IMMUNOTOXICITY OF ACID ANHYDRIDES IN THE LUNG

酸酐在肺中的免疫毒性

• 批准号: 2749675
• 负责人: JEAN F. REGAL
• 金额: $ 18.77万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2749675
• 关键词: chemical hydration; chemical hypersensitivity; complement pathway; diagnostic respiratory lavage; enzyme linked immunosorbent assay; guinea pigs; immunoglobulin G; immunotoxicity; phthalates; platelet activation; reptile poison; respiratory hypersensitivity; western blottings

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.

描述：（改编自研究者摘要）酸 酸酐，用于许多行业，导致免疫毒性 过敏反应。 长期目标是了解机制 肺中酸酐的免疫毒性， 可以设计治疗方法。 豚鼠模型 偏苯三酸酐（TMA）引起的过敏将被使用，因为它 与过敏性人类的许多症状相似。 动物将 用TMA致敏ID，3周后用 抗原（TMA偶联至血清白蛋白）。 免疫毒性成分 将被监测的对TMA的反应包括：支气管收缩和 循环血小板立即减少;气道增加 微血管和肺血管通透性;肺出血;和 嗜酸性粒细胞、中性粒细胞和单核细胞浸润到肺中。 假设TMA-GPSA与亲细胞性IgG 1和/或IgG 2结合， 空域和/或循环中的非嗜细胞性IgG 2 Ab， 补体激活导致循环血小板减少： 这两者都是对TMA的免疫毒性反应所需要的。 TMA- 将通过ELISA测量血清中的GPSA特异性IgG 1和IgG 2， 活性致敏动物的支气管肺泡灌洗（BAL）， 与免疫毒性反应相关。 净化能力 将测定介导免疫毒性反应的IgG 1/IgG 2 Ab， 被动致敏的动物为了确定哪种抗体介导 补体参与，动物将用IgG 1被动致敏 或IgG 2，用眼镜蛇毒因子耗尽补体， 对TMA的反应进行评估。 为了确定补体激活是否发生 在循环或空气中，补体裂解产物C3 a将被 通过蛋白质印迹法在血浆和BAL中测定。体外研究 将确定抗原、Ab和BAL细胞的组合， 在C3 a代或BAL细胞活化中。 一个孤立的气管 制备将用于确定抗原移动（具有或 不含Ab和C）受上皮渗透性限制。 的重要性 将通过确定血小板是否隔离在 以及是否消耗血小板或防止其聚集 影响免疫毒性反应。 这些研究将确定， 嗜细胞抗体可以引起补体系统的参与，如果 嗜细胞性和非嗜细胞性抗体可以预测免疫毒性反应。