Characterization of the TIGIT+ T regulatory cell subset in response to therapy with disease-modifying anti-rheumatic drugs in patients with Rheumatoid Arthritis

• Grant number: 20/02642-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: June 01, 2020
• End date: May 31, 2022
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Paulo Louzada Junior
• Grantee: Mikhael Haruo Fernandes de Lima
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID

Abstract

Rheumatoid Arthritis (RA) is a chronic inflammatory disease of autoimmune nature that primarily affecting the joints and affects about 1% of the world population. The main articular manifestations in RA are pain, swelling and joint redness which are due to inflammation in the synovial tissue that could progresses to the destruction of cartilage, bone erosion and loss of joint function if not treated properly. The initial therapeutic strategy is the administration of low doses of methotrexate (MTX), a dihydrofolate reductase inhibitor that has important antiproliferative and immunosuppressive effects. Although most patients are responsive to MTX, about 40% of individuals are refractory to this therapy. The mechanisms related to the ineffectiveness of MTX in the treatment of RA are still unknown and several efforts are being employed in clinical research to identify a biomarker capable of predicting such response. By demonstrating that therapeutic adherence to MTX was related to the optimal level of CD39 expression in regulatory T cells (Tregs), and consequent generation of adenosine, we are currently working on the development of a diagnostic kit based on the expression of CD39 in Tregs by flow cytometry in order to predict therapeutic adherence to MTX. Regarding the biology of Tregs, in recent years the TIGIT+ Treg subset has been identified as the most suppressive cells against Th1 and Th17 cells, which are known to be involved with the pathogenesis of RA. Interestingly, our preliminary data point that the levels of CD39 expression, as well as its hydrolytic activity on ATP in vitro, are higher on the TIGIT+Tregs cells. Therefore, the research on TIGIT-/TIGIT+ Treg repertoires on RA is extremely important for a greater understanding of these cells in immunopathogenesis of RA, as well as in the identification of new biomarkers for predicting the response to disease-modifying antirheumatic drugs, as methotrexate. Although our group has shown that IL-33 favors synovial injury by recruiting neutrophils into the joint, it has also been shown that, paradoxically, this cytokine has a potent immunosuppressive effect in the experimental RA. In this sense, data not published from our group indicate that the immune response shaped by IL-33 acting on M2 macrophages is essential for the expansion of TIGIT+Tregs repertoire. Thus, in order to extend such findings for a better understanding of the mechanisms involved with the response to antirheumatic drugs, the aim of the present study is to investigate the role of IL-33 in the TIGIT+ Tregs expansion in RA patients before and after treatment with MTX. (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)

CORSI-ZUELLI, FABIANA; DEAKIN, BILL; LIMA, MIKHAEL HARUO FERNANDES DE; QURESHI, OMAR; BARNES, NICHOLAS M.; UPTHEGROVE, RACHEL; LOUZADA-JUNIOR, PAULO; DEL-BEN, CRISTINA MARTA. T regulatory cells as a potential therapeutic target in psychosis? Current challenges and future perspectives. BRAIN, BEHAVIOR, & IMMUNITY - HEALTH, v. 17, p. 14-pg., 2021-11-01. (12/05178-0, 13/08216-2, 20/02642-3, 19/13229-2, 21/07448-3)

DE LIMA, MIKHAEL HARUO FERNANDES; MACHADO, CAIO CAVALCANTE; NASCIMENTO, DANIELE CARVALHO; SILVA, CAMILA MEIRELLES S.; TOLLER-KAWAHISA, JULIANA ESCHER; RODRIGUES, TAMARA SILVA; VERAS, FLAVIO PROTASSIO; PONTELLI, MARJORIE CORNEJO; CASTRO, ITALO A.; ZAMBONI, DARIO SIMOES; et al. The TIGIT⁺ T regulatory cells subset associates with nosocomial infection and fatal outcome in COVID-19 patients under mechanical ventilation. SCIENTIFIC REPORTS, v. 13, n. 1, p. 12-pg., 2023-08-21. (13/08216-2, 20/02642-3)