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Study on the Effect of PD-L1 on Inflammatory Bowel Disease : 염증성 장질환에서의 PD-L1의 효과에 관한 연구 원문보기

  • 저자

    송미영

  • 학위수여기관

    포항공과대학교 일반대학원

  • 학위구분

    국내박사

  • 학과

    융합생명공학부 세포 면역학

  • 지도교수

    성영철

  • 발행년도

    2014

  • 총페이지

    64

  • 키워드

    PD-L1 DSS colitis T cell colitis IBD;

  • 언어

    eng

  • 원문 URL

    http://www.riss.kr/link?id=T13533476&outLink=K  

  • 초록

    Programmed death-ligand 1 (PD-L1) has been shown to negatively regulate immune responses via its interaction with PD-1 receptor. In this study, the effects of PD-L1 on intestinal inflammation was investigated using two murine models of inflammatory colitis induced by dextran sulfate sodium (DSS) and CD4+ CD45RBhigh T cell transfer. The anti-colitis effect of adenovirus expressing nonlytic Fc-conjugated PD-L1 (Ad/PD-L1-Fc) and recombinant PD-L1-Fc protein was evaluated in DSS-treated wild-type and Rag-1 knockout (KO) mice. It was examined about differentiation of T helper cells, frequency of innate immune cells, and cytokine production by dendritic cells (DCs) in the colon from DSS-treated mice after PD-L1-Fc administration. In Rag-1 KO mice reconstituted with CD4+ CD45RBhigh T cells, treatment effect of PD-L1-Fc protein was assessed during development of colitis. This study demonstrated for the first time that administration of PD-L1-Fc, either in the form of recombinant protein or by utilizing adenoviral vector as a delivery vehicle, could ameliorate DSS-induced colitis. The therapeutic effect of PD-L1-Fc in DSS colitic mice was associated with decreased frequency of interleukin (IL)-17A-producing CD4+ T cells and increased IFN--producing CD4+ T cells in the colon. The anti-colitic effect of PD-L1-Fc treatment was also observed in DSS-treated Rag-1 KO mice, indicating lymphoid cell independency. PD-L1-Fc modulated cytokine secretion by colonic DCs and the effects was dependent on PD-1 expression upon toll-like receptor (TLR) stimulation. Furthermore, PD-L1-Fc protein could significantly reduce the severity of colitis in CD4+ CD45RBhigh T cell-transferred Rag-1 KO mice. Based on the protective effect of PD-L1-Fc against DSS-induced acute and T cell-induced chronic colitis, these results suggest that PD-1-mediated inhibitory signals have a crucial role in limiting the development of colonic inflammation. This implicates that PD-L1-Fc may provide a novel therapeutic approach to treat inflammatory bowel disease.


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