Modulation of immune response by aryl hydrocarbon receptor ligands in the search for an immunotherapeutic procedure for pulmonary Paracoccidioidomycosis

• Grant number: 17/20799-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: December 01, 2017
• End date: November 30, 2018
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Vera Lucia Garcia Calich
• Grantee: Nycolas Willian Preite
• 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 use AhR ligands to modulate T cell responses in the ongoing disease (mimicking the newly-diagnosed patient) looking for a novel immunotherapeutic procedure for pulmonary PCM. Thus, we 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

(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)

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)