调节性T细胞（Tregs）数量不足、功能失调以及与效应T细胞、Tfh之间失衡，是导致红斑狼疮（SLE）等自身免疫疾病致病的重要原因，我们前期研究提示高剂量热休克蛋白gp96免疫通过与TLRs作用活化NF-κB途径激活Treg，小鼠试验发现对SLE、肝衰竭、1型糖尿病等有明显疗效，更重要的是对SLE等自身免疫疾病患者志愿者的初步临床观察疗效明显，几乎没有毒副作用。本课题拟深入研究高剂量gp96活化Treg的免疫学机制，发现gp96作用的关键受体、靶点和通路，解析活化的Treg亚群和作用。进一步优化gp96免疫抑制功能(如突变体)和使用方式，增强活化Treg的特异性，通过小鼠模型，评价高剂量免疫gp96或修饰、突变体对SLE、1型糖尿病、肝衰竭治疗效果，查明活化免疫抑制应答的关键通路和Treg亚群，为研发以gp96为基础的新型治疗自身免疫疾病药物提供科学依据。

Inadequent number of T regulatory cells (Tregs) and their impaired founction, as well as imbalance between Tregs and T effectors cells or T follicular helper cells (Tfh) have been implicated for development and progress of autoimmune diseases including systemic lupus erythematosus (SLE). Our previous studies indicated that high dose heat shock protein gp96 immunization induces Treg via its interaction with Toll like receptors and subsequent NF-κB activation. Treatment with high dose gp96 in mouse models showed highly efficiency for SLE, liver failure, type 1 diabetes. Importantly, our preliminary observation demonstrated that high dose gp96 was effective for treating patients with autoimmune diseases including SLE with no obvious side effects. In this project we will explore the mechanisms of high dose gp96-induce Treg response, and define the key receptors, targets and pathways. In addition, Treg-cell subsets and their function will be characterized. Then, gp96 function and usage will be optimized by designing its mutant form and formulation to increase its specificity for targeint Treg. The therapeutic effects of designed gp96 mutant or its modification forms will be evaluated in mouse models of SLE, liver failure, type 1 diabetes. The key inhibitory Treg subsets and pathways will also be defined. The results from this project will provide therapeutic potential for developing new generation of gp96-based drugs to treat autoimmine diseases.