Modulation of cellular and humoral immune response to third party antigens in nematode-infected mice

线虫感染小鼠对第三方抗原的细胞和体液免疫反应的调节

• 批准号: 225759336
• 负责人: Professorin Dr. Minka Breloer
• 金额: --
• 依托单位: Arbeitsgruppe Helminthen-Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/225759336?language=en
• 关键词: Modulation; cellular; humoral; immune; response

One third of the human population is infected with helminth parasites. To avoid their expulsion and to limit pathology, helminths have developed sophisticated strategies to suppress and modulate the immune response of their hosts. As this immune suppression spills over to unrelated third-party antigens, a preexisting helminth infection may interfere with vaccination efficacy. We have shown before that transient infection of mice with Strongyloides ratti induced a diversion of antibody responses to model antigen vaccination towards a type 2 phenotype whereas a long lasting infection with Litomosoides sigmodontis led to a generalized suppression of all types of antibody responses. The observed suppression of antibody response was not mediated by direct interference with antibody-producing B cells but predominantly by interference with T helper cell function. In the current application we will use L. sigmodontis-infected mice to elucidate the molecular mechanisms leading to nematode-induced interference with T cell function and T cell dependent B cell responses. In the first part of this application we focus on modulated antibody response during nematode infection. We intend to compare the antibody response to model antigen vaccination in mice at different stages of L. sigmodontis infection, after spontaneous clearance of infection and after drug induced abortion of infection. We intend to search for adjuvants that render vaccinations functional despite a preexisting L. sigmodontis infection and we will analyze the phenotype of follicular T helper cells in detail. In the second part of this application we focus on the modulated T cell response during nematode infection. We will compare the proliferation and the effector functions of adoptively transferred T cell receptor transgenic ovalbumin-specific CD4+ T helper cells (OT-II) and CD8+ cytotoxic T cells (OT-I) within naïve and L. sigmodontis infected mice. Thereby we intend to analyze the role of regulatory cytokines, regulatory receptors and regulatory cell populations in the mediation of nematode-induced T cell suppression. In conclusion we expect to unravel the chain of events leading from established nematode infection to reduced vaccination efficacy. Based on the information gained, we intend to develop vaccination regimes that are functional on the background of preexisting helminth infections in the mouse model. These results may also be useful to develop functional vaccinations for the human population in helminth endemic areas.

三分之一的人口感染了蠕虫寄生虫。为了避免它们的驱逐和限制病理，蠕虫已经发展了复杂的策略来抑制和调节宿主的免疫反应。由于这种免疫抑制溢出到无关的第三方抗原，预先存在的蠕虫感染可能会干扰疫苗接种效果。我们已经表明，鼠与圆线虫的短暂感染诱导的抗体反应转向模型抗原疫苗接种对2型表型，而持久的感染与Litomosoides sigmodontis导致的所有类型的抗体反应的普遍抑制。观察到的抗体反应抑制不是通过直接干扰产生抗体的B细胞介导的，而是主要通过干扰T辅助细胞功能介导的。在当前应用程序中，我们将使用L。sigmodontis感染的小鼠，以阐明导致线虫诱导的干扰T细胞功能和T细胞依赖性B细胞应答的分子机制。在本申请的第一部分中，我们关注线虫感染期间的调制抗体应答。我们打算比较不同阶段的小鼠对模型抗原接种的抗体应答。乙状结肠炎感染、自发清除后感染和药物流产后感染。我们打算寻找佐剂，使疫苗的功能，尽管预先存在的L。sigmodontis感染，我们将详细分析滤泡T辅助细胞的表型。在本申请的第二部分中，我们专注于线虫感染期间的调制T细胞反应。我们将比较过继转移的T细胞受体转基因卵清蛋白特异性CD 4 + T辅助细胞（OT-II）和CD 8+细胞毒性T细胞（OT-I）在幼稚和L. sigmodontis感染小鼠。因此，我们打算分析的作用，调节细胞因子，调节受体和调节细胞群体在介导的线虫诱导的T细胞抑制。总之，我们希望解开从确定的线虫感染导致疫苗接种效力降低的事件链。基于所获得的信息，我们打算开发在小鼠模型中预先存在蠕虫感染的背景下起作用的疫苗接种方案。这些结果也可能是有用的蠕虫流行区的人群开发功能性疫苗。