Immune Responses to Giardia lamblia

对蓝氏贾第鞭毛虫的免疫反应

• 批准号: 7002264
• 负责人: STEVEN M SINGER
• 金额: $ 26.52万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7002264
• 关键词: Giardia; T lymphocyte; cellular immunity; defensins; disease /disorder proneness /risk; gastrointestinal epithelium; gene expression; genetically modified animals; helper T lymphocyte; immunocytochemistry; interleukin 6; interleukin 9; intracellular parasitism; laboratory mouse; mast cell; mucosal immunity; nitric oxide; northern blottings; pathologic process; polymerase chain reaction; protein biosynthesis; protooncogene; protozoal infection; stem cell factor

DESCRIPTION: (provided by the applicant):Giardia lamblia is a protozoan parasite which replicates in the small intestine of many species of mammals, and infections with G. lamblia are one of the most common human infections in the word. Most infections are self-limiting and acquired immune responses are essential for controlling G. lamblia infections in humans and other host species. Understanding the immune response to G. lamblia is therefore essential for better control of this disease. We have recently shown that B cell, gamma-delta T cell, IL-4 and IFN-gamma deficient mice can control acute infections with G. lamblia. In contrast, CD4+, alpha-beta T cells are required to control infections. Thus, a T cell-dependent, but antibody-independent. mechanism exists which can control G. lamblia. We have also shown that mast cell-deficient mice and IL-6 deficient mice cannot control G. lamblia infections. Also, in vitro studies have shown that nitric oxide and anti-microbial peptides known as defensins can inhibit G. lamblia. Based on these findings, the following hypothesis has been formulated: CD4+ T cells activate mast cells to produce IL-6 during G. lamblia infections. IL-6 production then leads to epithelial cell production of nitric oxide and defensins that control acute G. lamblia infections. We will test this hypothesis with the following specific aims: 1.To determine the importance of IL-6 production during G. lamblia infections. We will confirm the importance of IL-6 by treating immnunodeficjent mice with recombinant IL-6 during infections. IL-6 production will also be measured in vivo during infections in wild type and immunodeficient mice using RT-PCR. 2. To determine the importance of mast cell IL-6 production during G. lamblia infections. We will confirm the role of mast cells during infections by measuring mast cell responses during infections, by immuno-depletion of mast cells, and by reconstitution of mast cell deficient mice. We will examine mast cell production of IL-6 using immunohistochemistry and adoptive transfers. 3. To determine the mechanism of mast cell activation during G. lamblia infections. We will examine cytokine production by T cells in vivo and in vitro. We will also examine infections in cytokine deficient mice. We will examine intestinal epithelial cell (IEC) production of stem cell factor in vitro and in vivo. 4. To determine the mechanisms by which IL-6 production leads to control of acute G. lamblia infections. We will examine production of defensins and nitric oxide by IEC in vivo using RT-PCR and in vitro by Northern blots and biochemistry. Mice deficient in defensin expression and nitric oxide production will then be infected to determine their importance in controlling infections. Successful completion of these experiments will give us insights into immunity to G. lamblia, as well as developing this organism as a model system for understanding mucosal immune responses.

描述：（由申请方提供）：贾第鞭毛虫是一种原生动物 在许多哺乳动物的小肠中复制的寄生虫， 感染G.兰氏杆菌是最常见的人类感染之一， 这个词大多数感染是自限性的，获得性免疫反应是 控制G.人类和其他宿主中的兰氏杆菌感染 物种了解G.因此，Lamblia至关重要 为了更好地控制这种疾病。我们最近发现B细胞， γ-δ T细胞、IL-4和IFN-γ缺陷小鼠可以控制急性 感染G.兰布利亚相反，需要CD 4+、α-β T细胞 来控制感染。因此，T细胞依赖，但抗体不依赖。 存在一种控制G.兰布利亚。我们还表明，桅杆 细胞缺陷小鼠和IL-6缺陷小鼠不能控制G.蓝氏 感染.此外，体外研究表明，一氧化氮和 称为防御素的抗微生物肽可以抑制G.兰布利亚基于 根据这些发现，提出了以下假设：CD 4 + T细胞 G期激活肥大细胞产生IL-6。兰氏杆菌感染IL-6 然后产生导致上皮细胞产生一氧化氮， 控制急性G.兰氏杆菌感染我们将测试这个 假设，具体目标如下： 1.确定IL-6在G.兰氏杆菌感染 我们将证实IL-6的重要性， 重组IL-6。IL-6的产生也将在 使用RT-PCR在野生型和免疫缺陷小鼠中感染期间体内。 2.目的：探讨肥大细胞IL-6在G.蓝氏 感染.我们将证实肥大细胞在感染过程中的作用， 通过肥大细胞的免疫耗竭， 细胞，并通过重建肥大细胞缺陷小鼠。我们会检查桅杆 使用免疫组织化学和过继转移检测IL-6的细胞产生。 3.目的探讨G.蓝氏 感染.我们将研究T细胞在体内和体外的细胞因子产生。 体外我们还将检查细胞因子缺陷小鼠的感染。我们将 检查肠上皮细胞（IEC）生产干细胞因子， 体外和体内。 4.为了确定IL-6的产生导致控制的机制， 急性G.兰氏杆菌感染我们将研究防御素和硝酸的生产 通过IEC在体内使用RT-PCR和在体外通过北方印迹和 生物化学防御素表达和一氧化氮产生缺陷的小鼠 将被感染，以确定它们在控制感染方面的重要性。 成功完成这些实验将使我们深入了解免疫 与g Lamblia，以及开发这种生物体作为模型系统， 了解粘膜免疫反应。