Enhancing antigen-based therapy for T1D by T cell coreceptor tuning

通过 T 细胞辅助受体调节增强基于抗原的 T1D 治疗

• 批准号: 10593245
• 负责人: Roland M Tisch
• 金额: $ 23.33万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-11 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10593245
• 关键词: Adjuvant; Affect; Antibodies; Antigens; Autoantigens; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; B-Lymphocyte Differentiation Antigens; B-Lymphocytes; Binding; CD4 Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Clinic; Clinical; Clinical Research; Combination immunotherapy; Conceptions; Data; Diabetes Mellitus; Diabetes prevention; Disease Progression; Dose; Down-Regulation; Equilibrium; Eragrostis; Etiology; Event; FOXO1A gene; FOXP3 gene; Frequencies; Genetic Transcription; Goals; Human; Immune mediated destruction; Immunotherapy; Inbred NOD Mice; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukin-10; Mediating; Modeling; Nature; Pathogenicity; Pathology; Peptides; Prevention; Property; Regulatory T-Lymphocyte; Safety; Self Administration; Self Tolerance; Signal Transduction; T cell differentiation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Treatment Efficacy; Up-Regulation; Vaccination; Work; acquired immunity; adaptive immunity; combinatorial; diabetes mellitus therapy; diabetogenic; effector T cell; humanized mouse; immune function; in vivo; insight; mouse model; novel; novel strategies; peptide vaccination; pre-clinical; prevent; receptor; transcription factor

SUMMARY/ABSTRACT Currently no cure exists for Type 1 diabetes (T1D). Due to immune-mediated destruction of the insulin- producing  cells, treatment of T1D is limited to daily exogenous insulin administration. Needed are immunotherapies that effectively suppress  cell autoimmunity longterm in order to prevent and treat T1D. One approach is the administration of cell autoantigens to induce differentiation of adaptive regulatory CD4+ T cells (aTreg). The approach is appealing since autoimmunity can be selectively targeted while leaving acquired immunity unperturbed. A major hurdle, however, is inducing a sufficiently sized and subset diverse aTreg pool, while avoiding expansion of pathogenic effector T cells (Teff). The size and nature of the aTreg pool is particularly important at late preclinical T1D stages and at the onset of clinical diabetes, when a high frequency of diabetogenic CD4+ and CD8+ Teff is found. This R21 outlines a novel approach to enhance the efficacy of antigen therapy by “tuning” the function of CD4. CD4 binding to MHCII activates a signaling cascade that contributes to overall TCR signaling strength. We hypothesize that modulating CD4 function and TCR signaling strength, results in increased and selective induction of aTreg by antigen vaccination. In our model, differentiation of aTreg subsets is determined by varying the level of coreceptor tuning (CoT). We will employ nondepleting CD4 antibody to achieve CoT. Key objectives of this R21 are to gain initial insight into the mechanism(s) by which CoT selectively promotes aTreg differentiation (Aim 1), and determine the therapeutic efficacy of this combinatorial approach (Aim 2). If successful, combined CoT and self-antigen vaccination is expected to be applicable not only for the prevention and treatment of T1D, but also for other T cell-mediated autoimmune diseases and pathologies.

总结/摘要 目前还没有治愈1型糖尿病（T1 D）的方法。由于免疫介导的胰岛素破坏- 由于T1 D细胞产生，T1 D的治疗仅限于每天给予外源性胰岛素。需要的是 长期有效抑制T1 D细胞自身免疫的免疫疗法，以预防和治疗T1 D。一 一种方法是给予自体抗原，诱导适应性调节性CD 4 + T细胞分化， 细胞（aTreg）。这种方法很有吸引力，因为自身免疫可以选择性地靶向，同时使获得性 免疫力未受干扰。然而，一个主要的障碍是诱导足够大小和子集多样的aTreg库， 同时避免致病性效应T细胞（Teff）的扩增。aTreg池的大小和性质是 在晚期临床前T1 D阶段和临床糖尿病发作时，当高频率 糖尿病的CD 4+和CD 8 + Teff的发现。这R21概述了一种新的方法，以提高疗效， 通过“调节”CD 4的功能来进行抗原治疗。CD 4与MHCII结合激活信号级联， 有助于整体TCR信号强度。我们假设调节CD 4功能和TCR信号传导 强度，导致通过抗原疫苗接种增加的和选择性的aTreg诱导。在我们的模型中， 通过改变共受体调节（CoT）的水平来确定aTreg亚群的分化。我们会委聘 非消耗性CD 4抗体以实现CoT。R21的主要目标是初步了解 CoT选择性促进aTreg分化的机制（Aim 1），并确定治疗 这种组合方法的有效性（目的2）。如果成功，CoT和自身抗原联合疫苗接种是 预期不仅适用于T1 D的预防和治疗，而且适用于其他T细胞介导的疾病。 自身免疫性疾病和病理学。