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）：长期以来，Helminth寄生虫血吸虫寿命长，导致其自然人类和实验小鼠宿主的慢性感染。人们认识到，在血吸虫病期间，寄生虫诱导的Th2反应，如体外抗原刺激的T细胞增殖或细胞因子分泌测定法测量，尽早达到峰值，然后下降，尽管持续感染，这一过程被称为免疫调节。血吸虫病中的免疫调节似乎在最小化免疫病理学的情况下似乎起着至关重要的作用，在免疫系统无法消除病原体的情况下。在这里，我们建议探讨表征慢性血吸虫病的Th2反应减少的基础和功能意义。我们假设慢性血块感染会导致Th2细胞功能障碍的状态，类似于适应性耐受性。我们建议通过三个特定目的检验这一假设：1。使用IL-4记者小鼠在整个感染过程中表征Th2细胞。 2。确定来自长期感染小鼠的Th2细胞是否具有不可逆转的功能失调，或者是否需要持续的环境信号以维持在这种状态。 3。确定负责在慢性感染期间免疫调节的机制。最近，使用4GET和KN2 IL-4报告基因小鼠，其中分别通过GFP和表面人CD2的表达来报告IL-4转录和蛋白质的产生，我们能够明确地识别在感染过程中对TH2差异响应的CD4 T细胞，并通过使IL-4能够使TH2差异化。可以立即检测到这些细胞，并实际上是原位，并使我们能够在理解慢性血吸虫病期间发生的事情方面迈出了重要一步。我们的研究共同承诺将对允许调节慢性血吸虫病中Th2反应的过程产生新的见解，并可能与其他慢性蠕虫感染有关，这些慢性蠕虫感染已记录了Th2细胞的低调。我们认为，我们的工作有可能识别出由哮喘，过敏和溃疡性结肠炎等发达国家干预的目标，这些疾病是由慢性，控制不良的TH2反应介导的。血吸虫病是由长寿命寄生虫引起的重要慢性热带疾病。期间这种寄生虫感染的慢性阶段，免疫反应得到控制并减少通过知之甚少的机制，并将在此详细研究。提议。我们认为，我们的工作有可能确定干预重要的目标发达国家的疾病，例如哮喘，过敏和溃疡性结肠炎，这些疾病由慢性，控制不良的TH2响应。