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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：
7469963
负责人：
Matthias G. Von Herrath
金额：
$ 43.11万
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 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7469963
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 Exhibits Future Gastrins Generations Goals Grant Hand Hyperglycemia IL2RA gene Immune Immunization Immunologics Immunotherapy In Vitro Individual Insulin Insulin-Dependent Diabetes Mellitus Interleukin-10 Interleukin-4 Interleukin-5 Intervention Measures Mediating Methods Modeling Monitor Monoclonal Antibody HuM291 Muromonab-CD3 Mus Natural regeneration Nose Oral Organ Outcome Pancreas Patients Peptides Peripheral Blood Mononuclear Cell Personal Satisfaction Pharmaceutical Preparations Phenotype Prevention Principal Investigator Process Production Protocols documentation Purpose RNA Interference Reagent Risk SELL gene Screening procedure Site Sorting - Cell Movement T-Lymphocyte Technology Testing Therapeutic Time Transgenic Mice Translations Treatment Efficacy Treatment Protocols Ursidae Family analog base caN protocol combinatorial concept dosage drug development glucagon-like peptide 1 in vitro Assay in vivo insight 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).

该提案是探索性合作资助的合理延续（R21,Herold - von）