IMMUNOTOXICITY OF ACID ANHYDRIDES IN THE LUNG

描述：(改编自《调查者摘要》)酸 酸酐，在许多工业中使用，会导致免疫毒性 过敏反应。长期目标是理解这种机制。 肺中酸酐的免疫毒性如此合理 治疗方法是可以设计的。一种豚鼠模型的建立 偏苯三酸酐(TMA)引起的过敏将被使用，因为它 模仿过敏患者的许多症状。动物将会是 用TMA致敏ID，3wk后经气管内挑战 抗原(TMA与血清白蛋白偶联)。免疫毒素的成分 对TMA的反应将受到监测，包括：支气管缩窄和 循环中的血小板立即减少；呼吸道增多 微血管和肺血管通透性；肺出血；以及 肺内嗜酸性粒细胞、中性粒细胞和单核细胞浸润。 假设TMA-GPSA与亲细胞的IgG1和/或 空域和/或循环中的非嗜细胞IgG2抗体引起 补体激活导致循环中的血小板减少： 这两个都是TMA免疫毒性反应所必需的。TMA- 用酶联免疫吸附试验检测血清和血清中GPSA特异性的IgG1和IgG2 主动致敏动物的支气管肺泡灌洗(BAL) 与免疫毒性反应有关。提纯的能力 介导免疫毒性反应的IgG1/IgG2抗体将在 被动敏感的动物。为了确定哪一种抗体在 补体参与，动物将被动致敏IgG1 或IgG2，与眼镜蛇毒素因子缺乏补体，以及 对TMA的反应进行了评估。以确定是否发生补体激活 在循环或空域中，补体裂解产物C3a将 用免疫印迹法检测血浆和BAL中的含量。体外研究 将决定抗原、抗体和BAL细胞的组合，从而导致 在C3a代或BAL细胞激活。一条孤立的气管 将使用制剂来确定抗原是否移动(有或 不含抗体和C)受上皮通透性的限制。它的重要性 将通过确定血小板是否在 肺和是否耗尽血小板或阻止其聚集 会影响免疫毒性反应。这些研究将确定是否 嗜细胞性抗体可以激发补体系统的参与，如果 亲细胞抗体加非亲细胞抗体可预测免疫毒性反应。

DESCRIPTION: (Adapted from the Investigator's Abstract) Acid anhydrides, used in a number of industries, cause the immunotoxic response of allergy. The long term goal is to understand the mechanism of immunotoxicity of the acid anhydrides in the lung so rational therapeutic approaches can be designed. A guinea pig model of trimellitic anhydride (TMA)-induced allergy will be used because it mimics many symptoms seen in the allergic human. Animals will be sensitized ID with TMA and 3 wk later challenged intratracheally with antigen (TMA coupled to serum albumin). Components of the immunotoxic response to TMA which will be monitored include: broncho-constriction and an immediate decrease in circulating platelets; increased airway microvascular and pulmonary vascular permeability; lung hemorrhage; and eosinophil, neutrophil and mononuclear cell infiltration into the lung. The hypothesis is that TMA-GPSA combines with cytophilic IgG1 and/or non-cytophilic IgG2 Ab in the airspace and/or the circulation to cause complement activation with a resultant decrease in circulating platelets: both of which are required for the immunotoxic response to TMA. TMA- GPSA-specific IgG1 and IgG2 will be measured by ELISA in the serum and bronchoalveolar lavage (BAL) of actively-sensitized animals and correlated with the immunotoxic response. The ability of purified IgG1/IgG2 Ab to mediate the immunotoxic response will be determined in passively-sensitized animals. To determine which antibody mediates complement participation, animals will be passively sensitized with IgG1 or IgG2, depleted of complement with Cobra Venom Factor, and the response to TMA assessed. To determine if complement activation occurs in the circulation or airspace, complement cleavage product C3a will be assayed in plasma and BAL by a Western blot method. In vitro studies will determine combinations of antigen, Ab, and BAL cells which result in C3a generation or BAL cell activation. An isolated tracheal preparation will be used to determine if antigen movement (with or without Ab and C) is limited by epithelial permeability. The importance of platelets will be assessed by determining if platelets sequester in the lung and whether depleting platelets or preventing their aggregation affects the immunotoxic response. These studies will determine if cytophilic Ab can evoke participation of the complement system and if cytophilic plus non-cytophilic Ab can predict the immunotoxic response.