A unique approach to control the CD40/CD154 inflammatory axis in type 1 diabetes

控制 1 型糖尿病 CD40/CD154 炎症轴的独特方法

• 批准号: 8716665
• 负责人: David H. Wagner
• 金额: $ 23.26万
• 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: 2013-08-07 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8716665
• 关键词: Address; Adipocytes; Affect; Amino Acid Sequence; Amino Acids; Antibodies; Antibody Formation; Antigen-Presenting Cells; Antigens; Autoantigens; Autoimmune Process; Autoimmunity; Binding; Blood Platelets; Cell Death; Cell Survival; Cell surface; Cells; Clinical; Data; Dendritic Cells; Diabetes Mellitus; Diagnosis; Dose; Effector Cell; Epithelial Cells; Experimental Autoimmune Encephalomyelitis; Goals; Grant; Human; Hyperglycemia; Immune response; Immunosuppression; Inbred NOD Mice; Inflammation; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukin-6; Invaded; Islets of Langerhans; Ligands; Modeling; Monoclonal Antibodies; Multiple Sclerosis; Mus; Natural regeneration; Pathogenicity; Peptide Sequence Determination; Peptide Signal Sequences; Peptides; Play; Population; Regulatory T-Lymphocyte; Research; Role; Signal Transduction; Site; Systemic Lupus Erythematosus; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; TNFRSF5 gene; TNFSF5 gene; Therapeutic; Thrombosis; Transplantation; Tumor Necrosis Factor Receptor; base; crosslink; cytokine; design; diabetes control; diabetic; efficacy testing; high risk; human subject; inhibitor/antagonist; innovation; islet; macrophage; member; mouse model; prevent; public health relevance; receptor; response; small molecule; success; trafficking

DESCRIPTION (provided by applicant): The CD40/CD154 inflammatory axis has proven critical in autoimmune inflammation. Attempts to control it have used antibodies and synthesized organic small molecules; each ultimately has failed to be useful as a therapeutic. Controlling that axis with anti- CD154 proved highly effective, but the antibody itself caused lethal problems in human trials. We designed a small (15-mer) therapeutic peptide (STP) derived from the CD154 amino acid sequence that is known to interact with CD40. We determined that the STP binds directly to cell surface expressed CD40, particularly to CD40+ T cells, a subset that we described as highly pathogenic in the NOD mouse model of T1D, and in human T1D. Pre-diabetic human subjects have elevated levels of CD4+CD40+ cells that respond to human islets. Treating only T cells with the peptide ablates islet response. Administration of the peptid prevents hyperglycemia in 96% of treated NOD mice compared to a scrambled peptide or smaller versions of the peptide. Importantly the number of amino acids comprising the peptide is crucial for efficacy. In this application we will examine the mechanism of action of this peptide. Aim 1: Hypothesis: The STP has direct effects on pathogenic effector T cells, specifically CD4+CD40+ cells: Exploring the mechanism(s) of tolerance. Aim 2 will explore how the peptide affects the overall immune response including antigen recall, potential antibody production to foreign antigens and the possibility that peptide treatment induces antibodies to CD154. The ultimate goals of this research plan are to create a therapeutic to control pathogenic effector T cells.

描述（由申请人提供）：已证明CD 40/CD 154炎症轴在自身免疫性炎症中至关重要。试图控制它已经使用抗体和合成的有机小分子;每一个最终都没有作为治疗剂。用抗CD 154抗体控制该轴被证明是非常有效的，但抗体本身在人体试验中引起了致命的问题。我们设计了一个小的（15聚体）治疗肽（STP）的CD 154的氨基酸序列，已知与CD 40相互作用。我们确定STP直接与细胞表面表达的CD 40结合，特别是与CD 40 + T细胞结合，CD 40 + T细胞是我们在T1 D的NOD小鼠模型和人T1 D中描述为高致病性的亚群。糖尿病前期人类受试者具有升高水平的响应于人类胰岛的CD 4 + CD 40+细胞。仅用肽处理T细胞可消除胰岛反应。与乱序肽或更小版本的肽相比，肽的施用在96%的经治疗的NOD小鼠中预防高血糖症。重要的是，构成肽的氨基酸的数量对于功效至关重要。在本申请中，我们将研究这种肽的作用机制。目的1：假设：STP对致病性效应T细胞，特别是CD 4 + CD 40+细胞具有直接作用：探索耐受的机制。目的2将探索肽如何影响整体免疫应答，包括抗原回忆，对外来抗原的潜在抗体产生以及肽治疗诱导针对CD 154的抗体的可能性。这项研究计划的最终目标是创造一种治疗方法来控制致病性效应T细胞。