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

除肿瘤坏死因子和凝血酶原激活剂(均为分泌型)外， 肿瘤坏死因子家族的成员是膜相关T细胞活化 抗原，其中一些是由IL-2诱导的。它们的受体 蛋白质(如Fas、CD40、LT-β受体)是 肿瘤坏死因子受体家族主要因其在B细胞帮助中的作用而闻名 (CD40)、诱导细胞凋亡(Fas)或淋巴结发育 (LT-β-R)。Fas、CD40和LT-β受体最近 已经在内皮细胞上展示过，在那里它们的功能是 很大程度上是未知的。然而，与p55肿瘤坏死因子受体一样，CD40 参与已被证明能诱导黏附分子在脑内的表达 这些细胞，从而增加了这些肿瘤坏死因子受体家族 成员可以在与激活的淋巴细胞接触时传递信号 在性质上与肿瘤坏死因子本身所诱导的相似。在……里面 除了Fas和p55肿瘤坏死因子受体，CD40和LT-β也是如此 最近发现，受体在某些情况下传递凋亡信号。 肿瘤细胞系，提示它们可能在肿瘤细胞中发挥作用 IL-2激活的淋巴细胞介导的细胞杀伤作用。我们已有的研究 在本申请中提出的将评估IL-2诱导 膜相关肿瘤坏死因子家族成员在不同组织中的表达 体外和体内的淋巴种群。规范这一现象的因素 它们各自的受体(如Fas、CD40、LT-β)的表达 受体)在培养的血管内皮细胞、皮肤和肿瘤相关细胞上的表达 血管内皮细胞也将被测定。几项关于肿瘤的研究- 建议用带胎小鼠来评估FAS-L的作用， CD_(40)-L和‘膜LT’在IL-2激活的淋巴细胞上的表达 IL-2诱导的肿瘤消退和内皮损伤。最终， 这些研究将探讨使用Fas-Ig G、CD40-Ig G、 LT-β受体-免疫球蛋白融合蛋白抑制微血管的研究 因使用IL-2而导致的病理改变。

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.