title: Dendritic cell-expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice.
abstract: 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 beta 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 5x10(4) 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.
authors.affiliation: Laboratory of Cellular Physiology and Immunology and Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021, USA. tarbelk@rockefeller.edu
authors.forename: Kristin V
authors.initials: KV
authors.lastname: Tarbell
authors.forename: Lucine
authors.initials: L
authors.lastname: Petit
authors.forename: Xiaopan
authors.initials: X
authors.lastname: Zuo
authors.forename: Priscilla
authors.initials: P
authors.lastname: Toy
authors.forename: Xunrong
authors.initials: X
authors.lastname: Luo
authors.forename: Amina
authors.initials: A
authors.lastname: Mqadmi
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.forename: Manikkam
authors.initials: M
authors.lastname: Suthanthiran
authors.forename: Svetlana
authors.initials: S
authors.lastname: Mojsov
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Steinman
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007328:Insulin / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D007515:Islets of Langerhans / Q000276:immunology*; D019041:L-Selectin / Q000378:metabolism*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011236:Prediabetic State / Q000097:blood / Q000276:immunology / Q000628:therapy; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation
chemical_list: D001786:Blood Glucose; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007328:Insulin; D053645:Interleukin-2 Receptor alpha Subunit; D019041:L-Selectin