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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 ? 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 ? cell destruction by autoreactive T cells and thereby delayed recurrence of diabetes. CCL22 expression increased the frequency of Tregs, produced higher levels of TGF-? in the CD4+ T cell population near islets, and decreased the frequency of circulating autoreactive CD8+ T cells and CD8+ IFN-?–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 ? cells. CCL22-mediated recruitment of Tregs to islets may be a novel therapeutic strategy for type 1 diabetes.

SUBMITTER: Montane J 

PROVIDER: S-EPMC3148722 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Prevention of murine autoimmune diabetes by CCL22-mediated Treg recruitment to the pancreatic islets.

Montane Joel J   Bischoff Loraine L   Soukhatcheva Galina G   Dai Derek L DL   Hardenberg Gijs G   Levings Megan K MK   Orban Paul C PC   Kieffer Timothy J TJ   Tan Rusung R   Verchere C Bruce CB  

The Journal of clinical investigation 20110801 8


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 p  ...[more]

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