Immunomodulatory effects of cysteamine and its potential use as a host-directed therapy for tuberculosis
ObjectiveCysteamine, a drug approved to treat cystinosis, has been proposed as a host-directed therapy for M. tuberculosis (Mtb) and SARS-CoV-2. The impact of cysteamine on the immune responses has not been fully investigated. We aimed to in vitro evaluate the immunomodulatory effects of cysteamine...
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Frontiers Media S.A.
2024-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1411827/full |
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| author | Saeid Najafi-Fard Chiara Farroni Linda Petrone Anna Maria Gerarda Altera Andrea Salmi Valentina Vanini Valentina Vanini Gilda Cuzzi Tonino Alonzi Emanuele Nicastri Gina Gualano Fabrizio Palmieri Mauro Piacentini Mauro Piacentini Delia Goletti |
| author_facet | Saeid Najafi-Fard Chiara Farroni Linda Petrone Anna Maria Gerarda Altera Andrea Salmi Valentina Vanini Valentina Vanini Gilda Cuzzi Tonino Alonzi Emanuele Nicastri Gina Gualano Fabrizio Palmieri Mauro Piacentini Mauro Piacentini Delia Goletti |
| author_sort | Saeid Najafi-Fard |
| collection | DOAJ |
| description | ObjectiveCysteamine, a drug approved to treat cystinosis, has been proposed as a host-directed therapy for M. tuberculosis (Mtb) and SARS-CoV-2. The impact of cysteamine on the immune responses has not been fully investigated. We aimed to in vitro evaluate the immunomodulatory effects of cysteamine on peripheral blood mononuclear cells (PBMCs) using the purified protein derivative (PPD) as a recall antigen, and an unspecific stimulus as staphylococcal enterotoxin B (SEB).MethodsPBMCs isolated from subjects with tuberculosis infection (TBI), those with tuberculosis disease (TB), and healthy controls (HC) were in vitro stimulated with PPD or SEB and treated or not with cysteamine at different concentrations (50 µM–400 µM) for 6 hours (h) and 24 h. We evaluated the T helper1 (Th1) and T cytotoxic1 (Tc1) cell cytokine production by flow cytometry and immune-enzymatic assays. In HC, we also evaluated apoptosis and/or necrosis by flow cytometry.ResultsWe observed an immunomodulatory effect of cysteamine at 400 µM in PBMCs from TB and TBI subjects. It significantly reduced PPD-specific Th1 responses at 24 h and at 6 h (p=0.0004 and p=0.0009, respectively), and a similar non-significant trend was observed with cysteamine at 200 µM (p=0.06 at 24 h and p=0.14 at 6 h). Moreover, cysteamine at both 400 µM (p<0.0001 and p=0.0187 at 24 h, respectively, and p<0.0001 at 6 h for both) and 200 µM (p=0.0119 and p=0.0028 at 24 h and p=0.0028 and p=0.0003 at 6 h, respectively) significantly reduced SEB-induced Th1 and Tc1 responses. Furthermore, we found that cysteamine induced morphological lymphocyte changes and significantly reduced the lymphocyte percentage in a dose- and time-dependent manner. Cysteamine at 400 µM induced 8% late apoptosis and 1.6% necrosis (p<0.05) at 24 h. In contrast, despite significant differences from untreated conditions (p<0.05), cysteamine at 400 µM for 6 h induced approximately 1% late apoptosis and 0.1% necrosis in the cells.ConclusionsHigh doses of cysteamine in vitro reduce the percentages of PPD- and SEB-induced Th1 and Tc1 cells and induce late apoptosis and necrosis. Differently, cysteamine at lower doses retains the immunomodulatory effect without affecting cell viability. These findings suggest cysteamine as a potential adjunct to antimicrobial regimens as in the TB or COVID-19 field, for its ability to reduce the inflammatory status. |
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| id | doaj-art-7a8c9c9781b74e85a64bf793db272ef8 |
| institution | OA Journals |
| issn | 1664-3224 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-7a8c9c9781b74e85a64bf793db272ef82025-08-20T02:11:16ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-10-011510.3389/fimmu.2024.14118271411827Immunomodulatory effects of cysteamine and its potential use as a host-directed therapy for tuberculosisSaeid Najafi-Fard0Chiara Farroni1Linda Petrone2Anna Maria Gerarda Altera3Andrea Salmi4Valentina Vanini5Valentina Vanini6Gilda Cuzzi7Tonino Alonzi8Emanuele Nicastri9Gina Gualano10Fabrizio Palmieri11Mauro Piacentini12Mauro Piacentini13Delia Goletti14Translational Research Unit, National Institute for Infectious Diseases Lazzaro Spallanzani-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, ItalyTranslational Research Unit, National Institute for Infectious Diseases Lazzaro Spallanzani-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, ItalyTranslational Research Unit, National Institute for Infectious Diseases Lazzaro Spallanzani-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, ItalyTranslational Research Unit, National Institute for Infectious Diseases Lazzaro Spallanzani-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, ItalyTranslational Research Unit, National Institute for Infectious Diseases Lazzaro Spallanzani-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, ItalyTranslational Research Unit, National Institute for Infectious Diseases Lazzaro Spallanzani-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, ItalyUnità Operativa Semplice (UOS) Professioni Sanitarie Tecniche, National