Schistosome egg induced Th2 responses

血吸虫卵诱导Th2反应

基本信息

批准号：
8239542
负责人：
EDWARD J. PEARCE
金额：
$ 37.24万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-11-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8239542
关键词：
Acute Antigens Asthma Biological Assay Bromodeoxyuridine CD4 Positive T Lymphocytes Cell Count Cell Separation Cell physiology Cells Chronic Commit Coupled Dendritic Cells Development Disease Environment Functional disorder Genetic Transcription Granuloma Helminthiasis Helminths Human Hypersensitivity Immune response Immune system In Situ In Vitro Infection Interleukin-10 Interleukin-13 Interleukin-4 Intervention Life Measures Mediating Molecular Profiling Mus Parasites Pathologic Pharmaceutical Preparations Phase Physiologic pulse Play Process Production Proliferating Property Proteins Regulation Regulatory T-Lymphocyte Reporter Reporting Resistance Role Schistosoma Schistosoma mansoni Schistosomiasis Signal Transduction Staging Surface T-Cell Proliferation Testing Th2 Cells Time Tissues Tropical Disease Ulcerative Colitis Work base cytokine egg falls immunopathology immunoregulation in vivo insight macrophage pathogen research study response

项目摘要

DESCRIPTION (provided by applicant): The helminth parasite Schistosoma mansoni is long lived, causing chronic infections in its natural human and experimental mouse hosts. It is recognized that during schistosomiasis the parasite-induced Th2 response, as measured by in vitro antigen-stimulated T cell proliferation or cytokine secretion assays, peaks early and then declines despite ongoing infection, a process that is referred to as immunomodulation. Immunomodulation in schistosomiasis appears to play a vital role in minimizing immunopathology in a setting where the immune system is incapable of eliminating the pathogen. Here we propose to explore the underlying basis and functional significance of the diminished Th2 responses that characterize chronic schistosomiasis. We hypothesize that chronic schistosome infection leads to a state of Th2 cell dysfunction akin to adaptive tolerance. We propose to test this hypothesis through three specific aims: 1. To use IL-4 reporter mice to characterize Th2 cells throughout infection. 2. To establish whether Th2 cells from chronically infected mice are irreversibly dysfunctional or whether ongoing environmental signals are required to maintain them in this state. 3. To identify the mechanism responsible for immunomodulation during chronic infection. Recently, using 4get and KN2 IL-4 reporter mice, in which IL-4 transcription and protein production are reported by the expression of GFP and surface human CD2 respectively, we have been able to unequivocally identify CD4 T cells that have responded during infection and committed to Th2 differentiation by becoming capable of making IL-4. These cells can be detected immediately ex-vivo, and indeed in situ, and have allowed us to make significant steps forward in understanding what is happening during chronic schistosomiasis. Together, our studies promise to generate new insights into the processes that allow the regulation of Th2 responses during chronic schistosomiasis and are likely to be of relevance to other chronic helminth infections where Th2 cell hyporesponsiveness has been documented. We believe that our work has the potential to identify targets for intervention in important diseases of the developed world, such as asthma, allergy and ulcerative colitis, that are mediated by chronic, poorly controlled Th2 responses. Schistosomiasis is an important chronic tropical disease caused by long-lived parasitic worms. During the chronic stage of infection with this parasite, the immune response is controlled and diminishes through mechanisms that are poorly understood and which will be investigated in details as part of this proposal. We believe that our work has the potential to identify targets for intervention in important diseases of the developed world, such as asthma, allergy and ulcerative colitis, that are mediated by chronic, poorly controlled Th2 responses.

描述（由申请人提供）：曼氏血吸虫是一种蠕虫寄生虫，寿命很长，会在自然人类和实验小鼠宿主中引起慢性感染。人们认识到，在血吸虫病期间，通过体外抗原刺激的 T 细胞增殖或细胞因子分泌测定来测量，寄生虫诱导的 Th2 反应在早期达到峰值，然后尽管持续感染，但随后下降，这一过程称为免疫调节。在免疫系统无法消除病原体的情况下，血吸虫病的免疫调节似乎在最大限度地减少免疫病理方面发挥着至关重要的作用。在这里，我们建议探索慢性血吸虫病特征的 Th2 反应减弱的根本基础和功能意义。我们假设慢性血吸虫感染会导致类似于适应性耐受的 Th2 细胞功能障碍状态。我们建议通过三个具体目标来检验这一假设： 1. 使用 IL-4 报告小鼠来表征整个感染过程中的 Th2 细胞。 2. 确定慢性感染小鼠的 Th2 细胞是否出现不可逆的功能障碍，或者是否需要持续的环境信号来维持它们的这种状态。 3. 确定慢性感染期间免疫调节的机制。最近，使用 4get 和 KN2 IL-4 报告小鼠（其中分别通过 GFP 和表面人 CD2 的表达来报告 IL-4 转录和蛋白质产生），我们已经能够明确识别在感染和感染过程中做出反应的 CD4 T 细胞。通过变得能够制造 IL-4 来致力于 Th2 分化。这些细胞可以立即在体外甚至在原位进行检测，使我们在了解慢性血吸虫病期间发生的情况方面取得了重大进展。总之，我们的研究有望对慢性血吸虫病期间 Th2 反应的调节过程产生新的见解，并且可能与已记录到 Th2 细胞反应低下的其他慢性蠕虫感染相关。我们相信，我们的工作有可能确定干预发达国家重要疾病的目标，例如哮喘、过敏和溃疡性结肠炎，这些疾病是由慢性、控制不良的 Th2 反应介导的。血吸虫病是由长寿寄生虫引起的一种重要的慢性热带疾病。期间在这种寄生虫感染的慢性阶段，免疫反应受到控制并减弱通过人们知之甚少的机制，作为本研究的一部分，将对其进行详细调查提议。我们相信，我们的工作有可能确定重要干预目标发达国家的疾病，如哮喘、过敏和溃疡性结肠炎，都是由慢性、控制不良的 Th2 反应。