Modulation of Treg/Th17 responses by Aryl Hydrocarbon Receptor Ligands in the Search for an Immunotherapeutic Procedure for Pulmonary Paracoccidioidomycosis

• Grant number: 16/23189-0
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2017
• End date: May 31, 2019
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Vera Lucia Garcia Calich
• Grantee: Vera Lucia Garcia Calich
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Paracoccidioidomycosis (PCM) is a severe systemic mycosis that affects individuals in Latin America. Studies in the human disease and experimental models have shown that Th1/Th17 immune responses are protective while those mediated by Th2/Th3 and regulatory (Treg) T cells have been associated with disease severity Recent studies have shown that the enzyme indolamine 2, 3-dioxygenase (IDO) and the aryl hydrocarbon receptor (AhR) are important regulators of Treg/Th17 responses. Our previous studies revealed that Treg cells are usually associated with severe and progressive pulmonary PCM. These cells, when excessively expanded inhibit protective Th1/Th17 responses against PCM. Moreover, we have also observed that IDO and AhR are important regulators of immunity against PCM controlling the differentiation of Th17/Treg cells, fungal growth and tissue pathology. These facts led us to propose this study that aims to modulate T cell responses by depleting Treg cells in the ongoing disease (mimicking the newly-diagnosed patient) and use AhR ligands looking for a novel immunotherapeutic procedure for pulmonary PCM. Thus, we intend initially to manipulate the course of the established disease by reducing the number and activity of Treg cells using an adequate experimental model (DEREG model). We also intend to manipulate the immune response in PCM by using AhR agonists and antagonists. Several parameters of innate and adaptive immune responses as well as of disease severity will be used to evaluate these approaches and treatments. We intend to use the most adequate ligand and protocol for AhR to establish an original process of immunotherapy for PCM. Therefore, we believe that the elucidation of the immunomodulatory mechanisms mediated by AhR and the adequate balance of Treg/Th17 responses in pulmonary PCM may lead not only to a better understanding of the pathogenic mechanisms that govern the disease, but could also allow the description of an innovative immunotherapeutic process for this severe systemic mycosis. (AU)

Scientific publications

(7)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CALICH, VERA L. G.; MAMONI, RONEI L.; LOURES, V, FLAVIO. Regulatory T cells in paracoccidioidomycosis. VIRULENCE, v. 10, n. 1, p. 810-821, JAN 1 2019. (16/23189-0)

GALDINO, NAYANE A. L.; LOURES, V, FLAVIO; DE ARAUJO, ELISEU F.; DA COSTA, TANIA A.; PREITE, NYCOLAS W.; CALICH, VERA LUCIA G.. Depletion of regulatoryT cells in ongoing paracoccidioidomycosis rescues protective Thl/Th17 immunity and prevents fatal disease outcome. SCIENTIFIC REPORTS, v. 8, NOV 8 2018. (13/23536-3, 17/20799-4, 16/23189-0, 14/18668-0)

PREITE, NYCOLAS WILLIAN; FERIOTTI, CLAUDIA; DE LIMA, DHEMERSON SOUZA; DA SILVA, BRUNO BORGES; CONDINO-NETO, ANTONIO; PONTILLO, ALESSANDRA; GARCIA CALICH, VERA LUCIA; LOURES, FLAVIO VIEIRA. The syk-coupled C-Type lectin receptors Dectin-2 and Dectin-3 are involved in Paracoccidioides brasiliensis recognition by human Plasmacytoid Dendritic cells. FRONTIERS IN IMMUNOLOGY, v. 9, MAR 20 2018. (14/04783-2, 17/00711-5, 16/23189-0, 13/02396-9)

MORENO, ANA C. R.; PORCHIA, BRUNA F. M. M.; PAGNI, ROBERTA L.; SOUZA, PATRICIA DA CRUZ; PEGORARO, RAFAEL; RODRIGUES, KARINE B.; BARROS, TACITA B.; DE MELO MORAES APS, LUANA R.; DE ARAUJO, ELISEU F.; CALICH, VERA L. G.; et al. The Combined Use of Melatonin and an Indoleamine 2,3-Dioxygenase-1 Inhibitor Enhances Vaccine-Induced Protective Cellular Immunity to HPV16-Associated Tumors. FRONTIERS IN IMMUNOLOGY, v. 9, AUG 22 2018. (16/23189-0, 11/20917-0, 16/00708-1, 15/16505-0, 13/15360-2, 17/25544-4)

DE ARAUJO, ELISEU F.; LOURES, FLAVIO V.; PREITE, NYCOLAS W.; FERIOTTI, CLAUDIA; GALDINO, NAYANE A. L.; COSTA, TANIA A.; CALICH, VERA L. G.. AhR Ligands Modulate the Differentiation of Innate Lymphoid Cells and T Helper Cell Subsets That Control the Severity of a Pulmonary Fungal Infection. FRONTIERS IN IMMUNOLOGY, v. 12, APR 16 2021. (18/14762-3, 16/23189-0, 11/51258-2)

NOGUEIRA-NETO, JOES; LOURES, FLAVIO V.; SCHANOSKI, ALESSANDRA S.; ANDRADE, DAVID A. G.; GONZATTI, MICHELANGELO B.; COSTA, TANIA A.; VIVANCO, BRUNO C.; XANDER, PATRICIA; ROSA, DANIELA S.; CALICH, VERA L. G.; et al. Invariant Natural Killer T Cells as Key Players in Host Resistance against Paracoccidioides brasiliensis. JOURNAL OF IMMUNOLOGY RESEARCH, v. 2021, APR 16 2021. (16/02189-1, 16/23189-0, 12/04692-1, 11/51258-2)

DE ARAUJO, ELISEU FRANK; PREITE, NYCOLAS WILLIAN; VELDHOEN, MARC; LOURES, FLAVIO VIEIRA; GARCIA CALICH, VERA LUCIA. Pulmonary paracoccidioidomycosis in AhR deficient hosts is severe and associated with defective Treg and Th22 responses. SCIENTIFIC REPORTS, v. 10, n. 1, JUL 9 2020. (16/23189-0, 18/14762-3, 11/51258-2)