Elucidating the tolerogenic roles of plasmacytoid dendritic cells in the gastrointestinal system.

项目摘要 本研究的目的是探讨浆细胞样树突状细胞(PDC)在急性髓细胞白血病中的作用。 在胃肠道系统内产生免疫耐受。PDC在病毒感染过程中的生物学研究 已经得到了很好的研究，很明显，这些细胞拥有促进快速和 对病毒核酸作出反应的I型促炎干扰素的强健产生。但是，在模型中 对于癌症、移植和过敏，PDC可以诱导耐受并抑制免疫反应。此外， 以前的研究表明，肠道相关的PDC可能会抑制炎症的产生 对通过饮食传递的抗原的反应。为了进一步阐明这些细胞的耐受功能， 我们建议调查PDC如何影响食物过敏模型。利用BDCA2-DTR转基因小鼠 可以在较长时间内特别耗尽PDC，我们将1)检查PDC对 稳定状态和口服耐受消除过程中的CD4T细胞对饮食抗原的反应 联合给予佐剂，以及2)评估PDC在致敏和效应阶段的作用 食物过敏和过敏反应的临床前模型。来自我们之前在过敏性接触模型中的研究 超敏反应，我们发现PDC耗竭通过改变先天和 变应原免疫反应的适应性阶段。因此，我们假设PDC将限制病理学。 在食物过敏模型中，通过影响粘膜对变应原的免疫反应和/或通过抑制 效应Th2细胞的分化。拟议的研究将提供更好的洞察 胃肠道过敏的发病机制，并可能导致改善预防或治疗方案 受这种疾病影响的人口不断增加。

Project Summary The objective of this research proposal is to examine the role of plasmacytoid dendritic cells (pDC) in the generation of immune tolerance within the gastrointestinal system. The biology of pDC during viral infection has been well studied, and it is clear that these cells possess cellular machinery that facilitates rapid and robust production of proinflammatory type I interferons in response to viral nucleic acids. However, in models of cancer, transplant, and allergy, pDC can induce tolerance and inhibit an immune response. Furthermore, previous studies have suggested that gut associated pDC may suppress the generation of inflammatory responses to antigens delivered through the diet. To further elucidate the tolerogenic function of these cells, we propose to investigate how pDC impact a model of food allergy. Using the BDCA2-DTR transgenic mice which can be specifically depleted of pDC for extended periods of time, we will 1) examine how pDC influence the CD4 T cell response to dietary antigens during steady state and during abrogation of oral tolerance through coadministration of adjuvant, and 2) evaluate the role of pDC within the sensitization and effector phases of a preclinical model of food allergy and anaphylaxis. From our previous studies in a model of allergic contact hypersensitivity, we have discovered that pDC depletion exacerbates pathology by altering the innate and adaptive phases of the immune response to allergen. Thus, we hypothesize that pDC will limit pathology in a model of food allergy by influencing the mucosal immune response to allergen and/or by inhibiting the differentiation of effector Th2 cells. The proposed research will provide better insight into the pathogenesis of gastrointestinal allergy and may lead to improved preventative or therapeutic options for the growing population affected by this disease.