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Role of Runx3 in the regulatory mechanism of effector profile of TCD4+ encephalitogenic lymphocytes in experimental autoimmune encephalomyelitis

Grant number: 15/22052-8
Support type:Regular Research Grants
Duration: March 01, 2016 - April 30, 2018
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal researcher:Alessandro dos Santos Farias
Grantee:Alessandro dos Santos Farias
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Experimental autoimmune encephalomyelitis (EAE) is a widely accepted animal model of MS that has been used to study the pathophysiology of the disease since first being described in 1933. It shares many pathological features with MS, such as chronic neuroinflammation, demyelination, and neuronal damage, and is generated by autoimmune attack on the CNS3,4. EAE can be induced in susceptible animals by active immunization with self-epitopes of myelin or by the passive transfer of pre-activated lymphocytes. More specifically, EAE can be induced by the transfer of CD4+ T lymphocytes specific to the neuroantigen. These atuoagressive T cells clearly present a proinflamatory profile (Th1 and/or Th17). In this context, we have been studying the cytotoxic capacity of encephalitogenic CD4+ T cells during the evolution of EAE. Preliminary results from our laboratory showed that the CD4+ T lymphocytes infiltrated into the CNS express higher levels of inflammatory and cytotoxity-related molecules. Moreover, CD4+ T cells seem to progressively express key molecules for the cytotoxic activity, such as granzime B. Yet, the encephalitogenic clone (V²11TCR+) shows a higher expression of granzyme B. This find suggests that these helper cells may present a cytotoxic activity during the course of the disease, and, furthermore, this might help to elucidate how CD4+T cells could deflagrate the myelin damage and the subsequent neuroinflammation cascade. In general, CD4+ T encephalitogenic cells seem to behaviour like CD8+ T cells after reach the CNS in EAE. Interesting, after reach the CNS those cells not only behaviour like CD8+ T cells but also start to express CD8 molecules. This CD4+CD8±² T cell population present even higher cytotoxic activity. This mechanism seems to be specific for the encephalitogenic clones as well. Recent data from our laboratory indicate that the balance between Runx3 and ThPOK must be involved in this unconventional expression of cytotoxic molecules in CD4+ T cells. Therefore, our strategy will be to use tissue-specific conditional knockout mice for those transcription factors in order to evaluate their role in this mechanism. (AU)

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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)
BOLDRINI, VINICIUS O.; BRANDAO, CARLOS OTAVIO; PIMENTEL, V, MARIA LUCIA; VIDAL, ALINE; MANSUR, LETICIA F.; QUINTILIANO, RAPHAEL P. S.; SANTOS, LEONILDA M. B.; FARIAS, ALESSANDRO S. Massive activity of cytotoxic cells during refractory Neuromyelitis Optica spectrum disorder. Journal of Neuroimmunology, v. 340, MAR 15 2020. Web of Science Citations: 0.

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