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IMMUNOBIOLOGY OF LAK CELLS

LAK 细胞的免疫生物学

基本信息

批准号：
2732984
负责人：
JAMES W MIER
金额：
$ 20.4万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-02-01 至 2000-06-30
项目状态：
已结题

项目摘要

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.

体内注射IL-2也会导致淋巴细胞活化作为导致肿瘤消退的几种次级细胞因子的释放大约三分之一的肾癌或肾癌患者恶性黑素瘤。这种免疫疗法与严重的副作用，其中一些可能是由肿瘤坏死引起的因子、IL-1和其他因对IL-2的反应而产生的致热细胞因子。事实上，这些细胞因子的注入已被认为会引起发烧，受体中的低血压和急性呼吸窘迫综合征(ARDS) 动物，所有这些都与血液动力学和新陈代谢非常相似接受IL-2治疗的癌症患者观察到的变化。此外, 有几条证据表明，内皮细胞可能直接被IL-2激活的CD16+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，高水平的激活补体成分，其中一些是已知作为有效的过敏性毒素，已在接受IL-2免疫治疗的患者的血浆。这笔续期补助金应用程序将系统地评估白细胞与内皮细胞的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。患者体内补体被激活的机制使用IL-2的免疫治疗将进行深入的探索。该提案包含几项研究的重点是评估已知的拮抗剂血清中存在的一种细胞因子--肿瘤坏死因子激活中性粒细胞接受IL-2治疗的患者。其他研究将评估那些抑制肿瘤坏死因子和其他能够引起毛细血管形成的细胞因子的释放在实验动物中泄漏。因为毛细血管渗漏综合征也在接受肿瘤坏死因子α治疗的患者和在接受治疗的患者中观察到使用大剂量GM-CSF治疗，这项研究将提供与生物反应调节剂临床应用相关的信息除IL-2外。这些拟议的研究不仅将澄清 IL-2治疗增加血管通透性的机制但将涉及白细胞的几个基本方面--内皮细胞相互作用、淋巴因子网络和补体激活，这可能是与细胞因子诱导的肿瘤消退和毒性有关。