IL-3 and IL-4R in Mast Cell Growth and Hypersensitivity

IL-3 和 IL-4R 在肥大细胞生长和超敏反应中的作用

• 批准号: 6356075
• 负责人: CHRIS Steven LANTZ
• 金额: $ 12.19万
• 依托单位: JAMES MADISON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2005-08-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6356075
• 关键词: anaphylaxis; biological models; biological signal transduction; cell differentiation; cell growth regulation; cell population study; chemokine; contact dermatitis; gene expression; genetically modified animals; hematopoiesis; hypersensitivity; immunogenetics; immunoregulation; interleukin 13; interleukin 3; interleukin 4; laboratory mouse; mast cell; mastocytosis; model design /development; parasitic diseases; protein structure function; recombinant proteins; secretory immune system

DESCRIPTION (provided by the applicant): Mast cells are of hematopoietic origin but complete their differentiation in peripheral connective tissues where they are thought to function as important effector cells in IgE-associated immune responses. Indeed, a large body of evidence indicates that mast cell mediator secretion significantly contributes to both allergic disorders, such as anaphylaxis and asthma, and to host resistance to certain parasites. The long-term objectives of this project are to understand to what extent the production of interleukin (IL)-3, and interactions between IL-3 and IL-4 receptor a chain (IL-4R alpha) signaling pathways, regulate the development and function of mast cells, and hypersensitivity responses in vivo. Studies using IL-3-deficient mice indicate that IL-3 contributes to increased numbers of tissue mast cells and immunity in mice infected with certain parasites. However, the ability of IL-3 to influence IgE- and mast cell-associated immune responses has not yet been examined in these mice. Therefore, we wish to employ IL-3-deficient mice to test the hypotheses that IL-3 is required for the full expression of local and systemic anaphylactic responses in vivo. Because mast cell-derived chemokines represent potentially important mediators in allergic inflammation, we also wish to test the hypothesis that exogenous IL-3 can regulate mast cell chemokine production either in the absence or presence of IgE and specific antigen. Numerous in vitro studies have suggested that IL-4 may act in concert with IL-3 to control mast cell development and function in vivo, and recent evidence suggests that IL-3 and IL-4, and perhaps IL-l3, are involved in regulating contact hypersensitivity. It would be advantageous to study mouse lines in which the expression of all of these cytokines is disrupted. Unfortunately, the close linkage of these genes precludes the generation by simple interbreeding of mouse lines that simultaneously lack these cytokines. To circumvent this difficulty we will take advantage of an exciting new opportunity to develop and analyze mice with a combined deficiency of IL-3 and IL-4Ra (IL-4Ra is also a component of IL-13R), thereby allowing us to investigate the potential compensatory roles of these cytokines in vivo. Specifically, we will use mice deficient in both IL-3 and IL-4Ra to analyze the requirement of IL-3, IL-4, and IL-13 for: 1) generating physiological levels of tissue mast cells, 2) gastrointestinal parasite-induced mast cell hyperplasia, and 3) regulating the expression of contact hypersensitivity reactions to haptens.

性状（由申请方提供）：肥大细胞为造血来源 但在外周结缔组织中完成分化， 被认为在IgE相关免疫中作为重要的效应细胞发挥作用 应答事实上，大量证据表明肥大细胞介质 分泌物显著地促成两种过敏性疾病，例如 过敏反应和哮喘，以及宿主对某些寄生虫的抵抗力。的 该项目的长期目标是了解在多大程度上 白细胞介素（IL）-3的产生，以及IL-3和IL-4之间的相互作用 受体α链（IL-4 R α）信号通路，调节发育和 肥大细胞的功能和体内超敏反应。研究使用 IL-3缺陷小鼠表明IL-3有助于增加细胞凋亡的数量。 组织肥大细胞和某些寄生虫感染的小鼠的免疫。 然而，IL-3影响IgE和肥大细胞相关免疫的能力， 尚未在这些小鼠中检查反应。因此，我们希望雇用 IL-3缺陷小鼠，以测试IL-3是完全免疫所需的假设。 体内局部和全身过敏反应的表达。因为马斯特 细胞源性趋化因子是过敏性疾病中潜在的重要介质 我们还希望检验外源性IL-3可以 调节肥大细胞趋化因子的产生，无论是在缺乏或存在 IgE和特异性抗原。 大量体外研究表明，IL-4可能与IL-3协同作用， 在体内控制肥大细胞的发育和功能， 表明IL-3和IL-4，可能还有IL-13，参与调节 接触性过敏研究小鼠品系， 所有这些细胞因子的表达都被破坏。可惜 这些基因的紧密连锁排除了简单杂交的世代 同时缺乏这些细胞因子的小鼠品系。为了规避这个 困难，我们将利用一个令人兴奋的新机会，发展和 分析IL-3和IL-4 Ra联合缺乏的小鼠（IL-4 Ra也是一种 IL-13 R的组成部分），从而使我们能够研究 这些细胞因子在体内的代偿作用。具体来说，我们将使用老鼠 缺乏IL-3和IL-4 Ra两者，以分析对IL-3、IL-4和IL-10的需求。 IL-13用于：1）产生生理水平的组织肥大细胞，2） 胃肠道寄生虫诱导的肥大细胞增生，和3）调节 对半抗原的接触性超敏反应的表达。

项目成果

Absence of interleukin-3 does not affect the severity of local and systemic anaphylaxis but does enhance eosinophil infiltration in a mouse model of allergic peritonitis.

• DOI: 10.1016/j.imlet.2004.06.002
• 发表时间: 2004-08
• 期刊: Immunology letters
• 影响因子: 4.4
• 作者: N. Neel;B. Creasy;Jennifer N Rankin;E. M. Pierce;M. McCoy;Rebecca H Daner;J. Fowler;J. Daniel;C. Lantz