title: Prevention of murine autoimmune diabetes  by CCL22-mediated Treg recruitment  to the pancreatic islets.
abstract: Type 1 diabetes is characterized by destruction of insulin-producing β cells in the pancreatic islets by effector T cells. Tregs, defined by the markers CD4 and FoxP3, regulate immune responses by suppressing effector T cells and are recruited to sites of action by the chemokine CCL22. Here, we demonstrate that production of CCL22 in islets after intrapancreatic duct injection of double-stranded adeno-associated virus encoding CCL22 recruits endogenous Tregs to the islets and confers long-term protection from autoimmune diabetes in NOD mice. In addition, adenoviral expression of CCL22 in syngeneic islet transplants in diabetic NOD recipients prevented β cell destruction by autoreactive T cells and thereby delayed recurrence of diabetes. CCL22 expression increased the frequency of Tregs, produced higher levels of TGF-β in the CD4+ T cell population near islets, and decreased the frequency of circulating autoreactive CD8+ T cells and CD8+ IFN-γ–producing T cells. The protective effect of CCL22 was abrogated by depletion of Tregs with a CD25-specific antibody. Our results indicate that islet expression of CCL22 recruits Tregs and attenuates autoimmune destruction of β cells. CCL22-mediated recruitment of Tregs to islets may be a novel therapeutic strategy for type 1 diabetes.
authors: Departments of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Joel
authors: J
authors: Montane
authors: Loraine
authors: L
authors: Bischoff
authors: Galina
authors: G
authors: Soukhatcheva
authors: Derek L
authors: DL
authors: Dai
authors: Gijs
authors: G
authors: Hardenberg
authors: Megan K
authors: MK
authors: Levings
authors: Paul C
authors: PC
authors: Orban
authors: Timothy J
authors: TJ
authors: Kieffer
authors: Rusung
authors: R
authors: Tan
authors: C Bruce
authors: CB
authors: Verchere
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000378:metabolism; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D054422:Chemokine CCL22 / Q000235:genetics / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000517:prevention & control*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000166:cytology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051381:Rats; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*
chemical_list: C515483:Ccl22 protein, mouse; D054422:Chemokine CCL22; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit