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

变应性接触性皮炎是最常见的职业性皮肤病之一，并迫使受影响的患者的生活质量受到限制，社会经济成本高。在过去的几十年中，已经建立了良好的接触性超敏反应的小鼠模型，可以分析过敏性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持久治疗策略仍然缺乏。在我们的工作中，我们专注于特异性免疫耐受的诱导。一个目标是分析对接触过敏原的低区耐受性（LZT）的鼠模型，其类似于人类日常生活中对低亚免疫原性量的过敏原的生理性表皮暴露。我们发现在LZT的诱导阶段，调节性CD 4 + CD 25 + Foxp 3 + T细胞诱导耐受原性CD 11 c+树突状细胞DC，其是产生半抗原特异性LZT调节性CD 8 + T细胞所需的。此后，这些调节性T细胞诱导CD 11 c + CD 8 + DC的TNF产生增加。CHS的效应CD 8 + T细胞的凋亡由这种细胞因子驱动，导致预防过敏性皮肤免疫应答。最近，研究表明，接触性过敏原/半抗原直接或间接激活先天免疫过程（例如通过激活模式识别受体[PRR]），这对过敏性免疫应答至关重要。相比之下，尚未在对接触性过敏原的耐受性反应中探索先天免疫（细胞相关：中性粒细胞、巨噬细胞等或PRR相关）的机制。因此，我们设想分析先天免疫在接触过敏原/半抗原特异性免疫耐受反应（表皮和口服LZT）中的功能及其与适应性免疫机制的相互作用。我们打算把重点放在活化的调节性T细胞和它们的相互作用与致耐受性DC导致诱导半抗原特异性耐受反应。先天免疫过程的分析将包括免疫细胞（中性粒细胞，骨髓源性细胞）的功能和PRR相关机制（重点是TLR 2），以评估其在半抗原特异性耐受中的功能。应用项目的结果可以确定用于调节和预防过敏性免疫反应的新靶点。

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.