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Protective Role of Programmed Death 1 Ligand 1 (PD-L1)in Nonobese Diabetic Mice : The Paradox in Transgenic Models
OBJECTIVE—Coinhibitory signals mediated via programmed death 1 (PD-1) receptor play a critical role in downregulating immune responses and in maintaining peripheral tolerance. Programmed death 1 ligand 1 (PD-L1), the interacting ligand for PD-1, widely expressed in many cell types, acts as a tissue-...
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Formato: | Texto |
Lenguaje: | English |
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American Diabetes Association
2008
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2453619/ https://www.ncbi.nlm.nih.gov/pubmed/18420489 http://dx.doi.org/10.2337/db07-1260 |
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author | Wang, Chia-Jen Chou, Feng-Cheng Chu, Chi-Hong Wu, Jen-Chine Lin, Shih-Hua Chang, Deh-Ming Sytwu, Huey-Kang |
author_facet | Wang, Chia-Jen Chou, Feng-Cheng Chu, Chi-Hong Wu, Jen-Chine Lin, Shih-Hua Chang, Deh-Ming Sytwu, Huey-Kang |
author_sort | Wang, Chia-Jen |
collection | PubMed |
description | OBJECTIVE—Coinhibitory signals mediated via programmed death 1 (PD-1) receptor play a critical role in downregulating immune responses and in maintaining peripheral tolerance. Programmed death 1 ligand 1 (PD-L1), the interacting ligand for PD-1, widely expressed in many cell types, acts as a tissue-specific negative regulator of pathogenic T-cell responses. We investigated the protective potential of PD-L1 on autoimmune diabetes by transgenically overexpressing PD-L1 in pancreatic β-cells in nonobese diabetic (NOD) mice. RESEARCH DESIGN AND METHODS—We established an insulin promoter–driven murine PD-L1 transgenic NOD mouse model to directly evaluate the protective effect of an organ-specific PD-L1 transgene against autoimmune diabetes. Transgene expression, insulitis, and diabetic incidence were characterized in these transgenic NOD mice. Lymphocyte development, Th1 cells, and regulatory T-cells were analyzed in these transgenic mice; and T-cell proliferation, adoptive transfer, and islet transplantation were performed to evaluate the PD-L1 transgene–mediated immune-protective mechanisms. RESULTS—The severity of insulitis in these transgenic mice is significantly decreased, disease onset is delayed, and the incidence of diabetes is markedly decreased compared with littermate controls. NOD/SCID mice that received lymphocytes from transgenic mice became diabetic at a slower rate than mice receiving control lymphocytes. Moreover, lymphocytes collected from recipients transferred by lymphocytes from transgenic mice revealed less proliferative potential than lymphocytes obtained from control recipients. Transgenic islets transplanted in diabetic recipients survived moderately longer than control islets. CONCLUSIONS—Our results demonstrate the protective potential of transgenic PD-L1 in autoimmune diabetes and illustrate its role in downregulating diabetogenic T-cells in NOD mice. |
format | Text |
id | pubmed-2453619 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-24536192009-07-01 Protective Role of Programmed Death 1 Ligand 1 (PD-L1)in Nonobese Diabetic Mice : The Paradox in Transgenic Models Wang, Chia-Jen Chou, Feng-Cheng Chu, Chi-Hong Wu, Jen-Chine Lin, Shih-Hua Chang, Deh-Ming Sytwu, Huey-Kang Diabetes Immunology and Transplantation OBJECTIVE—Coinhibitory signals mediated via programmed death 1 (PD-1) receptor play a critical role in downregulating immune responses and in maintaining peripheral tolerance. Programmed death 1 ligand 1 (PD-L1), the interacting ligand for PD-1, widely expressed in many cell types, acts as a tissue-specific negative regulator of pathogenic T-cell responses. We investigated the protective potential of PD-L1 on autoimmune diabetes by transgenically overexpressing PD-L1 in pancreatic β-cells in nonobese diabetic (NOD) mice. RESEARCH DESIGN AND METHODS—We established an insulin promoter–driven murine PD-L1 transgenic NOD mouse model to directly evaluate the protective effect of an organ-specific PD-L1 transgene against autoimmune diabetes. Transgene expression, insulitis, and diabetic incidence were characterized in these transgenic NOD mice. Lymphocyte development, Th1 cells, and regulatory T-cells were analyzed in these transgenic mice; and T-cell proliferation, adoptive transfer, and islet transplantation were performed to evaluate the PD-L1 transgene–mediated immune-protective mechanisms. RESULTS—The severity of insulitis in these transgenic mice is significantly decreased, disease onset is delayed, and the incidence of diabetes is markedly decreased compared with littermate controls. NOD/SCID mice that received lymphocytes from transgenic mice became diabetic at a slower rate than mice receiving control lymphocytes. Moreover, lymphocytes collected from recipients transferred by lymphocytes from transgenic mice revealed less proliferative potential than lymphocytes obtained from control recipients. Transgenic islets transplanted in diabetic recipients survived moderately longer than control islets. CONCLUSIONS—Our results demonstrate the protective potential of transgenic PD-L1 in autoimmune diabetes and illustrate its role in downregulating diabetogenic T-cells in NOD mice. American Diabetes Association 2008-07 /pmc/articles/PMC2453619/ /pubmed/18420489 http://dx.doi.org/10.2337/db07-1260 Text en Copyright © 2008, American Diabetes Association https://creativecommons.org/licenses/by-nc-nd/3.0/Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. |
spellingShingle | Immunology and Transplantation Wang, Chia-Jen Chou, Feng-Cheng Chu, Chi-Hong Wu, Jen-Chine Lin, Shih-Hua Chang, Deh-Ming Sytwu, Huey-Kang Protective Role of Programmed Death 1 Ligand 1 (PD-L1)in Nonobese Diabetic Mice : The Paradox in Transgenic Models |
title | Protective Role of Programmed Death 1 Ligand 1 (PD-L1)in Nonobese Diabetic Mice : The Paradox in Transgenic Models |
title_full | Protective Role of Programmed Death 1 Ligand 1 (PD-L1)in Nonobese Diabetic Mice : The Paradox in Transgenic Models |
title_fullStr | Protective Role of Programmed Death 1 Ligand 1 (PD-L1)in Nonobese Diabetic Mice : The Paradox in Transgenic Models |
title_full_unstemmed | Protective Role of Programmed Death 1 Ligand 1 (PD-L1)in Nonobese Diabetic Mice : The Paradox in Transgenic Models |
title_short | Protective Role of Programmed Death 1 Ligand 1 (PD-L1)in Nonobese Diabetic Mice : The Paradox in Transgenic Models |
title_sort | protective role of programmed death 1 ligand 1 (pd-l1)in nonobese diabetic mice : the paradox in transgenic models |
topic | Immunology and Transplantation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2453619/ https://www.ncbi.nlm.nih.gov/pubmed/18420489 http://dx.doi.org/10.2337/db07-1260 |
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