CD27/CD27 LIGAND AND T CELL RESPONSES

CD27/CD27 配体和 T 细胞反应

• 批准号: 2443740
• 负责人: GERI R BROWN
• 金额: $ 8.88万
• 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/2443740
• 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.

CD 27，一种与肿瘤坏死因子（TNF）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， 被认为在T细胞活化和产生 细胞毒性T淋巴细胞（CTL）。 尽管可溶性CD 27水平升高 已经在类风湿性关节炎患者的血清中得到证实 和其他自身免疫性疾病，这种T细胞激活的确切作用 抗原在T细胞免疫应答中的作用仍然知之甚少。我们打算 为了建立有效中和所述抗体的体内鼠模型， 通过注射腺病毒介导的CD 27/CD 27配体（CD 27 L）相互作用 编码抑制剂分子的载体，即由以下形成的融合蛋白 将鼠CD 27受体的胞外结构域与鼠CD 27受体的胞外结构域连接， IgG重链（CD 27-Fc）。为了确定 体内CD 27/CD 27 L相互作用对CTL的中和作用， 通过初次和二次腹腔注射产生CTL 将P815（H-2d）肿瘤细胞接种到B6（H-2b）对照小鼠和感染的小鼠中 与含有CD 27-Fc构建体的腺病毒进行免疫组化。到 进一步评估CD 27/CD 27 L系统的免疫学重要性， 抗原特异性T细胞应答和迟发型 将在小鼠中评估和比较超敏反应（DTH）反应 感染含有CD 27-Fc抑制剂的腺病毒和对照 小鼠 CTL在小鼠移植物抗宿主病（GVHD）中起重要作用。的 CD 27/CD 27 L系统在小鼠GVHD演变中的重要性将 通过比较对照和腺病毒感染的动物 在2种GVHD模型中，一种诱导胆管损伤和门脉 炎症和模拟原发性胆汁性肝硬化病变， B6->B6 X BM 1小鼠;其他诱导广泛的结肠炎性 与使用DBA/2在人克罗恩病中检测到的病变相似的病变 -> B6 D2 F1小鼠。所有这些研究都应该更好地描述 CD 27/CD 27 L在T细胞免疫应答演变中的相互作用及 它们在GVHD发病机制中的作用。 最后，TNFR（受体）/TNF相互作用在肿瘤细胞的演变中的作用， 令人惊讶的是，类似的免疫应答仍然没有得到很好的理解。 TNF系统在CTL产生中的可比评估， 对发展DTH和GVHD的贡献将在 小鼠，其中TNFR/TNF相互作用通过注射 腺病毒载体编码的抑制剂TNFR-Fc，小鼠模型， 我们已经开发并在实验室中使用。