Institute for Infectious Diseases Lazzaro Spallanzani-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, ItalyTranslational Research Unit, National Institute for Infectious Diseases Lazzaro Spallanzani-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, ItalyTranslational Research Unit, National Institute for Infectious Diseases Lazzaro Spallanzani-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, ItalyClinical Division of Infectious Diseases, National Institute for Infectious Diseases Lazzaro Spallanzani-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, ItalyRespiratory Infectious Diseases Unit, National Institute for Infectious Diseases Lazzaro Spallanzani-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, ItalyRespiratory Infectious Diseases Unit, National Institute for Infectious Diseases Lazzaro Spallanzani-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, ItalyNational Institute for Infectious Diseases Lazzaro Spallanzani-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, ItalyDepartment of Biology, University of Rome “Tor Vergata”, Rome, ItalyTranslational Research Unit, National Institute for Infectious Diseases Lazzaro Spallanzani-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, ItalyObjectiveCysteamine, a drug approved to treat cystinosis, has been proposed as a host-directed therapy for M. tuberculosis (Mtb) and SARS-CoV-2. The impact of cysteamine on the immune responses has not been fully investigated. We aimed to in vitro evaluate the immunomodulatory effects of cysteamine on peripheral blood mononuclear cells (PBMCs) using the purified protein derivative (PPD) as a recall antigen, and an unspecific stimulus as staphylococcal enterotoxin B (SEB).MethodsPBMCs isolated from subjects with tuberculosis infection (TBI), those with tuberculosis disease (TB), and healthy controls (HC) were in vitro stimulated with PPD or SEB and treated or not with cysteamine at different concentrations (50 µM–400 µM) for 6 hours (h) and 24 h. We evaluated the T helper1 (Th1) and T cytotoxic1 (Tc1) cell cytokine production by flow cytometry and immune-enzymatic assays. In HC, we also evaluated apoptosis and/or necrosis by flow cytometry.ResultsWe observed an immunomodulatory effect of cysteamine at 400 µM in PBMCs from TB and TBI subjects. It significantly reduced PPD-specific Th1 responses at 24 h and at 6 h (p=0.0004 and p=0.0009, respectively), and a similar non-significant trend was observed with cysteamine at 200 µM (p=0.06 at 24 h and p=0.14 at 6 h). Moreover, cysteamine at both 400 µM (p<0.0001 and p=0.0187 at 24 h, respectively, and p<0.0001 at 6 h for both) and 200 µM (p=0.0119 and p=0.0028 at 24 h and p=0.0028 and p=0.0003 at 6 h, respectively) significantly reduced SEB-induced Th1 and Tc1 responses. Furthermore, we found that cysteamine induced morphological lymphocyte changes and significantly reduced the lymphocyte percentage in a dose- and time-dependent manner. Cysteamine at 400 µM induced 8% late apoptosis and 1.6% necrosis (p<0.05) at 24 h. In contrast, despite significant differences from untreated conditions (p<0.05), cysteamine at 400 µM for 6 h induced approximately 1% late apoptosis and 0.1% necrosis in the cells.ConclusionsHigh doses of cysteamine in vitro reduce the percentages of PPD- and SEB-induced Th1 and Tc1 cells and induce late apoptosis and necrosis. Differently, cysteamine at lower doses retains the immunomodulatory effect without affecting cell viability. These findings suggest cysteamine as a potential adjunct to antimicrobial regimens as in the TB or COVID-19 field, for its ability to reduce the inflammatory status.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1411827/fullcysteaminetuberculosishost-directed therapyinflammationAg-specific responsePPD-specific response |
| spellingShingle | Saeid Najafi-Fard Chiara Farroni Linda Petrone Anna Maria Gerarda Altera Andrea Salmi Valentina Vanini Valentina Vanini Gilda Cuzzi Tonino Alonzi Emanuele Nicastri Gina Gualano Fabrizio Palmieri Mauro Piacentini Mauro Piacentini Delia Goletti Immunomodulatory effects of cysteamine and its potential use as a host-directed therapy for tuberculosis Frontiers in Immunology cysteamine tuberculosis host-directed therapy inflammation Ag-specific response PPD-specific response |
| title | Immunomodulatory effects of cysteamine and its potential use as a host-directed therapy for tuberculosis |
| title_full | Immunomodulatory effects of cysteamine and its potential use as a host-directed therapy for tuberculosis |
| title_fullStr | Immunomodulatory effects of cysteamine and its potential use as a host-directed therapy for tuberculosis |
| title_full_unstemmed | Immunomodulatory effects of cysteamine and its potential use as a host-directed therapy for tuberculosis |
| title_short | Immunomodulatory effects of cysteamine and its potential use as a host-directed therapy for tuberculosis |
| title_sort | immunomodulatory effects of cysteamine and its potential use as a host directed therapy for tuberculosis |
| topic | cysteamine tuberculosis host-directed therapy inflammation Ag-specific response PPD-specific response |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1411827/full |
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