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Vaccination with a co‐expression DNA plasmid containing GAD65 fragment gene and IL‐10 gene induces regulatory CD4 + T cells that prevent experimental autoimmune diabetes
Author(s) -
Liu Xinyuan,
Zhang Song,
Li Xia,
Zheng Peilin,
Hu Fang,
Zhou Zhiguang
Publication year - 2016
Publication title -
diabetes/metabolism research and reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.307
H-Index - 110
eISSN - 1520-7560
pISSN - 1520-7552
DOI - 10.1002/dmrr.2780
Subject(s) - insulitis , nod mice , dna vaccination , foxp3 , il 2 receptor , immunology , nod , immune system , adoptive cell transfer , diabetes mellitus , biology , endocrinology , medicine , t cell , immunization
Abstract Background The non‐obese diabetic (NOD) mouse is a commonly used animal model for studying type 1 diabetes (T1D). The aims of our study were to explore the diabetes‐preventive effect in NOD mice and the potential mechanisms of an optimized co‐expression DNA vaccine containing GAD65 fragment gene with the IL‐10 gene (SGAD65 190‐315 /IL‐10). Methods Female NOD mice at the age of 3–4 weeks old were randomly divided into two groups and received intra‐muscular injection of either blank pBudCE4.l vector ( n = 34) or pBudCE4.l carrying the SGAD65 190‐315 /IL‐10 ( n = 32). The incidence of diabetes was monitored up to 30 weeks of age. The severity of insulitis, apoptosis rate of β cells and relevant mechanisms were examined. Results Administration with SGAD65 190‐315 /IL‐10 blocked the onset of autoimmune diabetes in NOD mice, significantly suppressed islet inflammation, inhibited the apoptosis of islet β cells, induced immune tolerance to autoantigen GAD65 and proinsulin and shifted the Th1/Th2 balance towards Th2. More importantly, the frequencies of CD4 + CD25 + Foxp3 + regulatory T cells (Tregs) in the spleen and pancreatic lymph nodes in vaccine‐immunized mice were significantly increased, and these Tregs were GAD65‐reactive. In addition, Treg depletion by anti‐CD25 mAb administration abolished the protective effects of SGAD65 190‐315 /IL‐10 on diabetes and insulitis. Moreover, depletion of CD4 + CD25 + T cells using magnetic‐activated cell sorting impaired the protective effect of SGAD65 190‐315 /IL‐10 vaccination on adoptive transfer of diabetes. Conclusions Our data suggested that SGAD65 190‐315 /IL‐10 DNA vaccine had protective effects on T1D by upregulating autoantigen‐reactive Tregs. Our findings may provide a novel preventive therapy for T1D. Copyright © 2016 John Wiley & Sons, Ltd.