 73: 7853–7859.
-
6.
Bacellar O, Lessa H, Schriefer A, Machado P, De Jesus AR, Dutra WO, Gollob KJ, Carvalho EM, 2002. Up-regulation of Th1-type responses in mucosal leishmaniasis patients. Infect Immun 70: 6734–6740.
-
7.
Faria DR, Souza PEA, Durães FV, Carvalho EM, Gollob KJ, MacHado PR, Dutra WO, 2009. Recruitment of CD8+ T cells expressing granzyme A is associated with lesion progression in human cutaneous leishmaniasis. Parasite Immunol 31: 432–439.
-
8.
da Silva Santos C et al. 2013. CD8+GrazymeB+-mediated tissue injury vs. CD4+IFNgamma+-mediated killing in human leishmaniasis. J Invest Dermatol 133: 1533–1540.
-
9.
Cardoso TM, Machado Á, Costa DL, Carvalho LP, Queiroz A, Machado P, Scott P, Carvalho EM, Bacellar O, 2015. Protective and pathological functions of CD8+ T cells in Leishmania braziliensis infection. Infect Immun 83: 898–906.
-
10.
Novais FO, Scott P, 2015. CD8+ T cells in cutaneous leishmaniasis: the good, the bad and the ugly. Seim Immunopathol 37: 251–259.
-
11.
Ferraz R, Cunha CF, Pimentel MIF, Lyra MR, Pereira-Da-Silva T, Schubach AO, Da-Cruz AM, Bertho AL, 2017. CD3+CD4negCD8neg (double negative) T lymphocytes and NKT cells as the main cytotoxic-related-CD107a+ cells in lesions of cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis. Parasit Vectors 10: 219.
-
12.
Lessa HA, Machado P, Lima F, Cruz ÁA, Bacellar O, Guerreiro J, Carvalho EM, 2001. Successful treatment of refractory mucosal leishmaniasis with pentoxifylline plus antimony. Am J Trop Med Hyg 65: 87–89.
-
13.
Cataldo JI et al. 2018. Favorable responses to treatment with 5 mg Sbv/kg/day meglumine antimoniate in patients with American tegumentary leishmaniasis acquired in different Brazilian regions. Rev Soc Bras Med Trop 51: 769–780.Lessa HA, Lessa MM, Guimarães LH, Lima CMF, Arruda S, Machado PR, Carvalho EM, 2012. A proposed new clinical staging system for patients with mucosal leishmaniasis. Trans R Soc Trop Med Hyg 106: 376–381.
-
14.
Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U, 1999. Pentoxifylline inhibits TNF-α production from. Am J Respir Crit Care Med. 159: 508–511.
-
15.
Machado PRL, Lessa H, Lessa M, Guimaraes LH, Bang H, Ho JL, Carvalho EM, 2007. Oral pentoxifylline combined with pentavalent antimony: a randomized trial for mucosal leishmaniasis. Clin Infect Dis 44: 788–793.
-
16.
Brito G, Dourado M, Guimarães LH, Merieles E, Schriefer A, Carvalho EM, Machado PRL, 2017. Oral pentoxifylline combined with pentavalent antimony: a randomized trial for cutaneoul leishmaniasis. Am J Trop Med Hyg 96: 1155–1159.
-
17.
Lessa HA, Lessa MM, Guimarães LH, Lima CMF, Arruda S, Machado PR, Carvalho EM, 2012. A proposed new clinical staging system for patients with mucosal leishmaniasis. Trans R Soc Trop Med Hyg 106: 376–381.
-
18.
Da-Cruz AM, De Oliveira MP, De Luca PM, Mendonça SC, Coutinho SG, 1996. Tumor necrosis factor-α in human American tegumentary leishmaniasis. Mem Inst Oswaldo Cruz 91: 225–229.
-
19.
Brito G, Dourado M, Polari L, Celestino D, Carvalho LP, Queiroz A, Carvalho EM, Machado PRL, Passos S, 2014. Clinical and immunological outcome in cutaneous leishmaniasis patients treated with pentoxifylline. Am J Trop Med Hyg 90: 617–620.
-
20.
Esterre P, Guerret S, Ravisse P, Dimier-David L, Dedet JP, Grimaud JA, 1994. Immunohistochemical analysis of the mucosal lesion in mucocutaneous leishmaniasis. Parasite 1: 305–309.
-
21.
da Costa DC et al. 2014. Oral manifestations in the American tegumentary leishmaniasis. PLoS One 9: e109790.
-
22.
Brunet LR, 2001. Nitric oxide in parasitic infections. Int Immunopharmacol 1: 1457–1467.
-
23.
Bottrel RLA et al. 2001. Flow cytometric determination of cellular sources and frequencies of key cytokine-producing lymphocytes directed against recombinant LACK and soluble leishmania antigen in human cutaneous leishmaniasis. Infect Immun 69: 3232–3239.
-
24.
Luna T, Santos SB, Nascimento M, Porto MAF, Muniz AL, Carvalho EM, Jesus AR, 2011. Effect of TNF-α production inhibitors on the production of pro-inflammatory cytokines by peripheral blood mononuclear cells from HTLV-1-infected individuals. Braz J Med Biol Res 44: 1134–1140.
-
25.
Ribeiro de Jesus A, Luna T, Pacheco de Almeida R, Machado PRL, Carvalho EM, 2008. Pentoxifylline down modulate in vitro T cell responses and attenuate pathology in Leishmania and HTLV-I infections. Int Immunopharmacol 8: 1344–1353.
-
26.
