GLUCOCORTICOID-RESISTANT LEUKEMIC LYMPHOCYTES

糖皮质激素耐药性白血病淋巴细胞

• 批准号: 3164647
• 负责人: ALLAN U MUNCK
• 金额: $ 11.49万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-06-01 至 1986-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3164647
• 关键词: T lymphocyte; chemical binding; cortisol; drug adverse effect; glucocorticoids; human subject; hybridomas; immunoglobulins; leukemia; lymphocyte; lymphocytic leukemia; lymphokines; lymphoma; membrane activity; monoclonal antibody; myelogenous leukemia; radioimmunoassay; radiotracer; thymus; tissue /cell culture; viral leukemia

These studies have two general goals, both related to the use of glucocorticoids in treatment of leukemias and lymphomas. One goal is to apply and extend our knowledge of glucocorticoid receptors and mechanisms of action to normal and malignant lymphocytes and related cells. For these studies we are applying our recently developed minicolumn procedure to the analysis of nonactivated, activated, and meroreceptor complexes in cytosols from the cells mentioned under various conditions. Of particular current interest to us is the role in stabilizing receptors of calpastatin, a naturally occurring protein inhibitor of a family of calcium-activated proteases called calpains. We have found that the relative stability of receptors in cytosols from cells of patients with chronic lymphocytic leukemia (CLL) compared to those from patients with acute nonlymphocytic leukemia (ANLL) is at least partly due to the presence in the former cells of a stabilizer that closely resembles calpastatin. The other goal is to extend our observations on glucocorticoid effects on lymphocytes and other cells that are mediated by inhibition of, or synergism with, lymphokines such as interleukin 2 (IL-2) and immune or gamma interferon. We have shown that gamma interferon is the major lymphokine that increased Fc-Receptors for IgG on human monocytes, and that glucocorticoids added together with gamma interferon augment this effect as well as antibody-dependent and\-independent tumor cell lysis and expression of class I and class II HLA antigens. We are now investigating the mechanisms of these effects. In relation to IL-2, an autocrine mechanism of neoplastic growth involving IL-2 production and response has been established in MLA 144, an IL-2 producing leukemia cell line derived from a Gibbon ape. (D)

这些研究有两个总体目标，都与使用 糖皮质激素在白血病和淋巴瘤治疗中的应用其中一个目标是 应用和扩展我们对糖皮质激素受体和机制的知识 对正常和恶性淋巴细胞及相关细胞的作用。为了这些 我们正在将我们最近开发的微柱程序应用于 胞浆中非活化、活化和膜受体复合体的分析 从各种条件下提到的细胞中分离出来。特定电流的 我们感兴趣的是在稳定钙调蛋白受体方面的作用 钙激活蛋白家族的天然蛋白抑制物 蛋白水解酶称为钙调蛋白。我们已经发现，相对稳定性 慢性淋巴细胞患者细胞液中的受体 白血病(CLL)与急性非淋巴细胞白血病患者的比较 白血病(ANLL)至少部分是由于前一代细胞的存在 指的是一种与钙调蛋白非常相似的稳定剂。 另一个目标是将我们对糖皮质激素影响的观察扩大到 淋巴细胞和其他细胞通过抑制或 与白细胞介素2(IL-2)等淋巴因子和免疫或 伽马干扰素。我们已经证明，伽马干扰素是主要的 淋巴因子增加人单核细胞上免疫球蛋白Fc受体，并 糖皮质激素和伽马干扰素一起使用可以增强这种效应 以及抗体依赖和非抗体依赖的肿瘤细胞裂解和表达 属于I类和II类的人类白细胞抗原。我们现在正在调查 这些影响的机制。与IL-2相关的自分泌机制 与IL-2的产生和反应有关的肿瘤生长 在MLA 144中建立了一种产生IL-2的白血病细胞系，该细胞系来源于一种 长臂猿。(D)