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Immunomodulatory effects of dehidroepiandrosterone (DHEA) in the immune response of Crohn's Disease patients refractory to anti-TNF treatment

Grant number: 17/08651-1
Support type:Regular Research Grants
Duration: April 01, 2018 - March 31, 2020
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Cristina Ribeiro de Barros Cardoso
Grantee:Cristina Ribeiro de Barros Cardoso
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Assoc. researchers:Omar Feres ; Rogerio Serafim Parra
Associated scholarship(s):19/20365-0 - Immunomodulatory effects of dehidroepiandrosterone (DHEA) in the immune response of Crohn's Disease patients refractory to anti-TNF treatment, BP.TT
18/12430-3 - Dehydroepiandrosterone immunomodulative effect (DHEA) in the immune response of Crohn disease patients not responsible for antiTNF- therapy, BP.TT

Abstract

Anti-TNF monoclonal antibodies are commonly used in IBD treatment. However, some patients are not responsive to this therapy and the concomitant use of this biologics with other immunosuppressive drugs that ameliorate treatment leads to important adverse effects. On the other hand, the levels of the hormone dehydroepiandrosterone (DHEA) are reduced in CD and UC patients, while the supplementation with DHEA ameliorates experimental colitis. Therefore, it is evident that the understanding of this immune-endocrine interaction may be an important tool to the development of alternative therapies for IBD to improve the responses to this high cost biological anti-TNF. Then, in this study we aim to evaluate the immune response profile of CD patients non responsive to anti-TNF treatment and to investigate the potential role of DHEA in reversing this non-responsiveness to the biological therapy. For that, the clinical, endocrine and immune (plasma mediators such as cytokines, LPS and oncostatin M) evaluations of the enrolled patients will be performed and correlated especially with patients DHEA levels. Peripheral blood mononuclear cells will be isolated for leukocyte phenotyping and to define a non-toxic DHEA dosis to be used in in vitro supplementation assays. The proliferation assays of PBMC from non-responsive patients will be performed in the presence of DHEA, as well as the evaluation of Th1, Th2, Th17, IL-9 and inflammatory responses in the culture supernatants. Another set of PBMC culture will be stimulated with LPS and treated with DHEA, to investigate the inflammatory profile of monocytes from patients non-responsive to anti-TNF therapy, as well as the capacity of the hormone to attenuate or reverse such hypo responsiveness to the biological treatment. Finally, we expect that the correlation between our results and the clinical data may point to the relevant immunomodulatory activity of DHEA in reversing the non responsiveness to anti-TNF therapy, in order to underline the development of novel treatments for IBD. (AU)