Mi-Young Song1, Chun-Pyo Hong2, Seong Jeong Park3, Jung-Hwan Kim2, Bo-Gie Yang4, Yunji Park1, Sae Won Kim3, Kwang Soon Kim4, Ji Yeung Lee5, Seung-Woo Lee6, Myoung Ho Jang4, Young-Chul Sung7. 1. Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Republic of Korea. 2. 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. 3. Department of Life Science, Pohang University of Science and Technology, Pohang, Republic of Korea. 4. Academy of Immunology and Microbiology, Institute for Basic Science, Pohang, Republic of Korea. 5. Research Institute, Genexine Co., Seongnam, Republic of Korea. 6. 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. 7. 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.
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 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: Julia Zöller; Jana-Fabienne Ebel; Vishal Khairnar; Verena Schmitt; Robert Klopfleisch; Jana Meiners; Virginia Seiffart; Wiebke Hansen; Jan Buer; Bernhard B Singer; Karl S Lang; Astrid M Westendorf Journal: Gut Microbes Date: 2020-06-10
Authors: Mohammad Yassin; Zuzanna Sadowska; Ditte Djurhuus; Brian Nielsen; Peter Tougaard; Jørgen Olsen; Anders Elm Pedersen Journal: Immunology Date: 2019-09 Impact factor: 7.397
Authors: Alessandra Petrelli; Gerdien Mijnheer; David P Hoytema van Konijnenburg; Maria M van der Wal; Barbara Giovannone; Enric Mocholi; Nadia Vazirpanah; Jasper C Broen; Dirkjan Hijnen; Bas Oldenburg; Paul J Coffer; Sebastian J Vastert; Berent J Prakken; Eric Spierings; Aridaman Pandit; Michal Mokry; Femke van Wijk Journal: J Clin Invest Date: 2018-08-02 Impact factor: 14.808