Regulation of food allergy and anaphylaxis by IL 33

描述(申请人提供)：IL-33是最近发现的IL-1细胞因子家族的成员。重组IL-33的应用已被证明对多种疾病有深远的影响，包括通过其受体ST2介导的关节炎、感染和过敏。几种不同类型的细胞都表达IL-33，我们和其他人已经证明，上皮细胞具有高结构性表达，并在损伤时释放它。因此，IL-33被称为“警报蛋白”，对组织细胞和免疫反应之间的交流非常重要。然而，我们已经证明，炎症细胞，如肥大细胞[和树突状细胞]，在静止时水平较低，但在激活时被诱导表达IL-33。这些不同来源的IL-33的功能后果还没有被研究，确定这些是我们研究的基础。我们的初步数据表明，ST2对于过敏原的敏化以及当敏化被绕过时有效地启动炎症反应都是必要的。有趣的是，我们的发现表明，ST2只需要通过肠道致敏，通过注射相同的抗原，ST2KO小鼠能够变得过敏。我们假设上皮细胞是驱动过敏性致敏的IL-33的必要来源，而肥大细胞衍生的IL-33是致敏发生后炎症的关键信号。我们将使用我们建立的食物过敏和过敏反应的小鼠模型来检验这一假设。由于食物过敏的患病率正在增加，而目前可用的治疗方案很少，我们的工作有可能促进这些患者的新疗法。我们建议用两个不同的具体目标来测试我们的假设，这两个目标涉及1)敏化和2)诱发过敏反应的总体主题。这些目标是：特定目标1：确定细胞特异性IL-33表达在花生特异性抗体产生和T细胞反应中的作用。具体目标2：确定IL-33调节组织对过敏原的炎症产生的机制。

DESCRIPTION (provided by applicant): IL-33 is a recently discovered member of the IL-1 family of cytokines. Administration of recombinant IL-33 has been shown to have profound effects on a diverse range of diseases, including arthritis, infection and allergy that are mediate though its receptor ST2. Several different cell types have been shown to express IL-33 and we, and others, have shown that epithelial cells have a high constitutive expression and release it during damage. Consequently, IL-33 has been coined an "alarmin", important for the communication between tissue cells and the immune response. However, we have demonstrated that inflammatory cells, such as mast cells [and dendritic cells], have low levels at rest but are induced to express IL-33 upon their activation. The functional consequences of these different sources of IL-33 have not been studied and determining these is the basis for our study. Our preliminary data establishes that ST2 is necessary for both the sensitization to allergens, as well as efficiently mounting an inflammatory response when sensitization in bypassed. Interestingly, our findings show that ST2 is only required for sensitization through the intestine and that, by injecting the same antigen, ST2 KO mice are capable of becoming allergic. We hypothesize that epithelial cells are the necessary source of IL-33 that drives allergic sensitization while mast cell-derived IL-33 is the critical signal for inflammation after sensitization has occurred. We will examine this hypothesis using murine models of food allergy and anaphylaxis that we have developed. Since food allergy is increasing in prevalence and there are very few therapeutic options available at this time, our work has the potential to facilitate new therapies for these patients. We propose to test our hypothesis with two distinct specific aims that address the overall theme of 1) sensitization and 2) elicitation of allergic responses. These aims are: Specific Aim 1: Determine the role of cell-specific IL-33 expression in the generation of peanut-specific antibody and T cell responses. Specific Aim 2: Determine the mechanisms through which IL-33 regulates the generation of tissue inflammation to allergens.