Achieving Therapeutic Antigent-Specific Tolerance in Type 1 Diabetes

实现 1 型糖尿病治疗性抗原特异性耐受

基本信息

批准号：
7897719
负责人：
Matthias G. Von Herrath
金额：
$ 45.74万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-20 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7897719
关键词：
Address Adverse effects Aftercare Agonist Air Animal Model Animals Antigen-Presenting Cells Antigens Autoimmunity Beta Cell Biological Assay Bystander Suppression CD3 Antigens CD44 gene CD8B1 gene Candidate Disease Gene Cells Characteristics Child Clinic Clinical Clinical Trials Collaborations Color Data Diabetes Mellitus Diagnosis Disease Dose Equilibrium Ethics Exhibits Future Gastrins Generations Goals Grant Hand Hyperglycemia IL2RA gene Immune Immunization Immunologics Immunosuppression Immunotherapy In Vitro Inbred NOD Mice Individual Insulin Insulin-Dependent Diabetes Mellitus Interleukin-10 Interleukin-4 Interleukin-5 Intervention Measures Mediating Methods Modeling Monitor Mus Natural regeneration Nose Oral Organ Outcome Pancreas Patients Peptides Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phenotype Prevention Principal Investigator Process Production Protocols documentation RNA Interference Reagent Regimen Regulatory T-Lymphocyte Risk SELL gene Screening procedure Site Sorting - Cell Movement T-Lymphocyte Technology Testing Therapeutic Time Transgenic Mice Translations Treatment Efficacy Ursidae Family analog base combinatorial dosage drug candidate drug development glucagon-like peptide 1 in vitro Assay in vivo insight insulin dependent diabetes mellitus onset interest islet liraglutide lymph nodes mouse model new technology novel prevent programs response success

项目摘要

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).

该建议是探索性合作赠款的逻辑延续（R21，Herold -von Herrath）专注于开发近期发作1型糖尿病（T1D）的新型组合方法。即将到来的两个独立糖尿病模型（NOD和RIP-LCMV）的结果已经建立了为了实现抗原特异性耐受性，免疫与胰岛的结合抗原和系统作用的免疫调节剂可以表现出很强的协同作用，并在临床上表现出由于以下原因有益：首先，高血糖的恢复可以发生在较低的剂量下在我们的情况下，系统作用的免疫调节剂抗CD3 Fab'2。其次，机械上，诱导特异性胰岛抗原特异性的诱导，可以介导长期公差和旁观者抑制得到了增强。该项目旨在加深我们的机械洞察力，并在附近与项目2和3的合作，解决了应促进翻译的关键问题近期发作的T1D联合治疗到诊所。我们将回答以下问题： 1。在近期发作的T1D体内T1D中哪种最佳组合治疗方案？当前的数据表明，胰岛素肽的口服或鼻腔给药最有希望。为了我们将最佳地与药物开发中的当前选择联系起来，我们将定义最佳候选人。在此外，我们将探索抗原特异性疗法与GLP-1激动剂和胃蛋白的组合再生β细胞。 2。哪个精确的函数定义了体内胰岛抗原引起的Treg的作用？当前的调查结果表明，抗CD3和抗原给药后的长期公差是很大的部分，由于诱导有效的胰岛抗原特异性调节T细胞（Treg），可以转移近期发作T1D的对接收者的容忍度。他们的精确行动机制将被定义使用新型技术和试剂最近获得的RNAi和Ins-TCR转基因小鼠。 3。在体内监测TREG和抗原 - 性耐受性的最佳体外测定法？我们将建立反映和预测临床的ASASE。这些测定应为临床项目的目标（＃3，Herold）提供强有力的指导。