| Summary: | 博士 === 國防醫學院 === 生命科學研究所 === 98 === Type 1 diabetes mellitus (T1D) results from the destruction of insulin-producing β cells in the islet of the pancreas by infiltrated lymphocytes. Islet transplantation has been established as a potential therapy for type 1 diabetes. However, inflammation, allorejection, and on-going autoimmune damage contribute to early graft loss and failure of islet transplantation. Melatonin is the major secretory product of the pineal gland during the dark period of each day and displays multifunctional properties including the regulation of circadian and seasonal rhythms, antioxidation reactions and immune modulation. Based on the immunosuppressive properties of melatonin, we investigated whether melatonin treatment prolonged the survival of islet grafts in non-obese diabetic (NOD) mice. The mean islet graft survival time was 7.33 ± 1.51 days and 7.75 ± 2.66 days in untreated controls and in the solvent-treated animals, respectively. Strikingly, the mean survival time of islet grafts in recipients treated with melatonin (200 mg/kg/bw) was 17.00 ± 7.76 days. Moreover, melatonin treatment reduced the proliferation of splenocytes in NOD mice. Using a T1 and T2 double transgenic mouse model, we found that T helper 1 (Th1) cells in mice treated with melatonin were significantly decreased. The reduction of Th1 cells and T cell proliferation may result from an increase in the immunosuppressive cytokine IL-10. Our results indicate that melatonin treatment suppresses autoimmune recurrence by inhibiting the proliferation of Th1 cells in NOD mice and thus prolongs the survival of syngeneic islet grafts. The pathogenesis of T1D is involving the infiltration of lymphocytes into pancreas and this process is dependent on the attraction of immune cells by chemokines. Islet cells in NOD mice have been found to express chemokines during the progress of diabetes development. Inflammatory CC chemokines, such as CCL2, CCL3 and CCL5, have been found to express by islets and may involve in the pathogenesis of T1D. The D6 is an inflammatory CC chemokine decoy receptor which can binds to a broad range of inflammatory CC chemokines and actively internalizes CC chemokines in a β-arrestin-dependent way and targets them for intracellular degradation to reduces the chemokine gradient in the inflamed site. Based on the biological function of D6, we transgenic overexpressed this chemokine decoy receptor D6 on islets of NOD mice to reduce the infiltration of lymphocytes into islets by decreasing the amount of inflammatory CC chemokines around islet. The diabetic frequency of transgenic mice is significant lower than transgenic negative control littermates and the insulitis score of transgenic mice is also milder than transgenic negative littermate. By analyzing the infiltration of lymphocytes in the pancreas, we found that the percentage of lymphocytes in pancreas is decreases in transgenic mice. Moreover, the activation of CD4+ and CD8+ T cells in the pancreas is decreased and the diabetogenecity of splenocytes is reduced in transgenic mice. Our study demonstrated that inflammatory CC chemokines contribute to the activation of autoreactive lymphocytes by inducing the migration of lymphocytes to pancreas and play a role on the pathogenesis of T1D in NOD mice.
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