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

除了TNF和LT（两者都是分泌的）之外， TNF家族的成员是膜相关的T细胞活化 抗原，其中几种是由IL-2诱导的。 这些受体 蛋白质（例如Fas、CD 40、LT-β受体）是 已知TNF受体家族主要在B细胞帮助中发挥作用 （CD 40）、诱导细胞凋亡（fas）或淋巴结发育 (the LT-β-R）。 Fas、CD 40和LT-β受体最近在 在内皮上被证明，它们的功能是 大部分未知。 然而，与p55 TNF受体一样，CD 40 已经显示接合引起粘附分子表达， 这些细胞，从而提高了这些TNF受体家族 成员可以在与活化的淋巴细胞接触时传递信号 其性质类似于TNF本身诱导的那些。 在 除了Fas和p55 TNF受体外，CD 40和LT-β 受体最近被证明在某些细胞中传递凋亡信号， 肿瘤细胞株，这表明它们可能在肿瘤细胞中发挥作用， IL-2致敏淋巴细胞介导的细胞溶解。 我们的研究 本申请中提出的方法将评估IL-2诱导免疫应答的能力。 膜相关的TNF家族成员在各种肿瘤中的表达 在体外和体内的淋巴细胞群。 调节的因素 它们各自的受体（例如Fas、CD 40、LT-β 受体）对培养的内皮细胞和皮肤和肿瘤相关 还将测定内皮细胞。 一些关于肿瘤的研究- 提出了荷瘤小鼠来评估fas-L所起的作用， CD 40-L和“膜LT”存在于IL-2激活的淋巴细胞上， IL-2诱导的肿瘤消退和内皮损伤。 最后， 这些研究将说明使用fas-IgG，CD 40-IgG， LT-β受体-IgG融合蛋白减弱微血管 IL-2给药导致的病理学。

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.