Intrinsic modulators of Treg lineage commitment and immunoregulation post-transplantation

Treg 谱系定型和移植后免疫调节的内在调节剂

• 批准号: 9806247
• 负责人: Johannes Wedel
• 金额: $ 13.28万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-13 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9806247
• 关键词: Age-Months; Allografting; Antigens; Autoimmune Diseases; Biological; Biological Assay; Biology; CD4 Positive T Lymphocytes; Cell Lineage; Cell Respiration; Cell Shape; Cell Transplantation; Cell Transplants; Cell physiology; Cells; Cellular biology; Clinical; Colitis; Complement; Complex; Disease; Drug Targeting; Effector Cell; Environment; FOXP3 gene; FRAP1 gene; Failure; Genes; Genetic; Genetic Models; Graft Rejection; Homeostasis; Immune Tolerance; Immune response; Immunology procedure; Inflammation; Inflammatory; Institutes; Investigational Therapies; Knock-out; Lymphoid; MAP Kinase Gene; Maintenance; Massachusetts; Mediating; Mentors; Metabolic; Metabolism; Mitogens; Modeling; Molecular; Molecular Analysis; Mus; Organ; Organ Transplantation; Outcome; Pathway interactions; Peripheral; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Postdoctoral Fellow; Property; Proteins; Regulation; Regulatory T-Lymphocyte; Research; Research Proposals; Resources; Role; STAT1 gene; Self Tolerance; Signal Pathway; Signal Transduction; Splenomegaly; T cell therapy; T-Cell Activation; T-Lymphocyte Subsets; Techniques; Technology; Testing; Therapeutic; Time; Transgenic Mice; Transplantation; Work; allograft rejection; career; clinically relevant; clinically significant; design; effector T cell; epigenetic regulation; heart allograft; immune activation; immunoregulation; in vivo; in vivo Model; insight; isoimmunity; medical schools; neoplasm immunotherapy; new therapeutic target; novel; overexpression; platelet protein P47; post-transplant; promoter; protein expression; research study; response; screening; skin lesion; small molecule; transcriptome sequencing; tumor

Allograft rejection is mediated by the recipient’s immunological response to donor antigen that is initiated and coordinated by CD4+ T cells, but it also involves other complex issues including adaptive responses within secondary lymphoid organs and within the graft itself. CD4+Foxp3+ regulatory T cells (Treg) are central to the maintenance of self-tolerance, the regulation of excessive immune responses, and experimental therapies use their immunoregulatory properties to suppress alloimmunity and to induce immunological tolerance towards the allograft. However, Treg based therapies are hindered by their instability and their potential to dedifferentiate into effector cells that can initiate/cause rejection. Our previous studies demonstrated that DEPTOR is expressed by CD4+ Treg cells, is markedly reduced upon mitogen activation, and that sustained expression of DEPTOR stabilizes lineage commitment via the epigenetic regulation of the Foxp3 promoter and by augmenting oxidative metabolism. In vivo, induced DEPTOR expression within Tregs is sufficient to promote immunoregulation and inhibit cardiac allograft rejection. This proposal tests the hypothesis that DEPTOR is a central modulator of Treg subset homeostasis and function, and that it is essential to maintain immunoregulation and tolerance following transplantation. It will also test whether DEPTOR functions via a novel regulatory signaling network and/or novel interactions with target genes within distinct Treg lineages or subsets. The approach is divided into three specific aims to: first, investigate mechanisms of DEPTOR function in Tregs and mTOR-independent targets of DEPTOR activity; second, systematically discover the extended DEPTOR-induced modulatory signaling network that enhances Treg function and lineage commitment; and third, identify small molecules that modulate DEPTOR protein expression, its downstream target genes and/or regulatory signaling activity as potential pro-tolerogenic therapeutic drugs. During the mentored phase of the K99, the results of the proposed studies will identify new roles for DEPTOR in Treg subsets and discover mTOR-independent effects of DEPTOR on Treg biology. These studies will launch the R00 phase of independent research to investigate the mechanistic function of the network of negative modulators and/or target genes in Treg subsets, and develop a pharmacological screening assay to identify small molecules that have potential as therapeutic drugs to induce immunological tolerance towards allografts and/or as a treatment for autoimmune disease. The broader implication of this work relates to the biological importance of Treg targeting as a component of tumor immunotherapy.

同种异体移植排斥反应是由受者对供者抗原的免疫反应所介导的，即 由CD4+T细胞启动和协调，但也涉及其他复杂的问题，包括 次级淋巴器官内和移植物本身内的适应性反应。CD4+Foxp3+ 调节性T细胞(Treg)是维持自我耐受的核心，调节 过度的免疫反应，实验疗法使用它们的免疫调节 抑制同种异体免疫和诱导免疫耐受的特性 异体移植。然而，基于Treg的治疗因其不稳定性和潜在的 去分化为可引发/引起排斥反应的效应细胞。我们之前的研究 证明DEPTOR是由CD4+Treg细胞表达的，在有丝分裂原上明显减少 激活，并且DEPTOR的持续表达通过 Foxp3启动子的表观遗传调控和增强氧化代谢。在体内，诱导 DEPTOR在Treg中的表达足以促进免疫调节和抑制心脏 同种异体排斥反应。这一建议验证了DEPTOR是Treg的中枢调节器的假设 亚群的动态平衡和功能，以及维持免疫调节和耐受是必不可少的 在移植后。它还将测试DEPTOR是否通过一种新的调节信号发挥作用 在不同的Treg谱系或子集内与靶基因进行网络和/或新颖的相互作用。这个 研究方法分为三个具体目的：第一，探讨DEPTOR在脑内的作用机制 Tregs和mTOR非依赖于DEPTOR活性的靶点；第二，系统地发现 扩展的DEPTOR诱导的增强Treg功能和谱系的调制信号网络 承诺；第三，识别调节DEPTOR蛋白表达的小分子，其 下游靶基因和/或调节信号活性作为潜在的促耐受治疗 毒品。在K99的指导阶段，拟议研究的结果将确定新的 DEPTOR在Treg亚群中的作用及其对Treg的mTOR非依赖性影响 生物学。这些研究将启动R00阶段的独立研究，以调查 Treg亚群中负调制子和/或靶基因网络的机械功能，以及 建立一种药物筛选试验，以确定具有潜在的 治疗药物，以诱导对同种移植的免疫耐受和/或作为治疗 自身免疫性疾病。这项工作的更广泛的含义与生物重要性有关 Treg靶向作为肿瘤免疫治疗的一个组成部分。