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DOI: 10.2337/db05-1576
© 2006 by the American Diabetes Association
Induction of Tolerance in Type 1 Diabetes via Both CD4+CD25+ T Regulatory Cells and T Regulatory Type 1 Cells
1 San Raffaele Scientific Institute, Telethon Institute for Gene Therapy (HSR-TIGET), Milan, Italy
2 San Raffaele Scientific Institute, Diabetes and Endocrinology Unit, Milan, Italy
3 Università Vita-Salute San Raffaele, Milan, Italy
Address correspondence and reprint requests to M.G. Roncarolo, HSR-TIGET, Via Olgettina 58, 20132 Milano, Italy. E-mail: m.roncarolo{at}hsr.it
Abbreviations:
CFSE, carboxyfluorescein diacetate succinimidyl ester; FACS, fluorescence-activated cell sorting; IFN-
, -interferon; ICAM, intracellular adhesion molecule; IL, interleukin; mAb, monoclonal antibody; TGF, transforming growth factor; Tr, T regulatory
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.
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