Achieving Therapeutic Antigent-Specific Tolerance in Type 1 Diabetes

该提案是探索性协作赠款(R21，Herold-von)的逻辑延续 Herrath)专注于开发治疗新近发病的1型糖尿病(T1D)的新组合方法。 在两个独立的糖尿病模型(NOD和RIP-LCMV)中即将到来的结果已经建立了 为了实现抗原特异性耐受，将免疫与胰岛相结合的概念 抗原和系统作用的免疫调节剂具有很强的协同性，可用于临床。 有益的原因有以下几点：第一，较低剂量的 系统作用的免疫调节剂，在我们的案例中是抗CD3 Fab‘2。第二，从机制上讲， 介导长期耐受和旁观者的胰岛抗原特异性树突状细胞的诱导 抑制作用增强。这个项目试图加深我们对机械的洞察，并在近距离 与项目2和3合作，解决应促进翻译的关键问题 综合疗法在新近发病的T1D中的临床应用。我们将回答以下问题： 1.新近发病的T1D在体内的最佳联合治疗方案是什么？当前 数据表明，口服或鼻腔给药胰岛素肽最有希望。为了 结合当前药物开发的选择，我们将确定最佳候选者。在……里面 此外，我们还将探索抗原特异性治疗与GLP-1激动剂和胃泌素的结合 以再生贝塔细胞。 2.胰岛抗原诱导的Tregs在体内的作用有哪些确切的功能？当前 研究结果表明，抗CD3抗体和抗原注射后的长期耐受性很大 部分，由于诱导了强大的胰岛抗原特异性调节性T细胞(Tregs)，可以 对新发T1D患者的耐受性。他们的确切作用机制将被定义 利用最近获得的新技术和试剂，RNAi和INS-TCR转基因小鼠。 3.哪些体外试验是监测Tregs和体内抗原特异性耐受的最佳方法？我们 将在每个动物的基础上建立一种反映和预测临床结果的方法。这些 化验应该为临床项目的目标提供强有力的指导(#3，Herold)。

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).