EFFECT OF CYTOKINES IN HOST DEFENSE AND INFLAMMATION

进行研究以确定细胞因子和其他细胞因子的积累。 实验性炎症模型中的炎症介质 正常人受试者和宿主防御异常的患者 或炎症。 通过抽吸和加热产生的皮肤水泡用于 研究皮肤的局部炎症。 出现的动力学 水疱液中的炎性细胞因子显示介质出现 早期（C5 a，LTB 4，IL-1 β和IL-8）和介质出现晚于12 小时或更晚（TNF-α和GM-CSF），未检测到IL-1 α和IL-2。 异常炎症反应患者皮肤水疱的研究 在急性胰腺炎患者中， 与韦格纳肉芽肿病相关的血管炎， 系统性肥大细胞增多症，以及高免疫球蛋白E综合征， 反复感染。 TNF-α的增加与 疾病活动表明，针对 这种细胞因子的调节在这些疾病中具有特殊的优点 states. 正常水疱渗出液中性粒细胞合成大量的 与对照外周血相比，IL-6、IL-8和TNF-α 中性粒细胞 正常人和过度炎症患者的研究 IL-8水平与血清IL-10水平呈线性关系。 渗出液中炎性中性粒细胞的数量。 中性粒细胞渗出液 合成IL-8，其储存在不同于特定 或嗜天青颗粒，但与富含碱性磷酸酶的 质膜分数 E.大肠杆菌内毒素 志愿者和患者根据长期的NIAID 议定书 TNF-α、TNF-α受体、IL-10、IL-11、IL-12、IL-13、IL-14、IL-18、IL-19、IL 1 α受体拮抗剂、IL-6和IL-8在4 h内出现，G-CSF 6 h时增加，但IL-1 α、IL-1 β、IL-2、IL-3、IL-10、IL-11、IL-12、IL-13、IL-14、IL-15、IL-16、IL-18、IL-19、IL 4、IL-10、干扰素-γ、TGF-β或C5 a。有一个 内毒素后2-4小时循环E-选择素显著增加 这是剂量相关的，表明E-选择素可能是 预测那些患有内毒素血症的患者将进展为休克。 不同疾病中异常的特定介质的定义 国家对开发治疗方法很重要。 在其他研究中， 慢性肉芽肿性疾病患者的长期监测 正在接受干扰素γ作为感染预防的儿童 表明无不良反应。 在其他研究中， 显示出在增强宿主抵抗感染中是有用的 包括MAI的分枝杆菌。

Studies were performed to define the accumulation of cytokines and other mediators of inflammation in experimental models of inflammation in normal human subjects and in patients with abnormalities of host defenses or inflammation. Skin blisters created by suction and heat were used to study local inflammation in the skin. The kinetics of the appearance of inflammatory cytokines in the blister fluid revealed mediators appearing early (C5a, LTB4, IL1beta, and IL-8) and mediators appearing late at 12 hrs or later (TNF-alpha and GM-CSF) with IL-1alpha and IL-2 not detected. Studies of skin blisters in patients with abnormal inflammatory responses revealed dramatic increases in TNF-alpha in patients with acute vasculitis in association with Wegeners granulomatosis, in patients with systemic mastocytosis, and in the syndrome of hyperimmunoglobulin E and recurrent infections. Increases in TNF-alpha correlated well with disease activity suggesting that targeting drug development for modulation of this cytokine will have specific merit in these disease states. Normal blister exudate neutrophils synthesize large amounts of IL-6, IL-8, and TNF-alpha compared with control peripheral blood neutrophils. Studies of normals and patients with excessive inflammation revealed a tight linear relationship between the level of IL-8 and the number of inflammatory neutrophils in the exudate. Exudate neutrophils synthesize IL-8 which is stored in a compartment different from specific or azurophil granules, but is co-eluted with an alkaline phosphatase rich plasma membrane fraction. E. coli endotoxin was administered to normal volunteers and patients in accordance with a long standing NIAID protocol. Increased plasma levels of TNF-alpha, TNF-alpha receptor, IL- 1alpha receptor antagonist, IL-6 and IL-8 occurred within 4h and G-CSF increased by 6 h, but not changes in IL-1alpha, IL-1beta, IL-2, IL-3, IL- 4, IL-10, interferon-gamma, TGF-beta or C5a were seen. There was a striking increase in circulating E-selectin by 2-4 h after endotoxin administration which was dose related suggesting that E-selectin may be predictive of those patients with endotoxemia who will progress to shock. Definition of specific mediators that are abnormal in different disease states is important for developing therapies. In other studies the long term monitoring of patients with chronic granulomatous disease of childhood who are receiving interferon gamma as infectious prophylaxis indicated no adverse effects. In other studies interferon-gamma was shown to be useful in enhancing host defense against infection with mycobacteria including MAI.