IN VIVO EFFECTS OF IL 2--ROLE OF TNF AND TNF R FAMILIES

IL 2 的体内作用——TNF 和 TNF R 家族的作用

• 批准号: 2683717
• 负责人: JAMES W MIER
• 金额: $ 19.88万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2683717
• 关键词: CD40 molecule; CD95 molecule; cytokine; cytokine receptors; epidermal growth factor; flow cytometry; human tissue; immunopharmacology; interleukin 2; laboratory mouse; leukocyte adhesion molecules; neoplasm /cancer immunotherapy; neoplasm /cancer remission /regression; receptor expression; surface antigens; tissue /cell culture; transforming growth factors; tumor necrosis factor alpha; vascular endothelium permeability; western blottings

With the exception of TNF and LT (both of which are secreted), members of the TNF family are membrane-associated T cell activation antigens, several of which are induced by IL-2. Receptors of these proteins (e.g. fas, CD40, the LT-beta receptor) are members of the TNF receptor family known primarily for their roles in B cell help (CD40), the induction of apoptosis (fas), or lymph node development (the LT-beta-R). Fas, CD40, and theLT-beta receptor have recently been demonstrated on the endothelium, where their functions are largely unknown. However, like the p55 TNF receptor, CD40 engagement has been shown to elicit adhesion molecule expression in these cells, thus raising the possibility that these TNF receptor family members may transmit signals upon contact with activated lymphocytes that are qualitatively similar to those induced by TNF itself. In addition to fas and the p55 TNF receptor, both CD40 and the LT-beta receptor were recently shown to transmit apoptotic signals in certain tumor cell lines, suggesting that they may play a role in tumor cell cytolysis mediated by IL-2-primed lymphocytes. The studies we have proposed in this application will assess the ability of IL-2 to induce the expression of membrane-associated TNF family members in various lymphoid populations in vitro and in vivo. The factors regulating the expression of their respective receptors (e.g. fas, CD40, the LT-beta receptor) on cultured endothelial cells and on skin and tumor-associated endothelium will also be determined. Several studies with tumor- bearing mice are proposed to assess the role played by the fas-L, CD40-L and 'membrane LT' present on IL-2-activated lymphocytes in IL-2-induced tumor regression and endothelial injury. Ultimately, these studies will address the feasibility of using fas-IgG, CD40-IgG, LT-beta receptor-IgG fusion proteins to attenuate the microvascular pathology resulting from the administration of IL-2.

除TNF和LT（两者都分泌）外， TNF家族的成员是与膜相关的T细胞激活 抗原，其中几种是由IL-2诱导的。 这些受体 蛋白质（例如FAS，CD40，LT-BETA受体）是 TNF受体家族主要以其在B细胞帮助中的作用而闻名 （CD40），凋亡诱导（FAS）或淋巴结发展 （LT-BETA-R）。 FAS，CD40和Thelt-Beta受体最近具有 已在其功能的内皮上证明 在很大程度上未知。 但是，像p55 TNF受体CD40一样 已显示参与引起粘附分子的表达 这些细胞，从而增加了这些TNF受体家族的可能性 成员可以在与活化的淋巴细胞接触后传输信号 与TNF本身引起的那些相似。 在 在FAS和p55 TNF受体中，CD40和LT-Beta都 最近显示受体在某些人中传输凋亡信号 肿瘤细胞系，表明它们可能在肿瘤细胞中起作用 由IL-2蛋白酶淋巴细胞介导的细胞解析。 我们拥有的研究 在本应用中提出的将评估IL-2诱导的能力 各种膜相关的TNF家族成员的表达 体外和体内淋巴样群体。 调节的因素 表达各自的受体（例如FAS，CD40，LT-BETA 受体）在培养的内皮细胞以及皮肤和肿瘤相关的受体上 内皮也将确定。 几项关于肿瘤的研究 提出了轴承小鼠来评估FAS-L的作用， 在IL-2激活的淋巴细胞上存在CD40-L和“膜LT” IL-2诱导的肿瘤消退和内皮损伤。 最终， 这些研究将解决使用FAS-IGG CD40-IGG的可行性， LT-BETA受体-IGG融合蛋白可减轻微血管 由IL-2给药引起的病理学。