Induced tolerogenic dendritic cell therapy of allergic diseases

T细胞介导针对自身和非自身抗原(AGS)的免疫反应，包括无害的环境AGS，有时被错误地解释为“危险的”。Th2极化效应T细胞对某些环境抗原的误导反应，称为过敏原，促进体液和细胞炎症反应的形成，从而引发临床症状，这些症状变成 表现为各种形式的过敏或哮喘。目前的临床实践采用治疗策略来耐受过敏患者对特定过敏原的影响，这表明，至少在某些情况下，可以对先前存在的病理性Th2反应进行再教育，从而获得永久治愈。然而，目前的免疫治疗方案通常需要数月的持续治疗，在相当一部分患者中不成功，并带有不良事件的风险，特别是过敏反应。项目3建议探索使用诱导耐受树突状细胞(ITDC)作为一种替代策略，以快速实现过敏性哮喘或食物过敏患者的过敏原特异性免疫耐受。 这个项目的基本原理是基于这样一个事实，即T细胞的功能由树突状细胞(DC)控制，树突状细胞获得并处理AGS，并根据其成熟和分化状态指示Ag特异性T细胞启动效应反应或产生耐受。大量的初步数据 表明小鼠和人DC短期暴露于雷帕霉素和转化生长因子B(TGFb)可将细胞转化为ITDC。初步的体外和体内实验表明，Ag冲击的ITDC通过将其转化为Foxp3+而对Ag特异性的常规T细胞起到耐受作用 调节性T细胞(Treg)和b)通过删除抗原挑战位点的Teff.根据这些发现，ITDC可能有助于治疗T细胞依赖型过敏性疾病的假设将得到检验。为了实现这一目标，目标1将确定ITDC是否以及在多大程度上对AgDrive小鼠模型发挥治疗作用 过敏性哮喘和食物过敏。目的2通过系统地探索患者来源的DC在自体T细胞亚群中诱导耐受反应的能力，将产生关于小鼠模型的研究结果对人类食物过敏和过敏性哮喘的临床可译性的关键线索。这些实验将与项目1和2密切协同进行，并依赖于技术、材料和 来自本计划每个核心的支持。如果我们的假设被证明是正确的，我们的目标将是将ITDC技术转化为食物过敏和哮喘的细胞治疗的临床平台。

T cells mediate immune responses against self and non-self antigens (Ags), including innocuous environmental Ags, which are sometimes erroneously interpreted as 'dangerous'. Misguided responses by Th2 polarized effector T cells (Teff) against certain environmental Ags, called allergens, promote the formation of humoral and cellular inflammatory responses that precipitate clinical symptoms, which become manifest as various forms of allergy or asthma. Current clinical practice employs therapeutic strategies to tolerize allergic patients against specific allergens, indicating that pre-existing pathological Th2 responses can be 're-educated' resulting, at least in some cases, in permanent cures. However, current immunotherapy schemes typically require many months of continuous treatment, are unsuccessful in a sizable fraction of patients and carry the risk of adverse events, particularly anaphylaxis. Project 3 proposes to explore the use of induced tolerogenic dendritic cells (itDC) as an alternative strategy to rapidly achieve allergen-specific immunological tolerance in individuals suffering from allergic asthma or food allergy. The rationale for this project is based on the fact that T cell function is controlled by dendritic cells (DC), which acquire and process Ags and, depending upon their maturation and differentiation status, instruct Agspecific T cells either to mount an effector response or to develop tolerance. A body of preliminary data indicates that short-term exposure of murine as well as human DC to rapamycin and transforming growth factor B (TGFB) coverts the cells into itDC. Preliminary in vitro and in vivo experiments suggest that Ag-pulsed itDC exert tolerogenic effects on Ag-specific conventional T cells a) by converting them into Foxp3+ regulatory T cells (Treg) and b) by deleting Teff at sites of Ag challenge. In light of these findings, the hypothesis will be tested that itDC may be useful to treat T cell-dependent allergic diseases. To achieve this goal, Aim 1 will establish whether and to what extent itDC exert therapeutic effects in mouse models of Agdriven allergic asthma and food allergy. Aim 2 will generate critical clues regarding the clinical translatability of findings in murine models to human food allergy and allergic asthma by systematically exploring the capacity of patient-derived DC to induce tolerogenic responses in autologous T cell subsets. These experiments will be performed in close synergy with Projects 1 and 2 and rely on technology, materials and support from each Core of this Program. If our hypothesis can be proven correct, our objective will be to translate the itDC technology into a clinical platform for cellular therapy of food allergy and asthma.