Analysis of the interaction between invariant natural killer T cells, intestinal microbes and microbial metabolites to prevent allergic airway and intestinal inflammation

肺部和肠道的慢性炎症，如在呼吸道和食物过敏中观察到的，是由于对其他无害的过敏原失去耐受性所致。在这里，我们最近发现淀粉酶胰蛋白酶抑制物(ATI)是小麦和相关谷物中的水溶性非面筋蛋白，是髓系天然免疫细胞的常见营养激活剂，也是肠道生物失调的诱导剂。在第一个项目期间，我们在体外证明了ATI作为过敏原特异性免疫反应的佐剂，并在体内促进了人源化过敏性小鼠模型的过敏性呼吸道和肠道炎症。在这个人源化的小鼠模型中，我们还可以证明CD56表达的不变自然杀伤T细胞(INKT)和可能下游激活的先天淋巴组织2型(ILC2)细胞在过敏原诱导的肠道和肺部炎症的发生中起关键作用。使用益生菌制剂BactoFlor®10/20或短链脂肪酸处理人源化小鼠，可以防止过敏性炎症，从而改变微生物区系。有趣的是，在无菌小鼠的肠道和肺中发现了更多的iNKT细胞，这表明微生物信号对它们的发育起着重要的调节作用。因此，在这个项目的扩展中，我们想要研究以BactoFlor®10/20为代表的有益细菌和选择性免疫调节代谢物与植入的人类固有细胞群体，特别是iNKT细胞之间的相互作用，这些代谢产物可能在预防过敏性疾病方面发挥重要作用。

Chronic inflammation of the lung and intestine, as is observed in airway and food allergy, is due to loss of tolerance to otherwise harmless allergens. Herein, we recently identified amylase trypsin inhibitors (ATI), water soluble non-gluten proteins in wheat and related cereals, as common nutritional activators of myeloid innate immune cells and as inducers of intestinal dysbiosis. In the first project period we demonstrated that ATI served as adjuvants for allergen-specific immune responses in vitro, and promoted allergic airway as well as intestinal inflammation in a humanized mouse model of allergy in vivo. In this humanized mouse model, we could also show that CD56-expressing invariant natural killer T (iNKT) and likely downstream activated innate lymphoid type 2 (ILC2) cells are critically involved in the development of allergen-induced gut and lung inflammation. Changes in the microbiota by treatment of humanized mice with either the probiotic bacterial formulation BactoFlor® 10/20 or with short-chain fatty acids prevented allergic inflammation. Interestingly, an increased number of iNKT cells was found in the intestine and lungs of germ-free mice, indicating that microbial signals are important to regulate their development. Therefore, in the extension of this project, we want to investigate the interaction of beneficial bacteria represented by BactoFlor® 10/20 and selective immunomodulatory metabolites, which might play an important role in the prevention of allergic diseases, with engrafted human innate cell populations, particularly iNKT cells.