CD27/CD27 LIGAND AND T CELL RESPONSES

CD27/CD27 配体和 T 细胞反应

• 批准号: 2134192
• 负责人: GERI R BROWN
• 金额: $ 7.88万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2134192
• 关键词: Adenoviridae; CD antigens; Crohn's disease; cell differentiation; chimeric proteins; cytokine receptors; cytotoxic T lymphocyte; delayed hypersensitivity; disease /disorder model; graft versus host disease; helper T lymphocyte; laboratory mouse; leukocyte activation /transformation; primary biliary cirrhosis; tissue /cell culture; transfection; tumor necrosis factor alpha

CD27, a cell-surface antigen, with homology to tumor necrosis factor (TNF) receptor family of molecules is found on a majority of T cells and has been suggested to play a role in T cell activation and generation of cytotoxic T lymphocytes(CTL). Although elevated levels of soluble CD27 have been demonstrated in serum from patients with rheumatoid arthritis and other autoimmune disease, the exact role of this T cell activation antigen in T cell immune responses is still poorly understood. We intend to establish an in vivo murine model that effectively neutralizes the CD27/CD27 ligand (CD27L) interaction by the injection of an adenoviral vector encoding an inhibitor molecule, i.e. a fusion protein formed by joining the extracellular domain of the murine CD27 receptor to a murine IgG heavy chain (CD27-Fc). In order to determine the effects of the neutralization of CD27/CD27L interaction in vivo on CTL, a comparison of the generation of CTL by primary and secondary intraperitoneal injection of P815 (H-2d) tumor cells into B6 (H-2b) control mice and mice infected with the adenovirus containing the CD27-Fc construct will be performed. To further assess the immunologic importance of the CD27/CD27L system, evaluation of antigen specific T cell responses and delayed type hypersensitivity (DTH) responses will be assessed and compared in mice infected with the adenovirus containing the CD27-Fc inhibitor and control mice. CTL play an important role in murine graft versus host disease (GVHD). The importance of the CD27/CD27L system in the evolution of murine GVHD will similarly be assessed by comparing control and adenovirus infected animals in 2 models of GVHD, one that induces bile duct damage and portal inflammation and simulates lesions in primary biliary cirrhosis utilizing B6->B6 X BM1 mice; the other inducing extensive colonic inflammatory lesions similar to those detected in human Crohn's disease utilizing DBA/2 ->B6D2F1 mice. All of these studies should better delineate the role of CD27/CD27L interaction in the evolution of T cell immune responses and their contribution to the pathogenesis of GVHD. Finally, the role of TNFR(receptor)/TNF interaction in the evolution of similar immunologic responses is surprisingly still not well understood. Comparable assessments of the TNF system in generation of CTL, contribution to the development of DTH and to GVHD will be performed in mice in which TNFR/TNF interactions are neutralized by injection of the adenovirus vector encoding the inhibitor TNFR-Fc, a murine model that was developed and is already being used in our laboratory.

CD27，一种与肿瘤坏死因子同源的细胞表面抗原 受体分子家族在大多数T细胞上发现，并具有 被认为在T细胞的激活和生成中发挥作用 细胞毒性T淋巴细胞(CTL)。尽管可溶性CD27水平升高 已在类风湿性关节炎患者的血清中发现 和其他自身免疫性疾病一样，这种T细胞激活的确切作用 T细胞免疫反应中的抗原仍然知之甚少。我们打算 建立一种体内小鼠模型，有效地中和 注入腺病毒后CD27/CD27配体(CD27L)的相互作用 编码抑制分子的载体，即由以下物质形成的融合蛋白 将小鼠CD27受体的胞外区连接到小鼠 免疫球蛋白重链(CD27-Fc)。为了确定这些措施的效果 体内中和CD27/CD27L相互作用对CTL的影响 一次和二次腹腔注射产生CTL的研究 将P815(H-2d)瘤细胞导入B6(H-2b)对照小鼠和感染小鼠 用含有CD27-Fc的重组腺病毒进行实验。至 进一步评估CD27/CD27L系统的免疫学重要性， 抗原特异性T细胞反应与延迟型的评价 将评估和比较小鼠的超敏反应(DTH) CD27-Fc抑制剂腺病毒感染与对照 老鼠。 CTL在小鼠移植物抗宿主病(GVHD)中起重要作用。这个 CD27/CD27L系统在小鼠移植物抗宿主病发生发展中的作用 同样地，通过比较对照和腺病毒感染的动物来评估 在两种GVHD模型中，一种导致胆管损伤和门静脉 炎症和模拟病变在原发性胆汁性肝硬变中的应用 B6-&GT；B6×BM1小鼠；另一只诱导广泛的结肠炎 利用DBA/2检测到的与人类克罗恩病相似的病变 -&gt；B6D2F1小鼠。所有这些研究都应该更好地描绘出 CD27/CD27L相互作用在T细胞免疫应答和免疫调节中的作用 它们在移植物抗宿主病发病机制中的作用。 最后，肿瘤坏死因子受体(TnFR)/肿瘤坏死因子相互作用在肿瘤发生发展中的作用 令人惊讶的是，类似的免疫反应仍然没有被很好地理解。 肿瘤坏死因子系统在CTL产生中的可比性评估， 将在#年为DTH和GVHD的发展作出贡献 小鼠中和肿瘤坏死因子受体/肿瘤坏死因子的相互作用 编码抑制物TNFR-Fc的腺病毒载体，这是一种小鼠模型 已经开发出来，并已在我们的实验室使用。