Protective effects of Fc-fused PD-L1 on two different animal models of colitis
| Autor: | Jung Hwan Kim, Seong Jeong Park, Sae Won Kim, Ji Yeung Lee, Chun-Pyo Hong, Yunji Park, Kwang Soon Kim, Seung-Woo Lee, Young-Chul Sung, Myoung Ho Jang, Mi-Young Song, Bo-Gie Yang |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Colon
Recombinant Fusion Proteins medicine.medical_treatment Genetic Vectors Drug Evaluation Preclinical Inflammation Inflammatory bowel disease B7-H1 Antigen Adenoviridae Immune system medicine Animals Immunologic Factors Intestinal Mucosa Colitis Immunity Mucosal Homeodomain Proteins Mice Knockout Innate immune system business.industry Dextran Sulfate Gastroenterology Interleukin Cell Differentiation Dendritic Cells T-Lymphocytes Helper-Inducer Immunotherapy medicine.disease Immunity Innate Immunoglobulin Fc Fragments Mice Inbred C57BL Disease Models Animal Cytokine Lymphocyte Transfusion Acute Disease Immunology Cytokines Th17 Cells Colitis Ulcerative medicine.symptom business |
| Zdroj: | Gut. 64:260-271 |
| ISSN: | 1468-3288 0017-5749 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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