Characterization of the physico-chemical conditions and immune-function at the human olfactory mucosa

人呼吸道，特别是鼻腔，具有大的吸收表面，具有不同类型的上皮细胞，即呼吸、嗅觉、鳞状和过渡粘膜。此外，鼻粘膜提供了非常重要的免疫功能，因为无数吸入的病原体在上呼吸道中被过滤并通过粘液纤毛清除转运到鼻相关淋巴组织（NALT）。与其他粘膜组织一样，鼻腔非常适合给药。临床数据表明，依赖于给药部位，可以靶向三种不同的递送途径至三种不同的药理学隔室：嗅觉粘膜使脑递送成为可能并绕过血脑屏障，血管化非常好的呼吸道上皮靶向中央（血液）隔室，并且NALT处的相互作用触发免疫反应，如鼻内疫苗给药所知。然而，治疗剂与NALT的接触也具有免疫原性的风险，这是一个严重的安全性问题。非常有趣的是，我们最近可以证明IgG抗体通过嗅觉粘膜中的Fc受体的有效摄取，并从那里快速分布到CNS。然而，很少有数据是如何分别针对不同的途径。我们可以在先前的研究中证明，靶向嗅觉或呼吸区域在CNS或外周中产生特异性生物活性。自我给药的条件和靶点对于安全有效的治疗至关重要。在以前的研究中，我们已经确定了气雾剂对区域特异性递送的有限适用性，气雾剂产生对蛋白质聚集的影响以及蛋白质制剂对稳定性和粘膜渗透的影响。此外，我们还开发了一种标准化的体内模型，专门用于鼻腔区域给药。在本项目中，我们将以整体方法表征人类嗅觉粘膜，其粘液和清除以及其免疫功能。该项目的结果将使我们能够更好地了解嗅觉，并设计新的药物递送策略，用于区域特异性，从而安全地鼻内给药，靶向中枢神经系统或气道的局部粘膜免疫系统，以对抗感染性疾病。

The human respiratory tract, and in particular the nasal cavity, has a large absorptive surface with different types of epithelia namely respiratory, olfactory, squamous and transitional mucosa. In addition, the nasal mucosa provides a very important immune function since countless inhaled pathogens are filtered in the upper airways and transported via mucocilliary clearance to the nose-associated lymphoid tissue (NALT). Like other mucosal tissues the nasal cavity is very suitable for the administration of drugs. Clinical data suggest that dependent from the site of administration three different delivery routes to three distinctive pharmacological compartments can be targeted: the olfactory mucosa enables brain delivery and bypasses the blood brain barrier, the very well vascularized respiratory epithelium targets the central (blood) compartment and interactions at the NALT trigger immune reactions as known from administration of intranasal vaccines. However, the contact of therapeutics with the NALT harbors also the risk of immunogenicity, a serious safety issue. Very interestingly, we could recently demonstrate an efficient uptake of IgG antibodies via Fc receptors in the olfactory mucosa and from there a rapid distribution to the CNS.However, very few data are available how to target the different routes separately. We could demonstrate in a previous study that targeting the olfactory or respiratory region results in specific bioactivity in the CNS or the periphery. The conditions and targets of self-administered drugs are critical for a save and efficient therapy. In previous studies we have determined the limited suitability of aerosols for region-specific delivery, the influence of aerosol generation on protein aggregation and the effects of protein formulation on stability and mucosal permeation. Furthermore, we have developed a standardized in vivo model to administer drugs specifically to a nasal region.In this project, we will characterize with a holistic approach the human olfactory mucosa, its mucus and clearance and its immune function. The results of this project will enable us to better understand olfaction and to design novel drug delivery strategies for a regional-specific and thereby safe intranasal drug administration targeting either the CNS or the local mucosal immune system of the airways to fight infectious diseases.