Regulation of food allergy and anaphylaxis by IL 33

描述（由申请人提供）：IL-33是最近发现的细胞因子IL-1家族的成员。已证明重组IL-33的施用对多种疾病具有深远的影响，包括通过其受体ST 2介导的关节炎、感染和过敏。几种不同的细胞类型已被证明表达IL-33，我们和其他人已经表明，上皮细胞具有高组成型表达，并在损伤期间释放它。因此，IL-33被称为“警报素”，对组织细胞和免疫应答之间的通讯很重要。然而，我们已经证明，炎性细胞，如肥大细胞[和树突状细胞]，在休息时具有低水平，但在激活时被诱导表达IL-33。这些不同来源的IL-33的功能后果尚未研究，确定这些是我们研究的基础。我们的初步数据确定，ST 2是必要的过敏原的敏化，以及有效地安装炎症反应时，敏化绕过。有趣的是，我们的研究结果表明，ST 2仅需要通过肠道致敏，并且通过注射相同的抗原，ST 2 KO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。我们将使用我们开发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，目前可用的治疗选择很少，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检验我们的假设，这两个目标涉及1）致敏和2）引发过敏反应的总体主题。这些目标是：具体目标1：确定细胞特异性IL-33表达在花生特异性抗体和T细胞应答产生中的作用。具体目标2：确定IL-33调节过敏原组织炎症产生的机制。

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.