IMMUNOBIOLOGY OF LAK CELLS

LAK 细胞的免疫生物学

• 批准号: 2091329
• 负责人: JAMES W MIER
• 金额: $ 27.74万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-02-01 至 1995-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2091329
• 关键词: CD antigens; adult respiratory distress syndrome; antiserum; biological response modifiers; biopsy; carcinoma; cell mediated lymphocytolysis test; cis platinum compound; complement; cytokine; cytolysis; endotoxins; gel electrophoresis; human subject; human therapy evaluation; immunosuppression; immunotoxicity; interferons; interleukin 2; interleukin 4; kidney neoplasms; killer cells; laboratory mouse; laboratory rabbit; leukocyte activation /transformation; liver function; lymphokines; melanoma; monoclonal antibody; monocyte; natural killer cells; neoplasm /cancer classification /staging; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; passive immunization; peripheral blood vessel; radioimmunoassay; radiotracer; stress proteins; tumor necrosis factor alpha; vascular endothelium permeability; western blottings

The administration of IL-2 leads to lymphocyte activation in vivo as well as the release of several secondary cytokines resulting in tumor regression in approximately one-third of patients with either renal cell carcinoma or malignant melanoma. This form of immunotherapy is associated with severe side effects, some of which are presumably mediated by tumor necrosis factor, IL-1, and other pyrogenic cytokines generated in response to IL-2. Indeed, the infusion of these cytokines is known to induce fever, hypotension, and an acute respiratory distress syndrome (ARDS) in recipient animals, all of which strongly resemble the hemodynamic and metabolic alterations observed in cancer patients treated with IL-2. In addition, several lines of evidence suggest that the endothelium may be directly injured by IL-2-activated CD16+ lymphocytes (NK cells), resulting in a diffuse increase in vascular permeability (capillary leak syndrome). Finally, high levels of activated complement components, some of which are known to function as potent anaphylatoxins, have been detected in the plasma of patients undergoing immunotherapy with IL-2. This renewal grant application will systematically evaluate leukocyte-endothelial interactions as they relate to endothelial injury and the induction of capillary leak. The mechanism by which complement is activated in patients undergoing immunotherapy with IL-2 will be explored in depth. The proposal contains several studies focused on the evaluation of agents known to antagonize the activation of neutrophils by TNF, one of the cytokines present in the serum of patients receiving IL-2. Other studies will evaluate agents that inhibit the release of TNF and other cytokines capable of causing capillary leak in experimental animals. Since the capillary leak syndrome has also been observed in patients receiving TNF alpha and in those undergoing treatment with high-dose GM-CSF, this investigation will provide information relevant to the clinical use of biological response modifiers in addition to IL-2. These proposed studies will not only clarify the mechanism of increased vascular permeability associated with IL-2 therapy, but will address several fundamental aspects of leukocyte-endothelial cell interactions, lymphokine networks, and complement activation, which may be relevant to cytokine-induced tumor regression as well as toxicity.

IL-2的给药也导致体内淋巴细胞激活 随着几种次要细胞因子的释放导致肿瘤回归 大约三分之一的肾细胞癌患者或 恶性黑色素瘤。 这种免疫疗法与严重有关 副作用，其中一些可能是由肿瘤坏死介导的 因IL-2而产生的因子，IL-1和其他热原细胞因子。 实际上，已知这些细胞因子的输注会诱导发烧， 低血压和受体中的急性呼吸窘迫综合征（ARDS） 动物，所有动物都非常类似于血流动力学和代谢 在接受IL-2治疗的癌症患者中观察到的改变。 此外， 几条证据表明内皮可能直接 由IL-2激活的CD16+淋巴细胞（NK细胞）受伤，导致 弥漫性增加血管通透性（毛细血管泄漏综合征）。 最后，高水平的激活补体组件，其中一些是 在 接受IL-2免疫疗法的患者血浆。 这项更新赠款 应用将系统地评估白细胞 - 内皮相互作用 当它们与内皮损伤和毛细血管泄漏的诱导有关时。 接受补体的机制在接受的患者中被激活 IL-2的免疫疗法将深入探讨。 该提案包含 几项研究重点是评估已知的剂量的剂量 TNF激活中性粒细胞，这是血清中存在的一种细胞因子 接受IL-2的患者。 其他研究将评估代理 抑制TNF和其他能够引起毛细管的细胞因子的释放 实验动物的泄漏。 由于毛细管泄漏综合症也有 在接受TNF alpha的患者中观察到 用大剂量GM-CSF治疗，此研究将提供 与生物反应修饰符的临床使用有关的信息 除了IL-2。 这些拟议的研究不仅会阐明 与IL-2治疗相关的血管通透性增加的机制， 但是将解决白细胞 - 内皮细胞的几个基本方面 相互作用，淋巴细胞因网络和补体激活，这可能是 与细胞因子诱导的肿瘤回归以及毒性有关。