EFFECTS OF CTLA-4 ON THE PROGRESSION OF T1D IN NEW ONSET SUBJECTS

CTLA-4 对新发受试者 T1D 进展的影响

• 批准号: 7950772
• 负责人: DESMOND Arthur SCHATZ
• 金额: $ 0.36万
• 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: 2008-12-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950772
• 关键词: Animals; Autoimmune Process; Autoimmunity; Beta Cell; CTLA4-Ig; Cell physiology; Chronic Childhood Arthritis; Clinical; Clinical Research; Complement; Computer Retrieval of Information on Scientific Projects Database; Critical Pathways; Cytotoxic T-Lymphocyte-Associated Protein 4; Diabetes Mellitus; FDA approved; Funding; Grant; Human; Immunoglobulin Class Switching; Immunoglobulin G; Inbred NOD Mice; Individual; Institution; Insulin-Dependent Diabetes Mellitus; Interleukin-10; Interleukin-2; Interleukin-4; Islets of Langerhans Transplantation; Mediating; Modeling; Multiple Sclerosis; Organ; Organ Survival; Pathway interactions; Peripheral; Play; Psoriasis; Research; Research Personnel; Resources; Rheumatoid Arthritis; Role; Signal Transduction; Source; Study models; T-Cell Activation; T-Lymphocyte; Testing; Transplantation; United States National Institutes of Health; antibody-dependent cell cytotoxicity; cytokine; patient population; prevent

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the well-studied models of diabetes, it is now widely accepted that Type1 diabetes mellitus-T1DM is mediated by beta-cell specific T-cells. Co-stimulatory pathways are critical in T cell activation and play a central role in organ specific autoimmunity. T cell activation is thought to involve a "two-signal" model of which the B7-1/2 CD28/CTLA-4 co-stimulatory pathway has been shown to play a crucial role in T-cell activation/tolerance. CTLA-4, CD152, is a major regulator of T cell activation and an important regulator of peripheral tolerance induction. The B7-CD28 blockade by administration of CTLA-4 Ig inhibits Th1- IL-2, INF-y but spares Th2 cytokines, IL-4 and IL-10, and leads to Th2 type IgG isotype switching- IgG 1 upregulated. In animal transplantation models, it significantly prolongs transplanted organ survival and in autoimmune models, is effective in animal pancreatic islet transplantation models as well as in preventing diabetes in NOD mice. Human CTLA-4 Ig (Abatacept - Bristol-Myers Squibb) has been extensively tested in subjects with rheumatoid arthritis and is now FDA approved and in clinical use in that patient population. The Ig Fc component of the Abatacept molecule has been modified so that it neither fixes complement nor takes part in antibody-dependent cellular cytotoxicity-ADCC. This agent inhibits/regulates T cell function, but does not deplete T cells in humans. Individuals with psoriasis, multiple sclerosis, and juvenile idiopathic arthritis have also been studied.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 在经过充分研究的糖尿病模型中，现在人们普遍认为 1 型糖尿病 -T1DM 是由 β 细胞特异性 T 细胞介导的。 共刺激途径对于 T 细胞激活至关重要，并在器官特异性自身免疫中发挥核心作用。 T 细胞激活被认为涉及“双信号”模型，其中 B7-1/2 CD28/CTLA-4 共刺激途径已被证明在 T 细胞激活/耐受中发挥关键作用。 CTLA-4、CD152 是 T 细胞激活的主要调节因子，也是外周耐受诱导的重要调节因子。通过给予 CTLA-4 Ig 阻断 B7-CD28 可抑制 Th1-IL-2、INF-y，但保留 Th2 细胞因子、IL-4 和 IL-10，并导致 Th2 型 IgG 同种型转换 - IgG 1 上调。 在动物移植模型中，它可显着延长移植器官的存活时间，在自身免疫模型中，对动物胰岛移植模型以及预防 NOD 小鼠糖尿病有效。 人类 CTLA-4 Ig（阿巴西普 - 百时美施贵宝）已在类风湿性关节炎受试者中进行了广泛测试，现已获得 FDA 批准并在该患者群体中临床使用。阿巴西普分子的 Ig Fc 成分已被修饰，因此它既不固定补体也不参与抗体依赖性细胞毒性 - ADCC。 该药物可抑制/调节 T 细胞功能，但不会耗尽人体 T 细胞。 还对患有牛皮癣、多发性硬化症和幼年特发性关节炎的个体进行了研究。