Goretsky T, Dirisina R, Sinh P, Mittal N, Managlia E, Williams DB, Posca D, Ryu H, Katzman RB, Barrett TA, 2012. P53 mediates TNF-induced epithelial cell apoptosis in IBD. Am J Pathol 181: 1306–1315.
-
27.
Wang R, Alam G, Zagariya A, Gidea C, Pinillos H, Lalude O, Choudhary G, Oezatalay D, Uhal BD, 2000. Apoptosis of lung epithelial cells in response to TNF-α requires angiotensin II generation de novo. J Cell Physiol 185: 253–259.
-
28.
Chopra DP, Menard RE, Januszewski J, Mattingly RR, 2004. TNF-α-mediated apoptosis in normal human prostate epithelial cells and tumor cell lines. Cancer Lett 203:145–154.
-
29.
Miller RA, Britigan BE, 1997. Role of oxidants in microbial pathophysiology. Clin Microbiol Rev 10: 1–18.
-
30.
Anderson P, Nagler-Anderson C, O’Brien C, Levine H, Watkins S, Slayter HS, Blue ML, Schlossman SF, 1990. A monoclonal antibody reactive with a 15-kDa cytoplasmic granule-associated protein defines a subpopulation of CD8+ T lymphocytes. J Immunol 144: 574–582.
-
31.
Trapani JA, Smyth MJ, 2002. Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol 2: 735–747.
-
32.
Lieberman J, 2003. The ABCs of granule-mediated cytotoxicity: new weapons in the arsenal. Nat Rev Immunol 3: 361–370.
-
33.
Fan Z, Zhang Q, 2005. Molecular mechanisms of lymphocyte-mediated cytotoxicity. Cell Mol Immunol 2: 259–264.
-
34.
Sower LE, Froelich CJ, Allegretto N, Rose PM, Hanna WD, Klimpel GR, 1996. Extracellular activities of human granzyme A. monocyte activation by granzyme A versus alpha-thrombin. J Immunol 156: 2585–2590.
-
35.
Dotiwala F, Mulik S, Polidoro RB, Ansara JA, Burleigh BA, Walch M, Gazzinelli RT, Lieberman J, 2016. Killer lymphocytes use granulysin, perforin and granzymes to kill intracellular parasites. Nat Med 22: 210–216.
-
36.
Liew FY, Li Y, Millott S, 1990. Tumor necrosis factor-alpha synergizes with IFN-gamma in mediating killing of Leishmania major through the induction of nitric oxide. J Immunol 145: 4306–4310.
-
37.
de Carsalade GY, Achirafi A, Flageul B, 2003. Pentoxifylline in the treatment of erythema nodosum leprosum. J Dermatol 30: 64–68.
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In Situ Cellular Response Underlying Successful Treatment of Mucosal Leishmaniasis with a Combination of Pentavalent Antimonial and Pentoxifylline
Mucosal leishmaniasis (ML) is characterized by high production of inflammatory cytokines. Administration of pentoxifylline (PTX), an inhibitor of TNF-alpha, with pentavalent antimony (Sbv), has been successfully used as alternative treatment for refractory ML. Our study aims to investigate the in situ cellular response underlying the effectiveness of this therapy, by evaluating the intensity of the inflammatory infiltrate, cellular composition, and expression of cytokines and granzyme A in lesions from ML before and after treatment with Sbv alone or in combination with PTX. Our data showed no differences in the intensity of inflammatory infiltrate comparing before and after treatment, and comparing between different treatments. However, although the number and frequency of CD4+ and CD8+ cells were not different before and after treatments or comparing different treatments, frequency of CD68+ cells decreased after treatment with Sbv + PTX, but not with Sbv. This was due to a reduction in CD68+ TNF-alpha+ and not in CD68+ IL-10+ cells. The frequency of TNF-alpha+ cells was correlated with the intensity of the inflammatory infiltrate before treatment, but this correlation was lost after treatment with Sbv + PTX. Although the total expression of granzyme A did not significantly change after treatments, a clear trend of decrease was observed after treatment with Sbv + PTX. Interestingly, patients who took longer to heal, regardless of the treatment, displayed a higher frequency of granzyme A+ cells. Our data suggest that treatment with Sbv + PTX acts in CD68+ cells reducing the expression of TNF-alpha but not IL-10, resulting in more efficient modulation of the inflammatory response, accelerating the healing process.
Author Notes
Financial support: This project was funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) via the Instituto Nacional de Ciência e Tecnologia em Doenças Tropicias (INCT-DT), FAPEMIG, and TMRC-NIH.
Authors’ addresses: Daniela Rodrigues de Faria, Luisa Cenisio Barbieri, Carolina Carolina Koh, and Walderez Ornelas Dutra, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil, E-mails: danifbarbosa@gmail.com, luisacbarbieri@hotmail.com, carolinakoh@gmail.com, and waldutra@gmail.com. Paulo Roberto Lima Machado, Serviço de Imunologia, Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, Bahia, Brazil, E-mail: prlmachado@uol.com.br. Carolina Cincura Barreto, Clara Monica Figueiredo de Lima, Marcus Miranda Lessa, and Edgar Carvalho, Serviço de Imunologia, Universidade Federal da Bahia, Salvador, Bahia, Brazil, E-mails: carolcincura@hotmail.com, clarafigueiredo@hotmail.com.br, marcusmlessa@gmail.com, and imuno@ufba.br. Kenneth J. Gollob, ACCamargo Cancer Center, International Research Center Sao Paulo, São Paulo, Brazil, E-mail: kjgollob@gmail.com.
These authors contributed equally to this work.