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Protective effects of Fc-fused PD-L1 on two different animal models of colitis
  1. Mi-Young Song1,
  2. Chun-Pyo Hong1,2,
  3. Seong Jeong Park3,
  4. Jung-Hwan Kim1,2,
  5. Bo-Gie Yang2,
  6. Yunji Park1,
  7. Sae Won Kim3,
  8. Kwang Soon Kim2,
  9. Ji Yeung Lee4,
  10. Seung-Woo Lee1,3,
  11. Myoung Ho Jang2,
  12. Young-Chul Sung1,3,4
  1. 1Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Republic of Korea
  2. 2Academy of Immunology and Microbiology, Institute for Basic Science, Pohang, Republic of Korea
  3. 3Department of Life Science, Pohang University of Science and Technology, Pohang, Republic of Korea
  4. 4Research Institute, Genexine Co., Seongnam, Republic of Korea
  1. Correspondence to Young-Chul Sung, Division of Integrative Biosciences and Biotechnology, Department of Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, Republic of Korea; ycsung@postech.ac.kr Myoung Ho Jang, Academy of Immunology and Microbiology, Institution for Basic Science, Pohang, Kyungbuk, 790-784, Republic of Korea; jangmh@ibs.re.kr

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.

Design 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 CD45RBhigh 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 CD45RBhigh 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.

  • Experimental Colitis
  • Immunotherapy
  • Drug Development
  • IBD Basic Research
  • Inflammatory Bowel Disease

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