Achieving Therapeutic Antigent-Specific Tolerance in Type 1 Diabetes

这一建议是一项探索性合作赠款的逻辑延续（R21，赫罗尔德-冯 Herrath）专注于开发新的1型糖尿病（T1 D）的组合方法。 即将在两个独立的糖尿病模型（NOD和RIP-LCMV）中获得的结果已经建立了 概念是，为了实现抗原特异性耐受，免疫与胰岛 抗原和全身作用的免疫调节剂可以表现出强的协同作用， 首先，高血糖症的逆转可以在较低剂量的胰岛素下发生， 全身作用的免疫调节剂，在我们的情况下是抗CD 3 Fab ′ 2。第二，从机制上讲， 可介导长期耐受和旁观者胰岛抗原特异性T细胞的诱导 抑制增强。这个项目旨在加深我们的机械洞察力，并在密切 与项目2和项目3合作，解决应有助于翻译 近期发作的T1 D的组合疗法。我们将回答以下问题： 1.哪一种是近期发作的T1 D体内最佳组合治疗方案？电流 数据表明胰岛素肽的口服或鼻腔给药最有希望。为了 最佳地结合到当前的药物开发选择，我们将确定最佳的候选人。在 此外，我们将探索抗原特异性治疗与GLP-1激动剂和胃泌素的组合 来再生β细胞 2.哪些确切的功能定义了胰岛抗原诱导的Tcl 4在体内的作用？电流 结果显示，抗CD 3和抗原给药后的长期耐受性在很大程度上 部分原因是诱导了有效的胰岛抗原特异性调节性T细胞（TCRs）， 对新近发作的T1 D受体的耐受性。其精确的作用机制将被定义 利用新近获得的新技术和试剂，RNAi和ins-TcR转基因小鼠。 3.哪种体外试验是监测体内Tcl 4和抗原特异性耐受性的最佳方法？我们 将建立一个能反映和预测每只动物临床结果的方法。这些 分析应该为临床项目的目标提供强有力的指导（#3，赫罗尔德）。

This proposal is the logical continuation of an exploratory collaborative grant (R21,Herold - von Herrath) focused to develop novel combinatorial approaches of recent-onset type 1 diabetes (T1D). Forthcoming results in two independent diabetes models (NOD and RIP-LCMV) have established the concept that, in order to achieve antigen-specific tolerance, combination of immunization with islet antigens and systemically acting immune modulators can exhibit strong synergy and be clinically beneficial for the following reasons: First, reversion of hyperglycemia can occur at lower dosages of the systemically acting immune modulator, in our case anti-CD3 Fab'2. Second, mechanistically, the induction of Tregs specific for islet antigens that can mediate long-term tolerance and bystander suppression is enhanced. This project seeks to deepen our mechanistic insight, and, in close collaboration with projects 2 and 3, address crucial issues that should facilitate translation of combinatorial therapy in recent-onset T1D to the clinic. Wewill answer the following questions: 1. Which is the optimal combinatorial therapeutic regimen in recent-onset T1D in vivo? Current data indicate that oral or nasal administration of insulin peptides bears most promise. In order to optimally tie into current choices in drug development, we will define the best candidate. In addition we will explore combination of antigen-specific therapy with GLP-1 agonists and gastrin to regenerate beta cells. 2. Which precise functions define the action of the islet antigen induced Tregs in vivo? Current findings show that long-term tolerance after anti-CD3 and antigen administration is, to a large part, due to induction of potent islet antigen-specific regulatory T cells (Tregs) that can transfer tolerance to recipients with recent-onset T1D. Their precise mechanism of action will be defined using novel technology and reagents recently acquired, RNAi and ins-TcR transgenic mice. 3. Which are optimal in vitro assays to monitor Tregs and antigen-sepcific tolerance in vivo? We will establish asays that reflect and predict the clinical out come on a per-animal basis. These assays should provide strong guidance to the goals of the clinical project (#3, Herold).