CD70 mediated costimulation of T cell responses

CD70 介导的 T 细胞反应共刺激

• 批准号: 7092641
• 负责人: TIMOTHY N BULLOCK
• 金额: $ 23.37万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-08 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7092641
• 关键词: CD antigens; CD40 molecule; T lymphocyte; active immunization; cell cell interaction; cytotoxic T lymphocyte; dendritic cells; helper T lymphocyte; immunologic memory; immunomodulators; laboratory mouse; leukocyte activation /transformation; neoplasm /cancer immunology; protein localization; receptor expression; tissue /cell culture; toll like receptor; tumor necrosis factor alpha; vaccinia virus

DESCRIPTION (provided by applicant): Immune-based therapies offer a promising alternative treatment to radiotherapy- or chemotherapy-resistant tumors, but enthusiasm is tempered by the fact that consistently successful treatment of patients has remained elusive. The broad, long-term objective of our research is to define immune modulators that can be used to enhance the immunological control of tumors. A comparative analysis of how the immune system successfully deals with invading pathogens, yet fails to prevent tumor outgrowth, should provide important information about activation of immune responses that can be incorporated into vaccine design. Dendritic cells that have been stimulated via CD40 become highly immunogenic and upregulate the expression of costimulatory molecules. One such molecule is CD70, a member of the TNF family of cytokines. Several lines of evidence from our laboratory suggest that CD70-mediated costimulation provides an important signal for full activation of CD8+ T cells, indicating that immune therapies that target CD27-CD70 interactions may result in increased control of tumor outgrowth. However, little is known about the regulation of CD70 expression in vivo. We hypothesize that CD70 expression is preferentially upregulated on dendritic cells, and perhaps T cells, after stimulation via CD40, and that activated CD4+ T cells prominently contribute to this process by supplying CD40-ligand. To test this hypothesis and to further the potential of targeting this costimulatory pathway for enhanced immunotherapy, we propose to 1) rigorously define the expression patterns and regulation of expression of CD70 on dendritic cells and T cells in vivo, and 2) determine the relative importance of CD70 expression on DC versus T cells for the development of T cell responses after immunization. The results obtained from these studies should provide insights into how this costimulatory molecule is regulated, and provide a framework for the intelligent design of therapeutic interventions based on its immunostimulatory properties.

描述（由申请人提供）：免疫疗法为放疗或化学疗法耐药性肿瘤提供了一种有希望的替代疗法，但是由于始终成功的患者治疗仍然难以捉摸，因此热情抑制了热情。我们研究的广泛，长期目标是定义可用于增强肿瘤免疫控制的免疫调节剂。对免疫系统如何成功处理入侵病原体但无法防止肿瘤生长的比较分析，应提供有关可将免疫反应激活的重要信息，这些信息可以纳入疫苗设计中。通过CD40刺激的树突状细胞变得高度免疫原性，并上调了共刺激分子的表达。这样的分子是CD70，它是TNF细胞因子家族的成员。我们实验室的几种证据表明，CD70介导的共刺激为完全激活CD8+ T细胞提供了重要信号，表明靶向CD27-CD70相互作用的免疫疗法可能会导致对肿瘤生长的控制增加。但是，对于体内CD70表达的调节知之甚少。我们假设通过CD40刺激后，CD70表达在树突状细胞和T细胞上优先上调，并且通过提供CD40-rigand来激活CD4+ T细胞在这一过程中激活了这一过程。为了检验这一假设，并进一步靶向这种共刺激途径以增强免疫疗法的潜力，我们建议1）严格定义CD70对树突状细胞和T细胞中CD70表达的表达模式和调节，以及2）2）确定CD70表达在DC与TC细胞中的相对重要性，以实现DC与T细胞的T细胞的发育，以进行T细胞反应的发育。从这些研究中获得的结果应提供有关如何调节这种共刺激分子的见解，并为基于其免疫刺激特性的治疗干预措施的智能设计提供了一个框架。