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| Article Authors: | Wendy W J Unger; Todd Pearson; Joana R F Abreu; Sandra Laban; Arno R van der Slik; Sacha Mulder-van der Kracht; Michel G D Kester; Dave V Serreze; Leonard D Shultz; Marieke Griffioen; Jan Wouter Drijfhout; Dale L Greiner; Bart O Roep |
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| Article Title: | Islet-Specific CTL Cloned from a Type 1 Diabetes Patient Cause Beta-Cell Destruction after Engraftment into HLA-A2 Transgenic NOD/SCID/IL2RG Null Mice. |
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| Reference ID: | 1025272 |
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| Abstract: | Despite increasing evidence that autoreactive CD8 T-cells are involved in both the initiation of type 1 diabetes (T1D) and the destruction of beta-cells, direct evidence for their destructive role in-vivo is lacking. To address a destructive role for autoreactive CD8 T-cells in human disease, we assessed the pathogenicity of a CD8 T-cell clone derived from a T1D donor and specific for an HLA-A2-restricted epitope of islet-specific glucose-6-phosphatase catalytic-subunit related protein (IGRP). HLA-A2/IGRP tetramer staining revealed a higher frequency of IGRP-specific CD8 T-cells in the peripheral blood of recent onset human individuals than of healthy donors. IGRP(265-273)-specific CD8 T-cells that were cloned from the peripheral blood of a recent onset T1D individual were shown to secrete IFNγ and Granzyme B after antigen-specific activation and lyse HLA-A2-expressing murine islets in-vitro. Lytic capacity was also demonstrated in-vivo by specific killing of peptide-pulsed target cells. Using the HLA-A2 NOD-scid IL2rγ(null) mouse model, HLA-A2-restricted IGRP-specific CD8 T-cells induced a destructive insulitis. Together, this is the first evidence that human HLA-restricted autoreactive CD8 T-cells target HLA-expressing beta-cells in-vivo, demonstrating the translational value of humanized mice to study mechanisms of disease and therapeutic intervention strategies. |
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| Affiliations: | Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands. |
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| Date: | 2012 |
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| Reference Type: | Literature |
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| PubMed ID: | 23155466 |
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| Journal: | PLoS One |
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| Journal Volume: | 7 |
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| Article Pages: | e49213 |
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| Journal ISSN: | 1932-6203 |
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| Curation Last Updated: | 2012-12-14 20:01:46 |
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