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In Situ Cellular Response Underlying Successful Treatment of Mucosal Leishmaniasis with a Combination of Pentavalent Antimonial and Pentoxifylline

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  • 1 Laboratory of Cell-Cell Interactions, Department of Morphology, Biological Sciences Institute, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil;
  • | 2 Centro Universitário de Formiga – UNIFOR-MG, Formiga, Brazil;
  • | 3 Immunology Service, Hospital Universitário Professor Edgar Santos, Universidade Federal da Bahia, Salvador, Brazil;
  • | 4 Instituto Nacional de Ciência e Tecnologia em Doenças Tropicais – INCT-DT, Salvador, Brazil;
  • | 5 International Research Center, ACCamargo Cancer Center, São Paulo, Brazil
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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

Address correspondence to Walderez Ornelas Dutra, Laboratory of Cell-Cell interactions, Department of Morphology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte-Minas Gerais, Av. Presidente Antônio Carlos, 6627, Pampulha, Belo Horizonte 31270-901, Brazil. E-mail: waldutra@gmail.com

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.

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