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CD27/CD27 LIGAND AND T CELL RESPONSES

CD27/CD27 配体和 T 细胞反应

基本信息

批准号：
2733790
负责人：
GERI R BROWN
金额：
$ 10.44万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-07-01 至 2000-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2733790
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

项目摘要

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.

CD27，一种细胞表面抗原，与肿瘤坏死因子 (TNF) 同源受体分子家族存在于大多数 T 细胞上，并且具有被认为在 T 细胞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得到证实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。我们打算建立有效中和的体内小鼠模型注射腺病毒导致 CD27/CD27 配体 (CD27L) 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小鼠 CD27 受体的细胞外结构域连接到小鼠 IgG 重链 (CD27-Fc)。为了确定效果 CTL 体内 CD27/CD27L 相互作用的中和，比较通过初次和二次腹腔注射产生CTL 将 P815 (H-2d) 肿瘤细胞注入 B6 (H-2b) 对照小鼠和感染小鼠中将使用含有 CD27-Fc 构建体的腺病毒进行。到进一步评估 CD27/CD27L 系统的免疫学重要性，评估抗原特异性 T 细胞反应和延迟型将在小鼠中评估和比较超敏反应（DTH）感染含有 CD27-Fc 抑制剂的腺病毒和对照老鼠。 CTL 在小鼠移植物抗宿主病 (GVHD) 中发挥重要作用。这 CD27/CD27L系统在小鼠GVHD进化中的重要性通过比较对照和腺病毒感染的动物来进行类似的评估在 2 种 GVHD 模型中，其中一种会引起胆管损伤和门静脉损伤炎症并模拟原发性胆汁性肝硬化的病变 B6->B6 X BM1 小鼠；另一种则引起广泛的结肠炎症与使用 DBA/2 在人类克罗恩病中检测到的病变相似 ->B6D2F1 小鼠。所有这些研究应该更好地描述 T 细胞免疫反应进化中的 CD27/CD27L 相互作用它们对 GVHD 发病机制的贡献。最后，TNFR（受体）/TNF 相互作用在进化中的作用令人惊讶的是，类似的免疫反应仍然没有得到很好的理解。 TNF 系统在 CTL 生成中的可比评估，对 DTH 和 GVHD 发展的贡献将在通过注射 TNFR/TNF 相互作用被中和的小鼠编码抑制剂 TNFR-Fc 的腺病毒载体，这是一种小鼠模型已开发并已在我们的实验室中使用。