SUPPRESSION OF IMMUNOPATHOLOGY IN SCHISTOSOMIASIS BY DAB

DAB 对血吸虫病免疫病理学的抑制

• 批准号: 2429424
• 负责人: S M PHILLIPS
• 金额: $ 23.13万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-01 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2429424
• 关键词: Schistosoma mansoni; T lymphocyte; cellular immunity; chimeric proteins; cytokine; diphtheria toxin; disease /disorder model; disease /disorder prevention /control; drug screening /evaluation; enzyme linked immunosorbent assay; epitope mapping; helminthic antigen; humoral immunity; immunopathology; immunosuppression; immunotherapy; interleukin 2; laboratory mouse; nonhuman therapy evaluation; polymerase chain reaction; schistosomiasis

Schistosomiasis causes pathology in an estimated 190 million individuals. Clinical disease is caused by a complex immunopathologic response to the parasite ova, which are deposited in the host tissues. This immunopathologic response is composed of two major elements, granulomas and hepatic fibrosis. These two elements are regulated by discrete populations of T lymphocytes through the production of inflammatory cytokines and growth factors. Therefore methods designed to influence T cell activation and subsequent cytokine release may reduce immunopathology. However, these approaches often are predicted on restricted T cell gene usage, genetic restriction, and precise epitopic definition. Therefore, the practicality of these approaches is limited in the human population because of the genetic heterogeneity of the human immune response. We propose to study a fusion toxin, DAB-IL-2. This mode of immunosuppression is not genetically restricted and preferentially attacks Schistosoma mansoni, Soluble Egg Antigen specific activated T cells. DAB-IL-2 is a Diphtheria toxin-IL-2 chimeric protein. When SEA activated T cells, the cells express the IL_2 high affinity receptor. The receptor binds the toxin and internalizes it. The cells are inactivated or killed and are no longer able to participate in the induction and/or the maintenance of egg-associated immunopathology. This approach provides a model which is relatively independent of genetic restriction and precise epitopic definition. DAB-IL-2 fusion toxin will be used to prevent the development and/or promote the resolution of immunopathology. We will define the efficacy, safety, and mechanisms of action of DAB-IL-2 in murine schistosomiasis mansoni. The mechanisms of suppression will be defined by studies on clonal deletion and subpopulation/cytokine regulation. DAB-IL-2 has been used safely and successfully in man to treat rheumatoid arthritis and juvenile onset diabetes mellitus. The immunopathology of these diseases has many analogies to the immunopathology of schistosomiasis. These studies will provide information on the genesis and treatment of schistosomiasis and facilitate the targeted reduction of immunopathology in man.

血吸虫病在估计的1.9亿人中导致病理学。 临床疾病是由于对 寄生虫OVA，沉积在宿主组织中。 这 免疫病理反应由两个主要元素，颗粒组成 和肝纤维化。 这两个要素受离散调节 通过产生炎症的T淋巴细胞种群 细胞因子和生长因素。 因此旨在影响影响的方法 T细胞激活和随后的细胞因子释放可能会减少 免疫病理学。但是，这些方法经常被预测 受限的T细胞基因使用情况，遗传限制和精确的表现 定义。 因此，这些方法的实用性是有限的 在人口中，由于人类的遗传异质性 免疫反应。 我们建议研究融合毒素Dab-il-2。 这 免疫抑制模式没有遗传限制，并且 优先攻击血吸虫，可溶性卵抗原特异性 活化的T细胞。 DAB-IL-2是白喉毒素-IL-2嵌合蛋白。 当海洋激活T细胞时，细胞表达IL_2高亲和力 受体。 受体结合毒素并将其内在化。 细胞 被灭活或杀死，不再能够参加 诱导和/或维持与卵相关的免疫病理学。 这 方法提供了一个相对独立于遗传的模型 限制和精确的表现定义。 DAB-IL-2融合毒素将 用于防止开发和/或促进解决方案 免疫病理学。 我们将定义功效，安全性和机制 DAB-IL-2在鼠血吸虫病Mansoni中的作用。 机制 抑制作用将通过对克隆缺失和 亚群/细胞因子调节。 DAB-IL-2已安全使用，并且 成功地治疗类风湿关节炎和少年发作 糖尿病。 这些疾病的免疫病理学有很多 类似于血吸虫病的免疫病理学。 这些研究会 提供有关血吸虫病的起源和治疗的信息 促进人类免疫病理学的靶向降低。