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

人的呼吸道，特别是鼻腔，有一个很大的吸收表面，有不同类型的上皮，即呼吸道、嗅觉、鳞状上皮和移行粘膜。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被过滤，并通过粘液纤毛清除输送到鼻相关淋巴组织(NALT)。像其他粘膜组织一样，鼻腔非常适合给药。临床数据表明，根据给药地点的不同，三种不同的递送途径可以针对三个不同的药理学隔室：嗅黏膜使脑递送并绕过血脑屏障，非常好的血管形成的呼吸上皮针对中央(血液)隔室，NALT处的相互作用触发免疫反应，就像鼻腔疫苗注射所知的那样。然而，治疗药物与NALT的接触也存在免疫原性的风险，这是一个严重的安全问题。非常有趣的是，我们最近可以证明，通过嗅黏膜中的Fc受体，我们可以有效地摄取IgG抗体，并从那里迅速分布到中枢神经系统。但是，如何分别针对不同的途径提供的数据很少。我们可以在之前的一项研究中证明，针对嗅觉或呼吸区会导致中枢神经系统或外周的特定生物活性。自我给药的条件和靶点对于节省和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定给药的有限适宜性，气雾剂的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，我们开发了一个标准化的体内给药模型，专门针对鼻部区域给药。在这个项目中，我们将以整体的方法表征人的嗅黏膜、它的粘液和清除以及它的免疫功能。该项目的结果将使我们能够更好地了解嗅觉，并设计新的药物输送策略，用于针对中枢神经系统或呼吸道局部粘膜免疫系统的区域特异性和安全的鼻腔给药，以对抗传染病。

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.