| Type 1 diabetes(T1D)is an organ-specific autoimmune disease caused by the autoimmune response against insulin-secreting ?-cells in pancreatic islets of Langerhans.The disease characterized by severe insulin deficiency and hyperglycemia,is triggered by numerous factors in genetically predisposed individuals and mediated by autoreactive ?-cell-specific CD4+ T helper(TH)cells and cytotoxic CD8+ T-lymphocytes that infiltrate islets and kill up to 90% of total ?-cells population.T lymphocytes are the key participants which involved in executing the autoreactive attacks on pancreatic islets.Our previous studies suggested that endogenous ?-3 polyunsaturated fatty acids(?-3 PUFAs)converted from ?-6 PUFAs by mfat-1 gene could protected the beta cells from cytokines-induced cell death.The goal of this study is to investigate the direct impact of ?-3 PUFAs and ?-6 PUFAs on the functions and viability of immune cells,immune molecules and related signaling pathways involved in type 1 diabetes.We proposed to further explore the potential therapeutic benefits of omega-3 PUFAs,particularly in animal models that are either type-1 diabetic or genetically prone to develop type 1 diabetes.The results presented in this study can be summarized as follows:First,?-3 PUFAs could significantly reduce the incidence of type 1 diabetes in NOD mice,lessen the development of peri-pancreatitis and insulitis,decrease the random blood glucose concentration and improve the intraperitoneal glucose tolerance;?-6 PUFAs have the opposite effect on the incidence and development of type 1 diabetes.We discovered that the ?-3 PUFAs upregulated the development of Th2 cells and corrected excessive polarization of Th1 cells,balance the ratio of Th1/Th2 in NOD mice.In the opposite,?-6 PUFAs improved the development of Th1 cells and exacerbate the polarization of Th1 cells.?-3 PUFAs down-regulated the proportion of Th17 cells in NOD mice and decreased the secretion of IL-17 in vitro;Thus,?-6 PUFAs significantly stimulated both the differentiation of Th17 cells and the secretion of IL-17.?-3 PUFAs significantly improved the differentiation of regulatory T cells,and ?-6 PUFAs had no obvious effect on regulatory T cells.The intervention of ?-3 PUFAs on CD4+ T cells enhanced the phosphorylation of S6 K and S6 which is the direct down-stream molecules of mTORC1,then the ?-3 PUFAs counteracted this effect and down-regulate the phosphorylation of S6 K as well as S6.In this study,we tested the possibility of gene therapy for type 1 diabetes using a lentivirus vector(LV)expressed a Caenorhabditis elegans mfat-1 gene.Diabetic NOD mice were treated with intravenous injection of mfat-1 LV encoding an ?-3 fatty acid desaturase through the caudal vein.Our results showed that the recombinant LV was efficient not only in decreasing the non-fasting blood glucose but also in rebalancing their CD4+ T cells differentiation after 6 weeks of lentivirus treatment.The application and achievement of mfat-1-containing lentivirus therapy improved normal secretion of insulin in pancreatic ? cells to maintain glucose metabolism in diabetic NOD mice and provided a powerful strategy to treat type 1 diabetes. |
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