title: Protective effects of Fc-fused PD-L1 on two different animal models of colitis.
abstract: OBJECTIVE
  Programmed death-ligand 1 (PD-L1) has been shown to negatively regulate immune responses via its interaction with PD-1 receptor. In this study, we investigated the effects of PD-L1-Fc treatment on intestinal inflammation using two murine models of inflammatory colitis induced by dextran sulfate sodium (DSS) and T-cell transfer.
  
  
  METHODS
  The anti-colitis effect of adenovirus expressing 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. We examined 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 CD45RB(high) T cells, we assessed the treatment effect of PD-L1-Fc protein on the development of colitis.
  
  
  RESULTS
  Administration of Ad/PD-L1-Fc significantly ameliorated DSS-induced colitis, which was accompanied by diminished frequency of interleukin (IL)-17A-producing CD4 T cells and increased interferon-γ-producing CD4 T cells in the colon of DSS-fed mice. 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 production by colonic DCs and the effect was dependent on PD-1 expression. Furthermore, PD-L1-Fc protein could significantly reduce the severity of colitis in CD4 CD45RB(high) T-cell-transferred Rag-1 KO mice.
  
  
  CONCLUSIONS
  Based on the protective effect of PD-L1-Fc against DSS-induced and T-cell-induced colitis, our 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.
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors.forename: Mi-Young
authors.initials: MY
authors.lastname: Song
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Republic of Korea Academy of Immunology and Microbiology, Institute for Basic Science, Pohang, Republic of Korea.
authors.forename: Chun-Pyo
authors.initials: CP
authors.lastname: Hong
authors.affiliation: Department of Life Science, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors.forename: Seong Jeong
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Republic of Korea Academy of Immunology and Microbiology, Institute for Basic Science, Pohang, Republic of Korea.
authors.forename: Jung-Hwan
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Academy of Immunology and Microbiology, Institute for Basic Science, Pohang, Republic of Korea.
authors.forename: Bo-Gie
authors.initials: BG
authors.lastname: Yang
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors.forename: Yunji
authors.initials: Y
authors.lastname: Park
authors.affiliation: Department of Life Science, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors.forename: Sae Won
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Academy of Immunology and Microbiology, Institute for Basic Science, Pohang, Republic of Korea.
authors.forename: Kwang Soon
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Research Institute, Genexine Co., Seongnam, Republic of Korea.
authors.forename: Ji Yeung
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Republic of Korea Department of Life Science, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors.forename: Seung-Woo
authors.initials: SW
authors.lastname: Lee
authors.affiliation: Academy of Immunology and Microbiology, Institute for Basic Science, Pohang, Republic of Korea.
authors.forename: Myoung Ho
authors.initials: MH
authors.lastname: Jang
authors.affiliation: Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Republic of Korea Department of Life Science, Pohang University of Science and Technology, Pohang, Republic of Korea Research Institute, Genexine Co., Seongnam, Republic of Korea.
authors.forename: Young-Chul
authors.initials: YC
authors.lastname: Sung
mesh_terms: D000208:Acute Disease; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D003093:Colitis, Ulcerative / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005822:Genetic Vectors; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D007155:Immunologic Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D007413:Intestinal Mucosa / Q000276:immunology; D017710:Lymphocyte Transfusion; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D016207:Cytokines; D018398:Homeodomain Proteins; D007141:Immunoglobulin Fc Fragments; D007155:Immunologic Factors; D011993:Recombinant Fusion Proteins; C064658:RAG-1 protein; D016264:Dextran Sulfate
keywords: Drug Development; Experimental Colitis; IBD Basic Research; Immunotherapy; Inflammatory Bowel Disease