Novel CD28 antagonist mPEG PV1-Fab' mitigates experimental autoimmune uveitis by suppressing CD4+T lymphocyte activation and IFN-gamma production

Autor(es)

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

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 12, n. 3 MAR 1 2017.
• Citações Web of Science: 6

Resumo

Autoimmune Uveitis is an important chronic inflammatory disease and a leading cause of impaired vision and blindness. This ocular autoimmune disorder is mainly mediated by T CD4(+) lymphocytes poising a TH1 phenotype. Costimulatory molecules are known to play an important role on T cell activation and therefore represent interesting therapeutical targets for autoimmune disorders. CD28 is the prototypical costimulatory molecule for T lymphocytes, and plays a crucial role in the initiation, and maintenance of immune responses. However, previous attempts to use this molecule in clinical practice achieved no success. Thus, we evaluated the efficacy of mPEG PV1-Fab' (PV1), a novel selective CD28 antagonist monovalent Fab fragment in the treatment of Experimental Autoimmune Uveitis (EAU). Here, we showed that PV1 treatment decreases both average disease score and incidence of EAU. A decrease in the activation profile of both T CD4(+) and T CD8(+) eye-infiltrating lymphocytes was evidenced. In the periphery, T CD4(+) cells from PV1-treated mice also showed a decrease in their activation status, with reduced expression of CD69, CD25, and PD-1 molecules. This suppression was not dependent on Treg cells, as both their frequency and absolute number were lower in PV1-treated mice. In addition, frequency of CD4(+) IFN-gamma+ T cells was significantly lower in PV1-treated group, but not of IL-17-producing T cells. Moreover, after specific restimulation, PV1 blockade selectively blocked IFN-gamma production by CD4(+) lymphocytes Taken together, our data suggest that mPEG PV1-Fab' acts mainly on IFN-gamma-producing CD4(+) T cells and emphasize that this specific CD28 blockade strategy is a potential specific and alternative tool for the treatment of autoimmune disorders in the eye. (AU)

• Processo FAPESP: 13/15448-7 - Avaliação da eficácia do antagonista seletivo de CD28 mPEG PV1-Fab´ no tratamento da uveíte autoimune experimental
• Beneficiário: Pedro Henrique Papotto Rosa
• Modalidade de apoio: Bolsas no Brasil - Mestrado