Abstract
Success in developing novel therapies to recommence self-tolerance in autoimmunity depends on the induction of T regulatory (Tr) cells. Here, we report that rapamycin combined with interleukin (IL)-10 efficiently blocks type 1 diabetes development and induces long-term immunotolerance in the absence of chronic immunosuppression in nonobese diabetic (NOD) mice. Rapamycin mediates accumulation in the pancreas of suppressive CD4(+)CD25(+)FoxP3(+) Tr cells, which prevent diabetes. IL-10 induces Tr type 1 (Tr1) cells, which reside in the spleen and prevent migration of diabetogenic T-cells to the draining lymph nodes. These two Tr cell subsets act in concert to control diabetogenic T-cells that are still present in long-term tolerant mice. Rapamycin plus IL-10 treatment, promoting distinct subsets of Tr cells, may constitute a novel and potent tolerance-inducing protocol for immune-mediated diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adoptive Transfer
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Animals
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / immunology*
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Cell Proliferation
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Cytokines / immunology
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Cytokines / metabolism
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Diabetes Mellitus, Type 1 / drug therapy
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Diabetes Mellitus, Type 1 / immunology*
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Diabetes Mellitus, Type 1 / metabolism
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Female
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Flow Cytometry
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Forkhead Transcription Factors / immunology
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Forkhead Transcription Factors / metabolism
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Immunohistochemistry
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Interleukin-10 / pharmacology
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Interleukin-2 Receptor alpha Subunit / immunology*
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Interleukin-2 Receptor alpha Subunit / metabolism
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Mice
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Mice, Inbred NOD
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Pancreas / immunology
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Pancreas / metabolism
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Polymerase Chain Reaction
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Sirolimus / pharmacology
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Spleen / cytology
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Spleen / immunology
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Spleen / metabolism
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T-Lymphocytes, Regulatory / drug effects
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / metabolism
Substances
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Cytokines
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Interleukin-2 Receptor alpha Subunit
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Interleukin-10
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Sirolimus