GLUCOCORTICOID-RESISTANT LEUKEMIC LYMPHOCUTES

长期目标是阐明以下行为和相互作用 糖皮质激素和细胞因子，如干扰素(干扰素)和 白介素2(IL-2)对肿瘤细胞增殖和失活的影响 免疫系统。我们将在体外细胞培养中研究这些现象 系统和在小鼠体内。提出的实验是基于大量的 最近对这些物质的观察。它们包括在这个上面制作的那些 项目，该项目证明糖皮质激素抑制血管生成 淋巴因子，但可抑制或增强其作用； 淋巴因子反过来又可以抵消某些免疫抑制作用。 糖皮质激素，提示有可能使用淋巴因子 选择性地抵消糖皮质激素治疗的不良副作用。 糖皮质激素已被广泛用于治疗慢性前列腺癌 白血病和淋巴瘤，以及淋巴因子，现在正在成为 普遍可用，正在进行癌症治疗的实验测试， 强调了解相互作用和机制的重要性 这些特工。 关于杀瘤活动，具体目标是两个 基本问题：(I)体外或小鼠体内的糖皮质激素是否会改变 抗肿瘤活性，特别是抗体依赖的细胞 对巨噬细胞和其他吞噬细胞的细胞毒性(ADCC) 淋巴毒素？(Ii)糖皮质激素是否会改变其杀瘤活性 干扰素和淋巴毒素治疗糖皮质激素敏感和耐药 淋巴样细胞系是在培养中还是在小鼠中？ 关于刺激免疫系统进行杀菌活性， 需要回答的问题是：(I)糖皮质激素是否会改变 干扰素-γ对培养的人和小鼠白细胞的杀菌活性 外加IL-2？(Ii)干扰素-γ和/或白介素2能否逆转增加的 小鼠对糖皮质激素引起的感染的易感性？ 最后，使用cdna探针来测量细胞中干扰素-γ的mRNA水平。 和IL-2，目标是回答以下问题：(I)是减少 糖皮质激素对人T淋巴细胞淋巴因子mRNA水平的影响 诱导蛋白(S)？(Ii)该等水平是否在负数以下 淋巴因子本身的反馈控制？

The long-term objectives are to elucidate the actions and interactions of glucocorticoids and cytokines such as gamma interferon (IFN-gamma) and interleukin 2 (IL-2) on tumor proliferation and on inactivation of the immune system. We will study these phenomena both in vitro in cell culture systems and in vivo in mice. Proposed experiments are based on numerous recent observations with these substances. They include those made on this project, which demonstrated that glucocorticoids inhibit production of lymphokines, but may inhibit or enhance their actions; and that the lymphokines, in turn, may counteract certain immunosuppressive actions of glucocorticoids, suggesting the possibility of using lymphokines to selectively counteract unwanted side effects of glucocorticoid therapy. The fact that glucocorticoids are already widely used in treatment of leukemias and lymphomas, and that lymphokines, which are now becoming generally available, are being tested experimentally in cancer therapy, emphasizes the importance of understanding interactions and mechanisms of these agents. With respect to tumoricidal activity, the specific aims are directed at two fundamental questions: (i) Do glucocorticoids in vitro or in mice alter tumoricidal activation, and in particular antibody-dependent cellular cytotoxicity (ADCC), of macrophages and other phagocytes by IFN-glamma and lymphotoxin? (ii) Do glucocorticoids alter the tumoricidal activity of interferons and lymphotoxin on glucocorticoid-sensitive and -resistant lymphoid cell lines in culture or in mice? With respect to stimulation of the immune system for bactericidal activity, the questions to be answered are: (i) Do glucocorticoids alter bactericidal activation of cultured human and mouse leukocytes by IFN-gamma plus IL-2? (ii) Can IFN-gamma and/or IL-2 reverse the increased susceptibility to infection in mice caused by glucocorticoids? Finally, using cDNA probes to measure cellular levels of mRNA for IFN-gamma and IL-2, the goals are to answer the following questions: (i) Is reduction by glucocorticoids of lymphokine mRNA levels in human T lymphocytes mediated by induced protein(s)? (ii) Are those levels under negative feedback control by the lymphokines themselves?