31 Koulmanda, M. Budo, E. Bonner-Weir, S. Qipo, A. Putheti, P. Degauque, N. Shi, H. Fan, Z. Flier, J. S. Auchincloss, H., Jr. Zheng, X. X. Strom, T. B. 2007 Proc Natl Acad Sci U S A 104 32 13074-9 Aug 7 0027-8424 (Print) 17670937 Interleukin-2/administration & dosage Interleukin-15/administration & dosage Insulin-Secreting Cells/immunology/pathology Insulin Resistance Insulin/blood Inflammation/*drug therapy Immune Tolerance Female Diabetes Mellitus, Type 1/*drug therapy/immunology/pathology Autoimmunity Animals Sirolimus/administration & dosage Mice, Inbred NOD Mice Diabetes Mellitus Inbred NOD Type 1/*drug therapy/immunology/pathology In nonobese diabetic (NOD) mice with overt new-onset type 1 diabetes mellitus (T1DM), short-term treatment with a "triple-therapy" regimen [rapamycin plus agonist IL-2-related and antagonist-type, mutant IL-15-related Ig fusion proteins (IL-2.Ig and mutIL-15.Ig)] halts autoimmune destruction of insulin-producing beta cells and restores both euglycemia and immune tolerance to beta cells. Increases in the mass of insulin-producing beta cells or circulating insulin levels were not linked to the restoration of euglycemia. Instead, the restoration of euglycemia was linked to relief from an inflammatory state that impaired the host's response to insulin. Both restoration of immune tolerance to beta cells and relief from the adverse metabolic effects of an inflammatory state in insulin-sensitive tissues appear essential for permanent restoration of normoglycemia in this T1DM model. Thus, this triple-therapy regimen, possessing both tolerance-inducing and select antiinflammatory properties, may represent a prototype for therapies able to restore euglycemia and self-tolerance in T1DM. DK 44523/DK/NIDDK NIH HHS/United StatesDK 66056/DK/NIDDK NIH HHS/United StatesP01-AI041521/AI/NIAID NIH HHS/United StatesR01 AI54976/AI/NIAID NIH HHS/United StatesR01 DK067632/DK/NIDDK NIH HHS/United StatesR37 DK 28082/DK/NIDDK NIH HHS/United StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tUnited States http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17670937