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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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Autores principales: Wang, Chia-Jen, Chou, Feng-Cheng, Chu, Chi-Hong, Wu, Jen-Chine, Lin, Shih-Hua, Chang, Deh-Ming, Sytwu, Huey-Kang
Formato: Texto
Lenguaje:English
Publicado: American Diabetes Association 2008
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.
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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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