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.

人类呼吸道，特别是鼻腔，具有较大的吸收表面，具有不同类型的上皮细胞，即呼吸道、嗅觉、鳞状和移行粘膜。此外，鼻粘膜提供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作用输送到鼻相关淋巴组织（NALT）。与其他粘膜组织一样，鼻腔非常适合给药。临床数据表明，根据给药部位，可以针对三个不同的药理区室的三种不同的递送途径：嗅粘膜实现脑递送并绕过血脑屏障，血管化良好的呼吸道上皮靶向中央（血液）区室，并且 NALT 处的相互作用触发免疫反应，如鼻内疫苗接种已知的那样。然而，治疗剂与 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 IgG 抗体可以通过嗅粘膜中的 Fc 受体有效摄取，并从那里快速分布到中枢神经系统。然而，如何分别针对不同途径的数据很少。我们可以在之前的研究中证明，针对嗅觉或呼吸区域会在中枢神经系统或外周产生特定的生物活性。自行给药的条件和目标对于安全有效的治疗至关重要。在之前的研究中，我们已经确定了气雾剂对于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配方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，可以专门向鼻腔区域给药。在这个项目中，我们将采用整体方法来表征人类嗅粘膜、其粘液和清除及其免疫功能。该项目的结果将使我们能够更好地了解嗅觉，并设计新颖的药物输送策略，用于针对中枢神经系统或气道局部粘膜免疫系统的区域特异性安全鼻内给药，以对抗传染病。