The role of the innate immune system on Treg reprogramming in human autoimmune di

先天免疫系统在人类自身免疫性疾病中 Treg 重编程中的作用

• 批准号: 8495933
• 负责人: David A. Hafler
• 金额: $ 73.41万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495933
• 关键词: Address; Affect; Anatomy; Antigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Biochemical Process; Biological Assay; CD3 Antigens; CXCR3 gene; Candidate Disease Gene; Cell physiology; Cell surface; Cells; Cellular biology; Characteristics; Collaborations; Complex; Data; Defect; Development; Disease; Effectiveness; Environment; Epigenetic Process; Exposure to; Failure; Frequencies; Genetic; Health; Hematological Disease; Hereditary Disease; Homeostasis; Human; IRF4 gene; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunosuppressive Agents; Immunotherapy; In Vitro; Inbred NOD Mice; Individual; Inflammation; Inflammatory; Inflammatory Response; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Interferons; Interleukin-1; Interleukin-12; Interleukin-17; Interleukin-6; Lead; Ligation; Location; Mediating; Molecular; Multiple Sclerosis; Mus; Pancreas; Pathogenesis; Pathway interactions; Patients; Peripheral; Phenotype; Physiological; Population; Prevention; Process; Property; Regulatory T-Lymphocyte; Role; STAT3 gene; Signal Transduction; Site; Staging; Suppressor-Effector T-Lymphocytes; Surface; T cell response; T-Lymphocyte; Therapeutic; Therapeutic Intervention; Thymus Gland; Tissues; autoreactive T cell; base; chemokine receptor; cytokine; design; diabetic; in vivo; migration; mouse model; natalizumab; novel; peripheral blood; peripheral tolerance; prevent; response; transcription factor

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) and type 1 diabetes (T1D) are complex genetic diseases where pathogenic T cell autoimmune responses target and destroy self-tissue. However, the presence of T cells reactive to self alone is not sufficient for disease o occur as autoreactive T cells can be found in healthy control subjects; thus various means are available that control unwanted responses. One of the most important mechanisms is the activity of regulatory T cells (Tregs), which arise both in thymus and in the peripheral immune system as a consequence of exposure to antigens. While it was originally thought that Tregs represented a homogenous, end-stage differentiated population, recent data suggest that Tregs exist in immune response-specific subsets, which parallel the Th subsets that they control, can under certain conditions, be reprogrammed to secrete pro-inflammatory cytokines. Thus, Treg adaptation to the inflammatory milieu and chameleon-like propensity to take on Th-like phenotypes is physiologic and a fundamental attribute observed in mouse models. We have recently found that there is an increased frequency of Tregs from MS or T1D patients that secrete IFN-? compared to healthy controls, suggesting that this reprogramming may be present in humans as well and under certain conditions can be involved in the pathogenesis of autoimmune diseases. Thus, one fundamental question, addressed in this proposal is "to determine the mechanisms that generate Th-Tregs in autoimmune diseases and how these cells function in vivo under basal, inflammatory and therapeutic conditions." In addition, the induction and effectiveness of Treg responses are affected by their anatomic location. Factors that have central roles in Treg homeostasis such as TGF-¿, IL-6 and others, are expressed differently at mucosal surfaces, in the CNS, and in the pancreas, and may affect Treg differentiation locally. Thus, in this proposal we will address a second hypothesize that "the anatomic location and immune environment of Tregs dictates their pathway of differentiation in humans and that these processes are altered in individuals prone to autoimmunity." The following aims represent a concerted effort between two centers that will allow us to address these questions using the same experimental and disease platforms. 1. To determine what mechanisms are involved in the differentiation and stability of Th-like Treg subsets in healthy individuals and patients with MS and T1D. 2. To determine whether innate factors, driven by TLR ligation modulate Th-like Tregs. 3. To determine the function of human Th-like Tregs in vivo and the effects of immune therapies in humans and humanized mouse models. These studies will identify wide-ranging and disease-specific features of Th-Tregs in autoimmunity, and, hopefully, identify novel mechanisms that are important for prevention of MS, T1D, and potentially other autoimmune diseases. In addition, these studies may identify pathways that may be targeted by existing or novel immune therapeutics.

描述（由申请人提供）：多发性硬化症（MS）和1型糖尿病（T1 D）是复杂的遗传疾病，其中致病性T细胞自身免疫反应靶向并破坏自身组织。然而，仅对自身反应的T细胞的存在不足以使疾病发生，因为可以在健康对照受试者中发现自身反应性T细胞;因此可以使用各种手段来控制不想要的反应。最重要的机制之一是调节性T细胞（Tcells）的活性，其作为暴露于抗原的结果在胸腺和外周免疫系统中产生。虽然最初认为TcR代表同质的终末期分化群体，但最近的数据表明TcR存在于免疫应答特异性亚群中，其平行于它们控制的Th亚群，可以在某些条件下重编程以分泌促炎细胞因子。因此，Treg对炎性环境的适应和呈现Th样表型的变色龙样倾向是生理性的，并且是在小鼠模型中观察到的基本属性。我们最近发现，有一个增加的频率Tcirrhosis从MS或T1 D患者分泌IFN-？与健康对照相比，这表明这种重编程可能也存在于人类中，并且在某些条件下可能参与自身免疫性疾病的发病机制。因此，在该提案中解决的一个基本问题是“确定在自身免疫性疾病中产生Th-T细胞的机制以及这些细胞在基础、炎症和治疗条件下如何在体内发挥功能。“此外，Treg反应的诱导和有效性受到其解剖位置的影响。在Treg体内平衡中具有核心作用的因子如TGF-β、IL-6等在粘膜表面、CNS和胰腺中表达不同，并且可能局部影响Treg分化。因此，在本提案中，我们将提出第二个假设，即“Tribunal的解剖位置和免疫环境决定了它们在人类中的分化途径，并且这些过程在倾向于自身免疫的个体中发生改变。“以下目标代表了两个中心之间的共同努力，这将使我们能够使用相同的实验和疾病平台来解决这些问题。1.确定健康个体和MS和T1 D患者中Th样Treg亚群的分化和稳定性涉及哪些机制。2.确定由TLR连接驱动的先天性因素是否调节Th样TcR。3.确定人Th样T细胞在体内的功能以及免疫疗法在人和人源化小鼠模型中的作用。这些研究将确定Th-TdR在自身免疫中的广泛和疾病特异性特征，并有望确定对预防MS，T1 D和潜在的其他自身免疫性疾病至关重要的新机制。此外，这些研究可以确定现有或新型免疫疗法可能靶向的途径。