Molecular Dissection of Insulin Targeting in Anti-Islet Autoimmunity

胰岛素靶向抗胰岛自身免疫的分子解析

• 批准号: 8562380
• 负责人: Maki Nakayama
• 金额: $ 33.08万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-20 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8562380
• 关键词: Address; Adverse effects; Affinity; Amino Acids; Animal Model; Animals; Antigens; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-insulin; Binding; CD8B1 gene; Clinical Research; Complex; Development; Diabetes Mellitus; Disease; Dissection; Epitopes; Frequencies; Genes; Goals; Histocompatibility Antigens Class II; Human; Immune system; Immunological Diagnosis; Immunotherapeutic agent; Immunotherapy; Inbred NOD Mice; Individual; Inflammation; Insulin; Insulin-Dependent Diabetes Mellitus; Knock-out; Knowledge; Lead; Major Histocompatibility Complex; Molecular; Mus; Mutate; Nature; Organ; Orthologous Gene; Pancreas; Pathway interactions; Patients; Peptide T; Peptides; Play; Predisposition; Regulatory T-Lymphocyte; Research; Research Design; Risk; Role; Specificity; Staging; T-Cell Receptor; T-Cell Receptor Genes; T-Cell Receptors alpha-Chain; T-Lymphocyte; T-Lymphocyte Epitopes; Techniques; Testing; Time; Tissues; alpha-beta T-Cell Receptor; base; congenic; design; endocrine pancreas development; insight; islet; mouse model; prevent; public health relevance; response; therapy development

DESCRIPTION (provided by applicant): The major histocompatibility complex (MHC) class II locus is strongly associated with the risk of type 1 diabetes, and tissue specificity of the autoimmunity causing diabetes is likely to be determined by the trimolecular complex composed of an MHC molecule, an antigen, and a T cell receptor (TCR). We hypothesize that the interactions between components of this trimolecular complex, all of which are encoded in the germline, determines the nature of T cells involved in the development of type 1 diabetes. Targeting of an insulin B chain 9-23 amino acid peptide (insulin B:9-23) is highly likely to be an essential determinant in the initiation of islet inflammation in the spontaneous diabetes animal model, NOD mouse. We recently discovered that TCRs containing the germline-encoded variable gene (Vgene) sequence called "TRAV5D-4" play a critical role to induce anti-islet autoimmunity via the recognition of insulin B:9-23 peptide. Thus, the trimolecular complex consisting of the insulin B:9-23 peptide and TRAV5D-4 TCR alpha chain plays a key role in developing anti-islet autoimmunity; however, how T cells expressing TRAV5D-4 TCRs contribute to the initiation and development of the disease remains to be elucidated. Given evidence that the DQ8 diabetes- susceptible HLA class II molecule is an ortholog of NOD I-Ag7 presenting the insulin B:9-23 peptide and that T cells expressing TRAV13-1 (human ortholog of TRAV5D-4) TCR alpha chains dominantly exist in the pancreas of a type 1 diabetes patient having DQ8, the ultimate goal of this proposal is to verify a proof of concept that insulin targetig by a specific germline-encoded TCR Vgene motif plays a critical role in the development of islet autoimmunity. In this proposal, we aim to determine the molecular mechanism of how TCRs, in particular those containing TRAV5D-4, target the critical peptide, insulin B:9-23, to initiate isle inflammation using the NOD mouse model (Aim 1), and to determine whether T cells expressing TRAV5D-4 are essential for diabetes development in NOD mice (Aim 2). If the development of anti-islet autoimmunity is completely suppressed in the absence of TRAV5D-4, targeting only T cells expressing such essential TRAV genes will enable us to develop a robust immunotherapy with the minimum of side effects. Finally, we will pursue the hypothesis that there is a conceptually similar interaction in the human trimolecular complex consisted of the insulin B:9-23 peptide and TRAV13-1 TCR Vgene motif underlying susceptibility to human type 1 diabetes (Aim 3). Findings from this proposal will provide a deeper understanding of the principles underlying the initiation of islet autoimmunity via the interaction within the insulin trimolecular complex, which will ultimately to be applied to design antigen-based immunodiagnostic and immunotherapeutic clinical studies for type 1diabetes in humans!

描述（由申请人提供）：主要的组织相容性复合物（MHC）II类基因座与1型糖尿病的风险密切相关，并且自身免疫的组织特异性可能由由MHC分子，抗原，抗原和TCR受体（TCR）组成的三膜分子复合物决定。我们假设该三分光复合物的成分之间的相互作用（所有这些都在种系中编码）决定了参与1型糖尿病发展的T细胞的性质。胰岛素B链9-23氨基酸肽（胰岛素B：9-23）的靶向极有可能是自发糖尿病动物模型中胰岛炎症开始的必不可少的决定因素。我们最近发现，包含种系编码的变量基因（VGENE）序列的TCR称为“ Trav5d-4”序列，通过识别胰岛素B：9-23肽诱导抗ISLET自身免疫性起着至关重要的作用。因此，由胰岛素B：9-23肽和TRAV5D-4 TCRα链组成的三分子复合物在发展抗ISLET自身免疫性方面起着关键作用。但是，表达TRAV5D-4 TCR的T细胞如何有助于疾病的起始和发展。给出的证据表明，DQ8糖尿病 - 易感HLA II类分子是呈现I-AG7的直系同源物，呈现胰岛素B：9-23肽和表达TRAV13-1的T细胞（Trav5d-4的人类直立性）TCR Alpha链链在该类型型糖尿病患者的培养基中占据了一定的验证，这是DQ8的pcriastion trave alpha链的主要存在，通过特定种系编码的TCR VGENE序列胰岛素靶向胰岛素的概念在胰岛自身免疫的发展中起着至关重要的作用。在该建议中，我们旨在确定TCR的分子机制，尤其是那些含有TRAV5D-4的TCR，靶向关键肽，胰岛素B：9-23，以使用NOD小鼠模型（AIM 1）启动小岛炎症，并确定表达TRAV5D-4的TRAV-T细胞对糖尿病的发育是否对于NOD小鼠中的糖尿病发育是必不可少的（AIL 2）。如果在没有TRAV5D-4的情况下完全抑制了反ISLET自身免疫性的发展，则仅针对表达这种必需TRAV基因的T细胞将使我们能够开发出强大的免疫疗法，而副作用的最小副作用。最后，我们将提出以下假设：人类三分子复合物在概念上相似的相互作用由胰岛素B：9-23肽和TRAV13-1 TCR VGENE基序对人类1型糖尿病的敏感性产生敏感性（AIM 3）。该提案的发现将对通过胰岛素三分子中的相互作用的胰岛自身免疫开始的原理有更深入的了解 复合物最终将用于设计基于抗原的免疫诊断和免疫治疗性临床研究，用于人类类型1Diabetes！