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

人类嗅粘膜理化条件和免疫功能的表征

• 批准号: 466915470
• 负责人: Professor Dr. Thomas Hummel
• 金额: --
• 依托单位: Zentrum Anatomie und Zellbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/466915470?language=en
• 关键词: Characterization; physico; chemical; conditions; immune

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.

人呼吸道，尤其是鼻腔，具有较大的吸收表面，具有不同类型的上皮，即呼吸道，嗅觉，鳞状和过渡性粘膜。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被过滤在上部气道中，并通过粘膜细胞间隙运输到鼻子相关的淋巴组织（NALT）。像其他粘膜组织一样，鼻腔非常适合给药。临床数据表明，可以针对三种不同的药理学室的三种不同的药理学室的依赖性：嗅觉粘膜可以使大脑递送并绕过血液脑屏障，这是在NALT触发免疫反应的中心（血液）隔室（血液）隔室（血液）隔室（血液）的呼吸良好的呼吸，该反应是由已知的内在造成的。但是，治疗药与NALT港口的接触也存在免疫原性的风险，这是一个严重的安全问题。有趣的是，我们最近可以通过FC受体在嗅觉粘膜中进行有效摄取IgG抗体的摄取。我们可以在先前的一项研究中证明，靶向嗅觉或呼吸区域会导致中枢神经系统或外围的特定生物活性。自我管理药物的条件和靶标对于保存和有效的治疗至关重要。在先前的研究中，我们确定了气溶胶对特异性递送的有限适用性，气溶胶产生对蛋白质聚集的影响以及蛋白质配方对稳定性和粘膜渗透的影响。此外，我们已经开发了一种标准化的体内模型，以专门为鼻部区域施用药物。在该项目中，我们将通过整体方法来表征人类嗅觉粘膜，其粘液和清除率及其免疫功能。该项目的结果将使我们能够更好地理解嗅觉，并为区域特异性的新型药物输送策略设计新颖的药物输送策略，从而针对CNS或呼吸道局部粘膜免疫系统的安全性鼻内药物管理，以抗击感染性疾病。