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Efficacy evaluation of murine selective CD28 antagonist, mPEG PV1-Fab', for the treatment of experimental autoimmune uveitis.

Grant number: 13/15448-7
Support type:Scholarships in Brazil - Master
Effective date (Start): January 01, 2014
Effective date (End): December 31, 2014
Field of knowledge:Biological Sciences - Immunology - Applied Immunology
Principal Investigator:Luiz Vicente Rizzo
Grantee:Pedro Henrique Papotto Rosa
Home Institution: Instituto Israelita de Ensino e Pesquisa Albert Einstein (IIEPAE). Sociedade Beneficente Israelita Brasileira Albert Einstein (SBIBAE). São Paulo , SP, Brazil

Abstract

Uveitis is an inflammation of the uvea, a layer of the eye located between the sclera and the retina that includes the iris, ciliary body, and choroid, but can also extend to adjacent tissues, such as retina, optic nerve, and vitreous humor. The disease is broadly classified into infectious and non-infectious uveitis (which includes Autoimmune Uveitis) and in humans, can affect the anterior, intermediate, and posterior portions of the eye. Although many features of uveitis have been extensively studied, therapeutic interventions have often failed due to the heterogeneity of this disorder. Many of the approaches are not disease-specific leading to enhancement of local and systemic side effects. Current treatments focus on immunomodulatory therapies to control acute inflammation and to ensure the maintenance of long-term remission. Corticosteroids are usually among the first-chosen medical therapy due to their effectiveness at controlling inflammation both in the short and in the long term. However, a myriad of possible side effects as well as ocular sequelae may be observed. Overall, though considerable success in stemming clinical progression of uveitis has been achieved, the search for safe and effective alternative therapies and disease-specific interventions are still going on. EAU is the most frequently used animal model for uveitis. It is a T-cell-mediated intraocular inflammatory disease induced by immunization with retinal antigens. In mice the resulting disease is mainly confined to the posterior part of the eye, with focal lesions affecting both retina and choroid. Areas with vasculitis and the presence of granulomas in the posterior layers of the eye are often seen and are accompanied by serous detachment of the retina and disorganization of the photoreceptor layer. The cellular features of EAU involving T-cell mediated inflammation resemble those of the human disease. The cells are mainly CD4+ T lymphocytes poising a TH1 phenotype in vivo. The CD28:B-7 interaction activates an important signaling pathway in T lymphocytes and is known to be involved in different autoimmune diseases. However, little is known about the involvement of CD28 in ocular autoimmune diseases. Thus, in this study, we evaluated the efficacy of CD28 mPEG PV-1-Fab', a specific CD28 antagonist, which doesn't interferes with CTLA-4 signaling, in the treatment of EAU. Therefore, we will evaluate histopathological features, cytokine profile, lymphocyte phenotype and proliferation capacity in eyes and lymph nodes from mice treated with mPEG PV-1-Fab'.

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)
PAPOTTO, PEDRO HENRIQUE; MARENGO, ELIANA BLINI; SARDINHA, LUIZ ROBERTO; CARVALHO, KARINA INACIO; ZULIM DE CARVALHO, ANA EDUARDA; CASTILLO-MENDEZ, SHEYLA; JANK, CARINA CALIXTO; VANHOVE, BERNARD; GOLDBERG, ANNA CARLA; RIZZO, LUIZ VICENTE. Novel CD28 antagonist mPEG PV1-Fab' mitigates experimental autoimmune uveitis by suppressing CD4+T lymphocyte activation and IFN-gamma production. PLoS One, v. 12, n. 3 MAR 1 2017. Web of Science Citations: 6.
PAPOTTO, PEDRO HENRIQUE; MAEDA, SOLANGE; TOMIMORI, JANE; XAVIER, MARILIA BRASIL; RIZZO, LUIZ VICENTE; KALLAS, ESPER GEORGES; CARVALHO, KARINA INACIO. New Players in the Same Old Game: Disturbance of Group 2 Innate Lymphoid Cells in HIV-1 and Mycobacterium leprae Coinfected Patients. PLoS Neglected Tropical Diseases, v. 9, n. 9 SEP 2015. Web of Science Citations: 1.

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