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GLUCOCORTICOID-RESISTANT LEUKEMIC LYMPHOCYTES

糖皮质激素耐药性白血病淋巴细胞

基本信息

批准号：
3164651
负责人：
ALLAN U MUNCK
金额：
$ 12.04万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
1978
资助国家：
美国
起止时间：
1978-06-01 至 1992-05-31
项目状态：
已结题

项目摘要

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?

长期目标是阐明以下方面的作用和相互作用：糖皮质激素和细胞因子如γ干扰素（IFN-γ），白细胞介素2（IL-2）对肿瘤增殖和灭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小鼠体内。拟议的实验是基于许多最近对这些物质的观察。包括在这上面做的该项目表明，糖皮质激素抑制淋巴因子，但可能抑制或增强其作用; 淋巴因子，反过来，可以抵消某些免疫抑制作用，糖皮质激素，这表明使用淋巴因子的可能性，选择性地抵消糖皮质激素治疗的不良副作用。糖皮质激素已经广泛用于治疗白血病和淋巴瘤，以及淋巴因子，一般可用，正在癌症治疗中进行实验测试，强调了解的相互作用和机制的重要性，这些代理人。关于杀肿瘤活性，具体目标针对两个方面：基本问题：（i）体外或小鼠中的糖皮质激素是否会改变杀肿瘤活化，特别是抗体依赖性细胞 IFN-γ对巨噬细胞和其他吞噬细胞的细胞毒性（ADCC），感光素？ (ii)糖皮质激素是否改变了干扰素和光敏素在糖皮质激素敏感和耐药中作用淋巴样细胞系培养或小鼠？关于刺激免疫系统的杀菌活性，需要回答的问题是：（i）糖皮质激素是否改变 IFN-γ对培养的人和小鼠白细胞的杀菌活化作用加上白细胞介素2 (ii)IFN-γ和/或IL-2能否逆转糖皮质激素引起的小鼠感染易感性？最后，使用cDNA探针测量IFN-γ的细胞mRNA水平，和IL-2，目标是回答以下问题：（i）减少糖皮质激素对人T淋巴细胞淋巴因子mRNA水平的影响由诱导蛋白介导？ (ii)这些水平低于负淋巴因子自身的反馈控制