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Blockade of the Programmed Death-1 (PD1) Pathway Undermines Potent Genetic Protection from Type 1 Diabetes
AIMS/HYPOTHESIS: Inhibition of PD1-PDL1 signaling in NOD mice accelerates onset of type 1 diabetes implicating this pathway in suppressing the emergence of pancreatic beta cell reactive T-cells. However, the molecular mechanism by which PD1 signaling protects from type 1 diabetes is not clear. We hy...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3938467/ https://www.ncbi.nlm.nih.gov/pubmed/24586872 http://dx.doi.org/10.1371/journal.pone.0089561 |
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author | Kochupurakkal, Nora M. Kruger, Annie J. Tripathi, Sudipta Zhu, Bing Adams, La Tonya Rainbow, Daniel B. Rossini, Aldo Greiner, Dale L. Sayegh, Mohamed H. Wicker, Linda S. Guleria, Indira |
author_facet | Kochupurakkal, Nora M. Kruger, Annie J. Tripathi, Sudipta Zhu, Bing Adams, La Tonya Rainbow, Daniel B. Rossini, Aldo Greiner, Dale L. Sayegh, Mohamed H. Wicker, Linda S. Guleria, Indira |
author_sort | Kochupurakkal, Nora M. |
collection | PubMed |
description | AIMS/HYPOTHESIS: Inhibition of PD1-PDL1 signaling in NOD mice accelerates onset of type 1 diabetes implicating this pathway in suppressing the emergence of pancreatic beta cell reactive T-cells. However, the molecular mechanism by which PD1 signaling protects from type 1 diabetes is not clear. We hypothesized that differential susceptibility of Idd mouse strains to type 1 diabetes when challenged with anti PDL1 will identify genomic loci that collaborate with PD1 signaling in suppressing type 1 diabetes. METHODS: Anti PDL1 was administered to NOD and various Idd mouse strains at 10 weeks of age and onset of disease was monitored by measuring blood glucose levels. Additionally, histological evaluation of the pancreas was performed to determine degree of insulitis. Statistical analysis of the data was performed using Log-Rank and Student's t-test. RESULTS: Blockade of PDL1 rapidly precipitated type 1 diabetes in nearly all NOD Idd congenic strains tested, despite the fact that all are moderately (Idd5, Idd3 and Idd10/18) or highly (Idd3/10/18 and Idd9) protected from spontaneous type 1 diabetes by virtue of their protective Idd genes. Only the Idd3/5 strain, which is nearly 100% protected from spontaneous disease, remained normoglycemic following PDL1 blockade. CONCLUSIONS: These results indicate that multiple Idd loci collaborate with PD1 signaling. Anti PDL1 treatment undermines a large portion of the genetic protection mediated by Idd genes in the NOD model of type 1 diabetes. Basal insulitis correlated with higher susceptibility to type 1 diabetes. These findings have important implications since the PD1 pathway is a target for immunotherapy. |
format | Online Article Text |
id | pubmed-3938467 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-39384672014-03-04 Blockade of the Programmed Death-1 (PD1) Pathway Undermines Potent Genetic Protection from Type 1 Diabetes Kochupurakkal, Nora M. Kruger, Annie J. Tripathi, Sudipta Zhu, Bing Adams, La Tonya Rainbow, Daniel B. Rossini, Aldo Greiner, Dale L. Sayegh, Mohamed H. Wicker, Linda S. Guleria, Indira PLoS One Research Article AIMS/HYPOTHESIS: Inhibition of PD1-PDL1 signaling in NOD mice accelerates onset of type 1 diabetes implicating this pathway in suppressing the emergence of pancreatic beta cell reactive T-cells. However, the molecular mechanism by which PD1 signaling protects from type 1 diabetes is not clear. We hypothesized that differential susceptibility of Idd mouse strains to type 1 diabetes when challenged with anti PDL1 will identify genomic loci that collaborate with PD1 signaling in suppressing type 1 diabetes. METHODS: Anti PDL1 was administered to NOD and various Idd mouse strains at 10 weeks of age and onset of disease was monitored by measuring blood glucose levels. Additionally, histological evaluation of the pancreas was performed to determine degree of insulitis. Statistical analysis of the data was performed using Log-Rank and Student's t-test. RESULTS: Blockade of PDL1 rapidly precipitated type 1 diabetes in nearly all NOD Idd congenic strains tested, despite the fact that all are moderately (Idd5, Idd3 and Idd10/18) or highly (Idd3/10/18 and Idd9) protected from spontaneous type 1 diabetes by virtue of their protective Idd genes. Only the Idd3/5 strain, which is nearly 100% protected from spontaneous disease, remained normoglycemic following PDL1 blockade. CONCLUSIONS: These results indicate that multiple Idd loci collaborate with PD1 signaling. Anti PDL1 treatment undermines a large portion of the genetic protection mediated by Idd genes in the NOD model of type 1 diabetes. Basal insulitis correlated with higher susceptibility to type 1 diabetes. These findings have important implications since the PD1 pathway is a target for immunotherapy. Public Library of Science 2014-02-28 /pmc/articles/PMC3938467/ /pubmed/24586872 http://dx.doi.org/10.1371/journal.pone.0089561 Text en © 2014 Kochupurakkal et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Kochupurakkal, Nora M. Kruger, Annie J. Tripathi, Sudipta Zhu, Bing Adams, La Tonya Rainbow, Daniel B. Rossini, Aldo Greiner, Dale L. Sayegh, Mohamed H. Wicker, Linda S. Guleria, Indira Blockade of the Programmed Death-1 (PD1) Pathway Undermines Potent Genetic Protection from Type 1 Diabetes |
title | Blockade of the Programmed Death-1 (PD1) Pathway Undermines Potent Genetic Protection from Type 1 Diabetes |
title_full | Blockade of the Programmed Death-1 (PD1) Pathway Undermines Potent Genetic Protection from Type 1 Diabetes |
title_fullStr | Blockade of the Programmed Death-1 (PD1) Pathway Undermines Potent Genetic Protection from Type 1 Diabetes |
title_full_unstemmed | Blockade of the Programmed Death-1 (PD1) Pathway Undermines Potent Genetic Protection from Type 1 Diabetes |
title_short | Blockade of the Programmed Death-1 (PD1) Pathway Undermines Potent Genetic Protection from Type 1 Diabetes |
title_sort | blockade of the programmed death-1 (pd1) pathway undermines potent genetic protection from type 1 diabetes |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3938467/ https://www.ncbi.nlm.nih.gov/pubmed/24586872 http://dx.doi.org/10.1371/journal.pone.0089561 |
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