Analyses of interactions between innate and adaptive immunity during contact allergen-specific immune responses

接触过敏原特异性免疫反应期间先天免疫和适应性免疫之间相互作用的分析

• 批准号: 236648302
• 负责人: Professorin Dr. Kerstin Steinbrink
• 金额: --
• 依托单位: Klinik für Hautkrankheiten
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/236648302?language=en
• 关键词: Analyses; interactions; between; innate; adaptive

The allergic contact dermatitis is one of the most frequent occupational dermatological diseases and forces a restricted quality of life in affected patients and high socio-economic costs. In the last decades the well-established murine model of contact hypersensitivity has allowed for analysis of the underlying immune mechanisms of the allergic skin reaction. However, effective strategies for preventive and long-lasting therapeutic strategies of the allergic contact dermatitis are still lacking. In our work, we have focused on the induction of specific immune tolerance. One goal is the analysis of the murine model of low zone tolerance (LZT) to contact allergens which resembles the physiologic epicutaneous exposure to low sub-immunogenic amounts of allergens in everyday live of humans. We found that during the induction phase of LZT regulatory CD4+CD25+Foxp3+ T cells induce tolerogenic CD11c+ dendritic cells DC which are required for the generation hapten-specific LZT regulatory CD8+ T cells. Thereafter, these regulatory T cells induce an increased TNF production of CD11c+CD8+ DC. Apoptosis of effector CD8+ T cells of the CHS is driven by this cytokine resulting in prevention of the allergic skin immune response. Recently, it was demonstrated that contact allergens/haptens directley or indirectly activated processes of the innate immunity (e.g. by activation of pattern recognition receptors [PRR]) that were critical for the allergic immune response. In contrast, mechanisms of the innate immunity (cell-related: neutrophils, macrophages, etc. or PRR-related) have not yet been explored in tolerance reactions to contact allergens. Therefore, we envisage to analyze the function of the innate immunity in contact allergen-/hapten-specific immune tolerance reactions (epicutaneous and oral LZT) and their interaction with mechanisms of the adaptive immunity. We intend to focus on the activation of regulatory T cells and their interaction with tolerogenic DC resulting in induction of hapten-specific tolerance reactions. Analyses of processes of the innate immunity will encompass the function of immune cells (neutrophils, myeloid-derived cells) and PRR-related mechanisms (with focus on TLR2) to evaluate their functions in hapten-specifc tolerance. The results of the applied project may identify novel targets for the modulation and prevention of allergic immune responses.

过敏性接触性皮炎是最常见的职业性皮肤病之一，严重影响患者的生活质量和社会经济成本。在过去的几十年里，成熟的接触性超敏反应小鼠模型已经为分析皮肤过敏反应的潜在免疫机制提供了条件。然而，对于变态反应性接触性皮炎的预防和长效治疗策略仍然缺乏有效的策略。在我们的工作中，我们专注于诱导特定的免疫耐受。一个目标是分析接触变应原的低区域耐受性(LZT)小鼠模型，这种模型类似于人类日常生活中生理上暴露于低亚免疫原量变应原的皮肤。我们发现在LZT的诱导期，CD4+CD25+Foxp3+T细胞诱导产生耐受性CD11c+树突状细胞DC，这是产生半抗原特异性LZT调节性CD8+T细胞所必需的。此后，这些调节性T细胞诱导CD11c+CD8+DC产生更多的肿瘤坏死因子。CHS的效应CD8+T细胞的凋亡是由该细胞因子驱动的，从而阻止了过敏皮肤的免疫反应。最近的研究表明，接触性变应原/半抗原可直接或间接激活天然免疫过程(如通过模式识别受体[PRR]激活)，而这些过程对过敏免疫反应至关重要。相比之下，天然免疫的机制(细胞相关：中性粒细胞、巨噬细胞等或PRR相关)在接触变应原的耐受反应中尚未被探索。因此，我们打算分析天然免疫在接触性变应原/半抗原特异性免疫耐受反应(皮肤和口服LZT)中的作用及其与获得性免疫机制的相互作用。我们打算专注于调节性T细胞的激活及其与致耐受树突状细胞的相互作用，从而诱导半抗原特异性耐受反应。对先天免疫过程的分析将包括免疫细胞(中性粒细胞、髓系细胞)的功能和PRR相关机制(重点是TLR2)，以评估它们在半抗原特异性耐受中的功能。应用项目的结果可能确定调节和预防过敏免疫反应的新靶点。