SUPPRESSION OF IMMUNOPATHOLOGY IN SCHISTOSMIASIS BY ANTI

抗血吸虫病的免疫病理学抑制

• 批准号: 6374401
• 负责人: S M PHILLIPS
• 金额: $ 20.01万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2002-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6374401
• 关键词: B lymphocyte; RNase protection assay; Schistosoma mansoni; T lymphocyte; antibody specificity; antigen antibody reaction; antigen presentation; apoptosis; artificial immunosuppression; cytokine; daunorubicin; drug screening /evaluation; flow cytometry; immunoconjugates; immunofluorescence technique; immunopathology; immunotherapy; laboratory mouse; leukocyte activation /transformation; nonhuman therapy evaluation; protein biosynthesis; schistosomiasis; statistics /biometry; tissue /cell culture

Schistosomiasis causes disease in nearly 200 million people. Clinical disease hepatic granulomas and fibrosis, result from an immunopathologic response to the parasite ova. We have developed an approach to target this pathological immune response, a fusion toxin, composed of antigen(Ag) derived from S. mansoni and the cytotoxic agent, daunomycin(Dm). This fusion toxin prevents immunopathology in an immunologically specific manner, avoiding the deleterious consequences of nonspecific immune suppression. Ag-Dm will be used alone and in conjunction with anthelminthic cure by Praziquantel to simulate its projected use in human disease. First, we will study the efficacy, safety, and specificity of action of Ag-Dm in murine schistosomiasis mansoni. Next we will study the mechanisms of action of Ag-Dm and its consequences on the host immune response. Because our initial studies suggest that Ag-Dm works by suppressing antigen presentation, we will first study the effects of Ag-Dm on B cell and macrophage antigen-presentation in mutant mice. Since antigen presentation results in skewing the immune response toward Th2 dominance, we next will examine the consequences of Ag-Dm treatment on discrete subpopulations of T cells. We will measure cell cycle and activation kinetics, cytokine production, and apoptosis. We will compare the effects of Ag-Dm on the systemic immune response and on the unique microenvironment within the granulomas. These studies are necessary to optimize the safety and efficacy of Ag-Dm for subsequent use in infected people. Defining the mechanisms of immunologic regulation by Ag-Dm will allow us to better target immunopathology and reduce immunopathology in humans.

血吸虫病引起近2亿人的疾病。临床疾病肝肉芽肿和纤维化是由对寄生虫OVA的免疫病理反应引起的。 我们已经开发了一种方法来靶向这种病理免疫反应，一种融合毒素，该毒素由源自链球菌的抗原（Ag）和细胞毒性剂Daunomycin（DM）组成。 这种融合毒素以免疫学特异性的方式阻止了免疫病理学，避免了非特异性免疫抑制的有害后果。 AG-DM将单独使用，并与Praziquantel一起使用Anthelminthic Cure来模拟其在人类疾病中的预计用途。 首先，我们将研究AG-DM在鼠血吸虫病Mansoni中的作用的疗效，安全性和特异性。接下来，我们将研究AG-DM的作用机理及其对宿主免疫反应的后果。 由于我们的初步研究表明AG-DM通过抑制抗原表现而起作用，因此我们将首先研究AG-DM对突变小鼠中B细胞和巨噬细胞抗原 - 体现的影响。 由于抗原表现会导致对Th2优势的免疫反应偏向，因此我们接下来将检查AG-DM治疗对T细胞离散亚群的后果。 我们将测量细胞周期和激活动力学，细胞因子产生和凋亡。 我们将比较AG-DM对系统性免疫反应以及颗粒中独特的微环境的影响。 这些研究对于优化AG-DM的安全性和有效性是在感染者中的随后使用所必需的。 定义AG-DM的免疫调节机制将使我们能够更好地靶向免疫病理学并减少人类的免疫病理学。