IMMUNOBIOLOGY OF LAK CELLS

LAK 细胞的免疫生物学

• 批准号: 3186453
• 负责人: JAMES W MIER
• 金额: $ 26.5万
• 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 1995-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3186453
• 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的施用也导致体内淋巴细胞活化 由于释放几种次级细胞因子导致肿瘤消退， 在大约三分之一的肾细胞癌患者中， 恶性黑素瘤 这种形式的免疫疗法与严重的 副作用，其中一些可能由肿瘤坏死介导 因子、IL-1和响应于IL-2产生的其他致热细胞因子。 事实上，已知这些细胞因子的输注会引起发热， 低血压和急性呼吸窘迫综合征（ARDS 动物，所有这些都非常类似于血液动力学和代谢 在用IL-2治疗的癌症患者中观察到的改变。 此外，本发明还提供了一种方法， 一些证据表明，内皮细胞可能直接 IL-2激活的CD 16+淋巴细胞（NK细胞）损伤，导致 血管通透性弥漫性增加（毛细血管渗漏综合征）。 最后，高水平的活化补体成分，其中一些是 已知作为强效过敏毒素发挥作用， 用IL-2进行免疫治疗的患者的血浆。 这份续约补助金 应用程序将系统地评价白细胞-内皮细胞相互作用 因为它们与内皮损伤和毛细血管渗漏的诱导有关。 补体在经历过以下过程的患者中被激活的机制 IL-2的免疫治疗将被深入研究。 该提案包括 几项研究集中于评价已知拮抗 TNF（血清中存在的细胞因子之一）激活中性粒细胞 接受IL-2治疗的患者。 其他研究将评估 抑制肿瘤坏死因子和其他细胞因子的释放， 在实验动物中泄漏。 由于毛细血管渗漏综合征也 在接受TNF α治疗的患者和接受 高剂量GM-CSF治疗，这项研究将提供 与生物反应调节剂临床使用相关的信息 除了IL-2。 这些拟议的研究不仅将澄清 与IL-2治疗相关的血管通透性增加的机制， 但将阐述白细胞-内皮细胞的几个基本方面， 相互作用，淋巴因子网络和补体激活，这可能是 与马槟榔碱诱导的肿瘤消退以及毒性有关。