ROLE OF ICOS IN T CELL RESPONSES AND ANTI-TUMOR IMMUNITY

ICOS 在 T 细胞反应和抗肿瘤免疫中的作用

• 批准号: 6044396
• 负责人: Gordon James Freeman
• 金额: $ 21.53万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-13 至 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6044396
• 关键词: CD28 molecule; T cell receptor; T lymphocyte; antigen presenting cell; antineoplastics; biological signal transduction; cell differentiation; cell proliferation; chimeric proteins; disease /disorder model; gene expression; gene interaction; helper T lymphocyte; immunoregulation; immunosuppression; interleukin 10; interleukin 4; laboratory mouse; laboratory rat; leukocyte activation /transformation; monoclonal antibody; neoplasm /cancer genetics; neoplasm /cancer immunology; phosphatidylinositol 3 kinase; receptor expression

The BY-CD28/CTLA-4 co-stimulatory pathway has a critical role in regulating T cell activation, and manipulation of this key immunoregulatory pathway has great therapeutic potential. We have cloned a novel murine gene that is a third member of the CD28/CTLA4 gene family and is the murine homologue of the recently described human ICOS (Inducible Co-stimulatory) gene. ICOS is expressed on activated murine T cells and expression as restricted to T cells, similarly to CD28 and CTLA4. In humans, ICOS functions as a receptor for co-stimulatory signals leading to T cell proliferation and production of IL-4 and IL-10, but not IL-2. The relationships of ICOS with the receptors and ligands in the B7-CD28/CTLA-4 pathway need to be define. It is not yet known whether ICOS binds B7 co-stimulators or if ICOS binds to an as yet to be identified counter-receptor in a parallel pathway. It is also not clear when ICOS co-stimulation is needed during immune response. Because ICOS stimulates IL-4 and super-induces IL-10 production, ICOS co-stimulation may have an important role in T cell differentiation and the generation of regulatory T cells. Therefore, manipulation of ICOS signaling may have therapeutic potential. The goal of this research project is to elucidate the role of ICOS co-stimulation in T cell activation, differentiation, and tumor immunity. We have developed a murine ICOS fusion protein that enables us to analyze the function of ICOS on naive and previously activated T cells to characterize the expression and function of ICOS counter-receptor, and to analyze the function of ICOS interactions with the B7/CD28 pathway. In this project, we will characterize how ICOS functions as a receptor for co-stimulator signals from antigen presenting cells and how ICOS regulates T cell proliferation and differentiation. We will examine the role of ICOS co-stimulation in the generation of an effective anti-tumor response in vivo using the EL4 tumor model since the role of IL-4 and IL-10 in suppression of effective tumor immunity has been well defined in this model. ICOS function may deviate the immune response away from a protective cytolytic anti-tumor response and towards a suppressive anti-tumor Th2 response. To understand the role of ICOS in the T cell response and in anti-tumor immunity, I propose to: SPECIFIC AIM 1. To examine the role of ICOS in T cell activation and differentiations. SPECIFIC AIM 2. To examine the expression the expression of ICOS counter-receptor on APC and characterize its molecular structure. SPECIFIC AIM 3. To examine how blocking ICOS signals affect the immune response to murine tumors.

BY-CD28/CTLA-4共刺激途径在调节T细胞激活中具有关键作用，并且对该关键免疫调节途径的操纵具有很大的治疗潜力。我们克隆了一个新型的鼠基因，该基因是CD28/CTLA4基因家族的第三个成员，并且是最近描述的人类ICOS（诱导共刺激性）基因的鼠同源物。 ICO在活化的鼠T细胞上表达，并表达为限制于T细胞，类似于CD28和CTLA4。在人类中，ICOS充当共刺激信号的受体，导致T细胞增殖和IL-4和IL-10的产生，而不是IL-2。需要定义ICO与B7-CD28/CTLA-4途径中受体和配体的关系。尚不清楚ICOS是否结合B7共刺激剂或ICOS是否在平行途径中鉴定为尚未识别的反受体。在免疫反应期间需要ICOS共刺激时，还不清楚。由于ICO刺激IL-4和超级诱导IL-10的产生，因此ICOS共刺激可能在T细胞分化和调节T细胞的产生中具有重要作用。因此，对ICOS信号传导的操纵可能具有治疗潜力。该研究项目的目的是阐明ICOS共刺激在T细胞激活，分化和肿瘤免疫力中的作用。我们已经开发了一种鼠ICOS融合蛋白，使我们能够分析ICOS对NAIVE和先前激活的T细胞的功能，以表征ICOS反受体的表达和功能，并分析ICOS与B7/CD28途径的功能。在这个项目中，我们将表征ICOS如何充当来自抗原呈现细胞的共刺激信号的受体以及ICO如何调节T细胞增殖和分化的受体。我们将使用EL4肿瘤模型研究ICOS共刺激在体内生成有效抗肿瘤反应中的作用，因为在该模型中，IL-4和IL-10在抑制有效肿瘤免疫中的作用已得到很好的定义。 ICOS功能可能会使免疫反应偏离保护性细胞溶解抗肿瘤反应，并偏向抑制性抗肿瘤TH2反应。为了了解ICO在T细胞反应和抗肿瘤免疫中的作用，我建议：特定目的1。检查ICOS在T细胞激活和分化中的作用。具体目的2。检查ICOS反感受器在APC上的表达并表征其分子结构。具体目的3。检查阻断ICOS信号如何影响对鼠肿瘤的免疫反应。