高剂量热休克蛋白gp96通过激活调节性T细胞预防1型糖尿病

High-dose heat shock protein gp96 immunization prevents type 1 diabetes via inducing regulatory T cells

摘要:

旨在以非肥胖糖尿病 (Non-obese diabetic, NOD) 小鼠为动物模型，研究高剂量昆虫细胞表达的重组热休克蛋白gp96 (Recombinant gp96, rgp96) 对1型糖尿病 (Type 1 diabetes, T1D) 的预防作用。以高剂量rgp96免疫NOD小鼠，用血糖仪监测小鼠血糖值，用流式细胞术检测小鼠脾脏CD4+ CD25+ Foxp3+调节性T细胞 (Regulatory T cells, Tregs) 亚群频率，然后用一系列体外实验探究高剂量rgp96对Tregs的影响。结果显示高剂量rgp96免疫有效地预防或延缓小鼠T1D发病，免疫诱导Tregs数量明显增加。体外实验发现rgp96蛋白促进Tregs增殖，诱导Foxp3表达上调和IL-10分泌增加。研究结果为开发基于rgp96的新型T1D预防和治疗性疫苗提供了依据。

Abstract:

Type 1 diabetes (T1D), the most prevalent human autoimmune disease, occurs in genetically susceptible individuals. Regulatory T cells (Tregs) are defective in T1D setting. Therefore, efforts to repair or restore Tregs in T1D may prevent or reverse this autoimmune disease. Here, we studied the potential role of rgp96 in preventing T1D, using non-obese diabetic (NOD) mice as an animal model. High-dose rgp96 immunization elicited efficient protection of mice against T1D, as evidenced by stable blood glucose, decreased disease incidence. Significantly increased CD4+ CD25+ Foxp3+ Tregs were observed in immunized mice. In vitro co-culture experiments demonstrated that rgp96 stimulation enhanced Treg proliferation and suppressive function by up-regulation of Foxp3 and IL-10. Our work shows that activation of Tregs by high-dose rgp96 immunization protects against T1D via inducing regulatory T cells and provides preventive and therapeutic potential for the development of an rgp96-based vaccine against T1D.