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Y. Usui, M. Takeuchi, Y. Okunuki, T. Kezuka, T. Hattori, J. Ma, C. Nishiyama, T. Okazaki, T. Honjo, H. Akiba, H. Goto; The Role of Programmed Death-1 (PD-1)/PD-L Pathway in Regulation of Murine Experimental Autoimmune Uveoretinitis (EAU). Invest. Ophthalmol. Vis. Sci. 2008;49(13):3882. doi: https://doi.org/.
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Experimental autoimmune uveitis (EAU) has been used as a model for human uveitis in relation to the autoimmune mechanism and proved to be a T-cell mediated autoimmune disease. The CD28 homologue programmed death-1 (PD-1) and its ligands, PD-L1 and PD-L2 (which are homologous to B7), constitute an inhibitory pathway of T cell costimulation. The PD-1 pathway is of interest for immune-mediated diseases given that PD-1 deficient mice develop autoimmune diseases. Here, we aimed to examine whether PD-1 pathway is involved in regulation for development of murine EAU.
To develop EAU, wild type or PD-1 deficient C57BL/6 mice were immunized with IRBP peptide 1-20 (IRBP-p) in CFA with M. tuberculosis H37RA and were injected i.p. with pertussis toxin. In some experiments, wild-type mice received antagonistic anti-PD-1 mAb three times on every other day prior to immunization were also used. Severity of EAU was evaluated clinically and histopathologically on day 21 after immunization. T cells were also collected from immunized mice on day 21, and measured for proliferation responses and cytokine production by stimulation with IRPB-p.
Severity of EAU was significantly exacerbated both clinically and histopathologically in PD-1 deficient mice compared with wild-type mice. T cell proliferation responses to IRBP-p were remarkably higher in PD-1 deficient mice than that of wild-type mice. As well as T cell proliferation responses, IL-17 and IFN-γ production by T cells stimulated with IRBP-p were strikingly more in PD-1 deficient mice than that of wild-type mice. Similar results were observed in mice treated with antagonistic anti-PD-1 mAb.
Since blockade of PD-1 pathway exacerbated the development of EAU by promoting Th1 and Th17 immune responses, it was demonstrated that PD-1 pathway plays a critical role in regulating EAU.
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