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Immunoregulation of pulmonary paracoccidioidomycosis: the blockade of checkpoint receptors PD-1 and CTLA-4 as a primary immunotherapeutic measure or as adjunct therapy to antifungals

Grant number: 20/08460-4
Support type:Regular Research Grants
Duration: February 01, 2021 - January 31, 2023
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal researcher:Vera Lucia Garcia Calich
Grantee:Vera Lucia Garcia Calich
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Assoc. researchers:Denise Morais da Fonseca ; Flávio Vieira Loures ; Lena Friederike Schimke Marques ; Otávio Cabral Marques

Abstract

Infectious diseases still cause one in four human deaths and are important agents of permanent dysfunction of the hosts due to tissue damage. New knowledge of the host-pathogen relationship, pathogenicity mechanisms, inflammatory patterns, and innate and adaptive immune responses have led to a wide advance in therapies aimed to modulate host homeostasis and not directed against the pathogen. In cancer and chronic infections, a persistent antigenic stimulation without elimination of the malignant cell or pathogen cell can lead to the expression of inhibitory immune checkpoint receptors such as CTLA-4 and PD-1, which lead to immune exhaustion and deactivation of effector mechanisms when interacting with their ligands. Thus, the use of monoclonal antibodies that block receptors involved in the suppression and exhaustion of the immune system has advanced the treatment of neoplastic and some infectious diseases. These findings led us to propose this project that aims: a) characterize the expression and involvement of the inhibitory markers CTLA-4, PD-1 and their ligands in the immunoregulation of experimental pulmonary paracoccidioidomycosis; b) propose a new therapeutic approach directed to host homeostasis using the monoclonal antibodies anti-CTLA-4 and anti-PD-1 (used alone or in combination) in an attempt to reverse the characteristic immune suppression of this chronic infection; c) associate the most promising results of immune checkpoint blockade therapy with the anti-fungal drug. If effective, these new therapeutic approaches will improve the treatment of this South American endemic mycosis, which often fails due to its long course, side effects and patient non-adherence. (AU)