IMMUNOBIOLOGY OF LAK CELLS

LAK 细胞的免疫生物学

• 批准号: 3186454
• 负责人: JAMES W MIER
• 金额: $ 27.56万
• 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/3186454
• 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.

给药IL-2也会导致体内淋巴细胞活化