Most treatments that prevent autoimmune diabetes in nonobese diabetic (NOD) mice require intervention at early pathogenic stages, when insulitis is first developing. We tested whether dendritic cell (DC)–expanded, islet antigen–specific CD4+ CD25+ suppressor T cells could treat diabetes at later stages of disease, when most of the insulin-producing islet β cells had been destroyed by infiltrating lymphocytes. CD4+ CD25+ CD62L+ regulatory T cells (T reg cells) from BDC2.5 T cell receptor transgenic mice were expanded with antigen-pulsed DCs and IL-2, and were then injected into NOD mice. A single dose of as few as 5 × 104 of these islet-specific T reg cells blocked diabetes development in prediabetic 13-wk-old NOD mice. The T reg cells also induced long-lasting reversal of hyperglycemia in 50% of mice in which overt diabetes had developed. Successfully treated diabetic mice had similar responses to glucose challenge compared with nondiabetic NOD mice. The successfully treated mice retained diabetogenic T cells, but also had substantially increased Foxp3+ cells in draining pancreatic lymph nodes. However, these Foxp3+ cells were derived from the recipient mice and not the injected T reg cells, suggesting a role for endogenous T reg cells in maintaining tolerance after treatment. Therefore, inoculation of DC-expanded, antigen-specific suppressor T cells has considerable efficacy in ameliorating ongoing diabetes in NOD mice.
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22 January 2007
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January 08 2007
Dendritic cell–expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice
Kristin V. Tarbell,
Kristin V. Tarbell
1Laboratory of Cellular Physiology and Immunology
2Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021
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Lucine Petit,
Lucine Petit
1Laboratory of Cellular Physiology and Immunology
2Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021
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Xiaopan Zuo,
Xiaopan Zuo
1Laboratory of Cellular Physiology and Immunology
2Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021
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Priscilla Toy,
Priscilla Toy
1Laboratory of Cellular Physiology and Immunology
2Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021
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Xunrong Luo,
Xunrong Luo
3Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021
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Amina Mqadmi,
Amina Mqadmi
1Laboratory of Cellular Physiology and Immunology
2Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021
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Hua Yang,
Hua Yang
3Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021
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Manikkam Suthanthiran,
Manikkam Suthanthiran
3Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021
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Svetlana Mojsov,
Svetlana Mojsov
1Laboratory of Cellular Physiology and Immunology
2Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021
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Ralph M. Steinman
Ralph M. Steinman
1Laboratory of Cellular Physiology and Immunology
2Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021
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Kristin V. Tarbell
1Laboratory of Cellular Physiology and Immunology
2Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021
Lucine Petit
1Laboratory of Cellular Physiology and Immunology
2Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021
Xiaopan Zuo
1Laboratory of Cellular Physiology and Immunology
2Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021
Priscilla Toy
1Laboratory of Cellular Physiology and Immunology
2Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021
Xunrong Luo
3Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021
Amina Mqadmi
1Laboratory of Cellular Physiology and Immunology
2Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021
Hua Yang
3Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021
Manikkam Suthanthiran
3Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021
Svetlana Mojsov
1Laboratory of Cellular Physiology and Immunology
2Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021
Ralph M. Steinman
1Laboratory of Cellular Physiology and Immunology
2Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021
CORRESPONDENCE Kristin Tarbell: [email protected]
Abbreviations used: CFSE, carboxyfluorescein diacetate succinimidyl ester; GLP-1, glucagon-like peptide 1; NOD, nonobese diabetic.
X. Luo's present address is Depts. of Medicine and Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
Received:
August 01 2006
Accepted:
December 12 2006
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2007
J Exp Med (2007) 204 (1): 191–201.
Article history
Received:
August 01 2006
Accepted:
December 12 2006
Citation
Kristin V. Tarbell, Lucine Petit, Xiaopan Zuo, Priscilla Toy, Xunrong Luo, Amina Mqadmi, Hua Yang, Manikkam Suthanthiran, Svetlana Mojsov, Ralph M. Steinman; Dendritic cell–expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice . J Exp Med 22 January 2007; 204 (1): 191–201. doi: https://doi.org/10.1084/jem.20061631
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