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Study of the cytotoxic activity of CD4+ t lymphocytes in the experimental autoimmune neuritis

Grant number: 12/20935-1
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): April 01, 2013
Effective date (End): March 31, 2017
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Alessandro dos Santos Farias
Grantee:Fernando Pradella
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated research grant:11/18728-5 - Study of migratory, effector and regulatory pattern of autoreactive t lymphocytes, previously transduced with GFP in experimental demyelinating diseases, AP.JP

Abstract

Guillain-Barré Syndrome is a human peripheralnervous system acute inflammatory disease. The disease may culminatein paresis of the whole patient body or even in its death.Despite the evolution of the treatment in the last decade, acute inflammatory autoimmune diseases of peripheral nervous system (PNS) are still a concern due to the considerable morbidity and mortality. The current treatment to Guillain-Barré syndrome is based on immunoglobulin (IgG) administered intravenously and/or plasma exchange. However, about 40% of the patients still need artificial ventilation or are unable to walk. Therefore, new strategies of treatment are crucial to fill the gaps of the current treatments. Experimentalautoimmune neuritis (EAN), due to its wide range of similarities with GBS, themajority of scientific knowledge we have about this disorder was provided bystudies in the animal model. During the development of the EAN, a cell-mediated monophasic autoimmune phenomenon occurs and the lesions are confined to the nerve roots of the spinal cord, as well as to the ganglionic and to the peripheral nerves. Histological sections reveal various demyelinating foci and infiltration of mononuclear cells into the nerves.The inducing phase involves the presentation of neuritogenic epitopes to the CD4+ T lymphocytes, specially into the lymph nodes. The activated auto-reactive T cells get off the peripheral lymphoid tissues toward to the nerve, trespass the blood nerve barrier (BNB) and initiate a local inflammatory response. It is known that the axonal demyelination is deflagrated by the CD4+ T lymphocytes, which is followed by the phagocytic activity of mononuclear cells (mainly macrophages) that has been recruited later. It is believed that cytotoxic molecules, such as granzymes and perforins, very much expressed by CD8+ T lymphocytes and by NK cells, are essential for breaking the BNB. However, it is not yet clear how CD4+ T cells would be able to start the disease. Classically, CD4+ T lymphocytes are considered to exert helper functions, orchestrating the immunological innate and adaptive responses. Some studies show that CD4+ T cells can present a cytotoxic profile under special conditions, as cases of tumors, grafts and viral infections, what suggests a direct effector function of these CD4+ T cells. This may explain the mechanism by which the disease is initiated, as EAN can be induced through the adoptive transfer of CD4+ T lymphocytes previously sensitized to the neuroantigen and, at least in theory, CD4+ T cells would not have any cytotoxic capacity.Previous results of our laboratory (IC FAPESP 2012/06994-5) demonstrated a high cytotoxic activity into the spleen and lymph nodes, as well as into de sciatic nerves. Thus, in this study, our objective is to evaluate if this expression of cytotoxic molecule in the EAN model comes from T CD4+ cells sensitized to the neuroantigen and if this cytotoxic activity is indeed relevante for the development of EAN.