Schistosome egg induced Th2 responses

描述（由申请方提供）：蠕虫寄生虫曼氏血吸虫寿命长，在其天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，寄生虫诱导的Th 2应答，如通过体外抗原刺激的T细胞增殖或细胞因子分泌测定所测量的，早期达到峰值，然后下降，尽管正在进行感染，这一过程被称为免疫调节。血吸虫病的免疫调节似乎在免疫系统无法消除病原体的情况下，在最大限度地减少免疫病理学方面发挥着至关重要的作用。在这里，我们建议探讨慢性血吸虫病的特征减少的Th 2反应的基础和功能意义。我们假设慢性病毒感染导致Th 2细胞功能障碍，类似于适应性耐受。我们建议通过三个具体目标来检验这一假设：1。使用IL-4报告小鼠表征整个感染过程中的Th 2细胞。2.确定慢性感染小鼠的Th 2细胞是否不可逆地功能失调，或者是否需要持续的环境信号来维持它们在这种状态。3.确定慢性感染期间免疫调节的机制。最近，使用4get和KN 2 IL-4报告小鼠，其中IL-4转录和蛋白质产生分别通过GFP和表面人CD 2的表达报道，我们已经能够明确地鉴定在感染期间应答并通过变得能够产生IL-4而致力于Th 2分化的CD 4 T细胞。这些细胞可以立即在体外检测到，甚至在原位检测到，这使我们能够在了解慢性血吸虫病期间发生的事情方面迈出重要的一步。总之，我们的研究有望产生新的见解的过程中，允许调节的Th 2反应在慢性血吸虫病，并可能与其他慢性蠕虫感染的Th 2细胞低反应性已被记录。我们认为，我们的工作有可能确定发达国家重要疾病的干预目标，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Th 2反应介导的。血吸虫病是一种重要的慢性热带疾病，由长寿寄生蠕虫引起。期间 在感染这种寄生虫的慢性阶段，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，将对其进行详细研究 提议我们认为，我们的工作有可能确定重要的干预目标， 发达国家的疾病，如哮喘、过敏和溃疡性结肠炎， 慢性、控制不良的Th 2反应。

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.