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

描述(申请人提供)：肥大细胞来源于造血细胞 但在周围结缔组织中完成分化，在那里它们 被认为是免疫球蛋白E相关免疫中的重要效应细胞 回应。事实上，大量证据表明，肥大细胞介体 分泌物对这两种过敏性疾病都有重要作用，例如 过敏反应和哮喘，以及宿主对某些寄生虫的抵抗力。这个 该项目的长期目标是了解在多大程度上 白介素3的产生及其与白介素4的相互作用 受体a链(IL-4Rα)信号通路，调节发育和 肥大细胞的功能和体内的超敏反应。研究使用 IL-3缺陷小鼠表明IL-3有助于增加 感染某些寄生虫的小鼠的组织肥大细胞与免疫。 然而，IL-3影响IgE和肥大细胞相关免疫的能力 这些小鼠的反应还没有得到检验。因此，我们希望聘用 IL-3缺陷小鼠，以测试IL-3完全需要的假设 体内局部和全身过敏反应的表达。因为桅杆 细胞源性趋化因子是过敏反应中潜在的重要介质 对于炎症，我们还希望检验外源性IL-3可以 在没有或存在肥大细胞趋化因子时调节肥大细胞趋化因子的产生 免疫球蛋白和特异性抗原。 大量体外研究表明，IL-4可能与IL-3协同作用 控制肥大细胞在体内的发育和功能，以及最近的证据 提示IL-3和IL-4，可能还有IL-L3参与调节 接触性过敏症。研究小鼠品系将是有利的。 所有这些细胞因子的表达都被破坏了。不幸的是， 这些基因的紧密连锁排除了通过简单的杂交产生后代 同时缺乏这些细胞因子的小鼠品系。为了绕过这一点 困难我们将利用令人振奋的新机遇发展和 分析IL-3和IL-4ra(IL-4ra)联合缺乏的小鼠 IL-13R的成分)，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，我们将使用鼠标 同时缺乏IL-3和IL-4ra来分析对IL-3、IL-4和 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殖，以及3)调节 接触性超敏反应对半抗原的表达。

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.