CONTROL OF CYTOKINE RELEASE FROM HUMAN MUCOSAL T CELLS

控制人粘膜 T 细胞释放细胞因子

• 批准号: 6198056
• 负责人: James K. Roche
• 金额: $ 14.66万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6198056
• 关键词: T lymphocyte; cyclic AMP; cytokine; cytokine receptors; human tissue; mucosa; mucosal immunity; prostaglandin E; protein biosynthesis

DESCRIPTION (Adapted from applicant's abstract): Evidence suggests that chronic idiopathic inflammation, present in mucosa of human conjunctiva bronchial tree, GU and GI tracts, is often T lymphocyte-mediated. Few substances are known that can substantially retard immune-mediated injury in human mucosa without associated broad-spectrum T and B cell suppression. The challenge is to identify a locally active substance that reversibly retards tissue injurious T lymphocyte responses, particularly the cytokine secretion by CD4+ T-cells in humans at affected sites in mucosa, and which leaves the remainder of the immune system intact. PGE2 has been well-known to down regulate T lymphocyte function, especially cytokine release. The recent discovery that a single receptor type (EP4) for this potent locally active down regulator of T lymphokine release is present on T lymphocytes in many mucosa-bearing organs suggests an innovative approach to inflammation affecting mucosal organs. The hypotheses to be tested in the proposed studies are: (1) activation of the EP4 receptor on the T cell plasma membrane is associated with reduced cytokine-induced tissue injury; and (2) the insertion of non-EP4 receptors into the T cell membrane, as well as the use of EP receptor-specific pharmacological agonists and antagonists that alter the intra-cellular level of cAMP, will enhance the PGE2-driven reduction in pro- inflammatory cytokine release and subsequent tissue injury. Success in this endeavor could open up several new areas for study. Approaches to be used to achieve this long-term objective are physiological (receptor density by radioligand binding; transmonolayer electrical potential difference); molecular (transfection of mucosal T lymphocytes with EP receptor genes; immunological (characterization with specific immunoglobulin, and cell separation, based on surface markers); pharmacological (receptor induction and 131 binding studies) and biochemical (quantitating cAMP and receptor number). Thus, through the use of human T lymphocytes from many sites with mucosa throughout the body, as well as a potent macromolecule which new data suggests reduces cytokine secretion by T lymphocytes, the proposed research may reveal ways in which cellular receptors on mucosal T cells could be targeted to spare injury to adjacent tissue.

描述（改编自申请人的摘要）：证据表明 慢性特发性炎症，存在于人类结膜粘膜中 支气管树、胃肠道和胃肠道，通常是 T 淋巴细胞介导的。 很少 已知物质可以显着延缓免疫介导的损伤 人类粘膜，没有相关的广谱 T 和 B 细胞抑制。 这 面临的挑战是确定一种可逆地延迟的局部活性物质 组织损伤性 T 淋巴细胞反应，特别是细胞因子分泌 人类粘膜受影响部位的 CD4+ T 细胞 免疫系统的其余部分完好无损。 PGE2 众所周知可以降低 调节T淋巴细胞功能，特别是细胞因子的释放。 最近的 发现这种有效的局部活性的单一受体类型（EP4） 许多人的 T 淋巴细胞上都存在 T 淋巴因子释放的下调调节因子 粘膜承载器官提出了一种治疗炎症的创新方法 影响粘膜器官。 拟议研究中要检验的假设 是： (1) T 细胞质膜上 EP4 受体的激活是 与减少细胞因子诱导的组织损伤有关； (2) 插入 非 EP4 受体进入 T 细胞膜，以及 EP 的使用 受体特异性药理学激动剂和拮抗剂，改变 细胞内 cAMP 水平，将增强 PGE2 驱动的 pro- 减少 炎症细胞因子释放和随后的组织损伤。 在这方面取得成功 努力可以开辟几个新的研究领域。 用于实现这一长期目标的方法是生理学的 （放射性配体结合的受体密度；跨单层电位 不同之处）;分子（用EP受体转染粘膜T淋巴细胞） 基因；免疫学（用特定的免疫球蛋白和细胞表征 分离，基于表面标记）；药理学（受体诱导和 131 结合研究）和生物化学（定量 cAMP 和受体数量）。 因此，通过使用来自粘膜许多部位的人类 T 淋巴细胞 新数据表明，它是一种有效的大分子 减少 T 淋巴细胞的细胞因子分泌，拟议的研究可能揭示 粘膜T细胞上的细胞受体可以被靶向以免受伤害的方法 邻近组织损伤。