2D affinity and frequency of antigen specific Tregs

抗原特异性 Tregs 的 2D 亲和力和频率

• 批准号: 8967558
• 负责人: Brian D Evavold
• 金额: $ 38.79万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8967558
• 关键词: Address; Affinity; Antigens; Autoantigens; Autoimmune Diseases; Autoimmune Responses; Automobile Driving; Binding; Biological; Biological Assay; CD28 gene; CD3 Antigens; Cell membrane; Cells; Chronic; Clinical Treatment; Clinical Trials; Data; Demyelinating Diseases; Demyelinations; Development; Disease Outcome; Doctor of Philosophy; Eragrostis; Experimental Autoimmune Encephalomyelitis; Experimental Designs; Frequencies; Generations; Goals; Health; Human; Immune response; Inflammation; Investigation; Kinetics; Lead; Ligand Binding; Location; Lymph; MHC Class II Genes; Measures; Mediating; Modeling; Multiple Sclerosis; Mus; Myelin; Peptide/MHC Complex; Peripheral; Phenotype; Plant Roots; Play; Positioning Attribute; Prevention; Principal Investigator; Production; Property; Proteins; Protocols documentation; PubMed; Publishing; Regulation; Regulatory T-Lymphocyte; Relapse; Reporting; Role; Sensitivity and Specificity; Site; Source; Specificity; Stable Populations; Staging; Stimulus; System; T cell response; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Uses; Thymus Gland; Time; Tissues; Work; adaptive immunity; base; in vivo; novel; oligodendrocyte-myelin glycoprotein; preclinical trial; receptor; response; stem; text searching; thymocyte; transcription factor; two-dimensional

 DESCRIPTION (provided by applicant): Regulatory T cells (Tregs) are critical for proper control of the immune response and play a clear role in regulation of autoimmune disease. Further highlighting their importance, Tregs provide an antigen specific therapy that is currently being evaluated in preclinical and clinical trials. Although they are of unquestioned value, it is difficult to assess Treg specificity for antigen. In fact, many experimental protocols make use of non-specific TCR stimuli such as anti-CD3/anti-CD28 for their activation, and typical assessments of specificity such as peptide: MHC Class II tetramers and functional readouts are not especially effective when applied to Tregs. As TCR specificity and affinity are crucial to any T cell functional response, we need to understand what affinity range works best for optimal Treg use as well as for their differentiation. Our lab is in a unique position to examine questions on TCR specificity and affinity because we have developed a novel assay system based on two dimensional (2D) micropipette technology that provides the most sensitive means currently available to assess these parameters. The prevalent view of thymic derived Tregs (tTreg) in terms of affinity is that their repertoires are comprised of the highest affinity TCRs that escaped negative selection; however, our preliminary data has identified a range of affinities of tTregs specific for myelin oligodendrocyte glycoprotein (MOG). Instead of driving thymocyte negative selection, MOG supports development of thymic derived MOG specific Tregs. We propose that these Tregs will be of therapeutic use and based on our preliminary studies, propose the following two aims to track Treg specificity, location, kinetics, stability, and potency during chronic and relapsing/remitting demyelinating disease. Aim 1: To define MOG-specific Treg affinity and frequency during demyelinating disease- Aim 2: To determine Treg specificity and lineage stability for MOG-

 描述（由申请人提供）：调节性 T 细胞 (Treg) 对于正确控制免疫反应至关重要，并在自身免疫性疾病的调节中发挥明显作用。 Tregs 提供了一种抗原特异性疗法，目前正在临床前和临床试验中进行评估，进一步强调了它们的重要性。尽管它们具有无可置疑的价值，但评估 Treg 对抗原的特异性却很困难。事实上，许多实验方案利用非特异性 TCR 刺激（例如抗 CD3/抗 CD28）进行激活，而典型的特异性评估（例如肽：MHC II 类四聚体和功能读数）在应用于 Tregs 时并不是特别有效。由于 TCR 特异性和亲和力对于任何 T 细胞功能反应都至关重要，因此我们需要了解什么亲和力范围最适合 Treg 的最佳使用及其分化。我们的实验室处于研究问题的独特位置 TCR 特异性和亲和力，因为我们开发了一种基于二维 (2D) 微量移液器技术的新型测定系统，该系统提供了目前可用于评估这些参数的最灵敏的方法。就亲和力而言，胸腺来源的 Tregs (tTreg) 的普遍观点是，它们的库由逃逸的最高亲和力 TCR 组成。 负选择；然而，我们的初步数据已经确定了一系列针对髓鞘少突胶质细胞糖蛋白 (MOG) 的 tTreg 亲和力。 MOG 不驱动胸腺细胞负选择，而是支持胸腺衍生的 MOG 特异性 Tregs 的发育。我们建议这些Tregs将具有治疗用途，并根据我们的初步研究，提出以下两个目标来跟踪慢性和复发/缓解性脱髓鞘疾病期间Tregs的特异性、位置、动力学、稳定性和效力。目标 1：确定脱髓鞘疾病期间 MOG 特异性 Treg 亲和力和频率 - 目标 2：确定 MOG 的 Treg 特异性和谱系稳定性 -