Immune Regualtion and Type 1 Diabetes Pathogenesis

免疫调节与 1 型糖尿病发病机制

• 批准号: 7681500
• 负责人: MARK A. ATKINSON
• 金额: $ 26.33万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7681500
• 关键词: Activities of Daily Living; Address; Affect; Affinity; Age; Antigen-Presenting Cells; Apoptosis; Ascaridil; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Binding; Biological Assay; CD4 Positive T Lymphocytes; Cell physiology; Cells; Class; Cleaved cell; Conflict (Psychology); Data; Defect; Dendritic Cells; Development; Disease; Disease Progression; Disease susceptibility; Effector Cell; Equilibrium; Eragrostis; Failure; Frequencies; Genetic; Genetic Risk; Goals; Head; Helper-Inducer T-Lymphocyte; Hemoglobin; Homeostasis; Human; IL2RA gene; Immune; Immune response; Immune system; Immunity; Immunologic Factors; Immunologics; In Vitro; Individual; Insulin-Dependent Diabetes Mellitus; Interleukin-10; Investigation; Knowledge; Literature; Matrix Metalloproteinases; Mediating; Membrane; Metabolic Control; Methods; Modeling; Molecular; Monitor; Movement; Natural History; Nature; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Pathogenesis; Pathway interactions; Patients; Persons; Play; Population; Process; Publications; Publishing; Purpose; Regulation; Reporting; Research; Research Personnel; Resolution; Risk; Role; Self Tolerance; Self-control as a personality trait; Serum; Signal Transduction; Surface; Susceptibility Gene; T-Cell Antigen Receptor Specificity; T-Lymphocyte; TGFB1 gene; Testing; Therapeutic Intervention; Thymus Gland; Time; Urination; Work; Writing; autoreactive T cell; base; cell type; cytokine; design; disease natural history; disorder risk; illness length; immunological synapse; immunoregulation; improved; in vivo; interest; monocyte; non-diabetic; novel; prevent; response; tool; transcription factor

We and others have recently investigated patients with type 1 diabetes for the frequency and function of a population of regulatory T cells (Treg), characterized by the simultaneous expression of CD4 and CD25. Our studies did not support the notion that altered CD4+CD25+ T cell frequencies are associated with type 1 diabetes, but rather identified type 1 diabetes related alterations in the functional activities of these cells in terms of suppressing effector T (Teff) cell responses in vitro. The need to bring resolution to the aforementioned published discrepancies in frequency and function of Treg in type 1 diabetes, as well as investigate the potential for Teff cell defects, would be afforded with expanded studies that include the parameters of age, metabolic control, and disease duration, as well as to define (in association with Projects 1 and 2) the cellular and molecular mechanism(s) underlying this defect. Therefore, the overall objective of Project 3 is to improve our understanding the mechanisms of immune regulation afforded by CD4+CD25+ T cells, identify their contribution to the pathogenesis of type 1 diabetes, and evaluate the potential of these cells to serve as a marker for autoimmune disease activity. Our specific aims are designed to test the hypothesis that Treg cells are functionally defective in type 1 diabetes, as a result of dysregulated interactions with APC, Teff, and NKT cells, and that the cellular & molecular basis for this defect resides in pathways controlling the phenotypic signature of Treg including surface CD25, FOXP3, as well as TGFfS. This hypothesis has been formed based on our observations of deficient functional activities of Treg in human type 1 diabetes, recent data suggesting the surface expression/stability of CD25 is crucial to maintaining regulatory homeostasis between Treg and Teff, literature indicating the immunological synapse with other immune system cells (e.g., DC, NKT cells) may influence the functional activities of Treg, as well as information suggesting key roles for a limited number of cytokines (e.g., IL-2, IL-10, TGFp) and matrix metalloproteinases are associated with these regulatory processes. The Project has two specific aims: 1) Identify the influence of age, type 1 diabetes, and metabolic control on the frequency and function of regulatory T cells defined by co-expression of CD4 and CD25, as well as on the cellular expression of the fork-head transcription factor FoxPS. 2) Define the molecular mechanisms underlying deficiencies in CD4+CD25+ T cell function in subjects with type 1 diabetes. The successful completion of these studies could provide key information to fill an existing knowledge void regarding the mechanistic interactions between specific cell populations that underlie the failure of immune regulation which results in type 1 diabetes.

我们和其他人最近研究了1型糖尿病患者的频率和功能 调节T细胞（TREG）的种群，其特征在于CD4和CD25的同时表达。我们的 研究不支持改变CD4+ CD25+ T细胞频率与类型1相关的观念 糖尿病，但相当确定的是1型糖尿病与这些细胞功能活性相关的改变 抑制效应子t（TEFF）细胞反应的术语。需要将解决方案带入 上述已发表在1型糖尿病中Treg的频率和功能的差异，以及 研究TEFF细胞缺陷的潜力，将通过包括 年龄，代谢控制和疾病持续时间的参数以及定义（与项目相关联） 1和2）该缺陷的基础细胞和分子机制。因此，的总体目标 项目3是为了提高我们的理解CD4+ CD25+ T提供的免疫调节机制 细胞，确定它们对1型糖尿病发病机理的贡献，并评估这些糖尿病的潜力 细胞作为自身免疫性疾病活性的标记。我们的具体目标旨在测试 假设Treg细胞在1型糖尿病中功能有缺陷，这是由于失调的结果 与APC，TEFF和NKT细胞的相互作用，该缺陷的细胞和分子基础存在于 控制Treg的表型特征的途径，包括表面CD25，FOXP3以及TGFF。 根据我们对TREG缺乏功能活动的观察，已形成了这一假设 人类1型糖尿病，最近的数据表明CD25的表面表达/稳定性对 维持Treg和Teff之间的调节稳态，表明免疫突触 随着其他免疫系统细胞（例如DC，NKT细胞）也可能影响Treg的功能活性 作为提示有限数量的细胞因子（例如IL-2，IL-10，TGFP）和矩阵的关键作用的信息 金属蛋白酶与这些调节过程有关。该项目有两个具体的目标：1） 确定年龄，1型糖尿病和代谢控制对频率和功能的影响 调节性T细胞由CD4和CD25的共表达定义，以及 叉头转录因子foxps。 2）定义缺陷的分子机制 1型糖尿病的受试者中的CD4+ CD25+ T细胞功能。这些研究的成功完成 可以提供关键信息，以填补有关机械互动的现有知识空隙 在免疫调节失败的基础的特定细胞种群之间，导致1型 糖尿病。