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

过敏性接触性皮炎是最常见的职业性皮肤病之一，影响患者的生活质量，并造成较高的社会经济成本。在过去的几十年里，建立良好的小鼠接触性超敏反应模型已经允许分析过敏皮肤反应的潜在免疫机制。然而，对于过敏性接触性皮炎的有效预防和长效治疗策略仍然缺乏。在我们的工作中，我们主要关注特异性免疫耐受的诱导。一个目标是分析小鼠对接触过敏原的低区耐受（LZT）模型，该模型类似于人类日常生活中对低亚免疫原量的生理性表皮暴露。我们发现，在LZT调节性CD4+CD25+Foxp3+ T细胞的诱导阶段，诱导耐受性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的TNF生成增加。CHS的效应CD8+ T细胞凋亡是由这种细胞因子驱动的，从而防止过敏性皮肤免疫反应。近年来，研究表明，接触过敏原/半抗原可直接或间接激活固有免疫过程（如模式识别受体[PRR]的激活），这些过程对过敏性免疫应答至关重要。而先天免疫（细胞相关：中性粒细胞、巨噬细胞等或prr相关）在接触性过敏原耐受反应中的作用机制尚未探索。因此，我们设想分析先天免疫在接触性变应原/半抗原特异性免疫耐受反应（表皮和口服LZT）中的作用及其与适应性免疫机制的相互作用。我们打算关注调节性T细胞的激活及其与耐受性DC的相互作用，从而诱导半抗原特异性耐受性反应。对先天免疫过程的分析将包括免疫细胞（中性粒细胞、髓源性细胞）的功能和prr相关机制（重点是TLR2），以评估其在半抗原特异性耐受中的功能。应用项目的结果可能为调节和预防过敏性免疫反应确定新的靶点。

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.