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

肺和肠的慢性炎症，如在气道和食物过敏中观察到的，是由于对原本无害的过敏原的耐受性丧失。在此，我们最近确定淀粉酶胰蛋白酶抑制剂（ATI），水溶性非面筋蛋白在小麦和相关谷物，作为常见的营养激活剂的骨髓先天免疫细胞和诱导剂的肠道生态失调。在第一个项目期间，我们证明ATI在体外作为过敏原特异性免疫应答的佐剂，并在体内人源化小鼠过敏模型中促进过敏性气道和肠道炎症。在这种人源化小鼠模型中，我们还可以证明表达CD 56的恒定自然杀伤T（iNKT）和可能的下游激活的先天淋巴2型（ILC 2）细胞在过敏原诱导的肠道和肺部炎症的发展中起着关键作用。通过用益生菌制剂BactoFlor® 10/20或短链脂肪酸处理人源化小鼠来改变微生物群，从而预防过敏性炎症。有趣的是，在无菌小鼠的肠和肺中发现了数量增加的iNKT细胞，这表明微生物信号对调节它们的发育很重要。因此，在该项目的扩展中，我们希望研究以BactoFlor® 10/20为代表的有益细菌和选择性免疫调节代谢物与移植的人类先天细胞群，特别是iNKT细胞的相互作用，这些代谢物可能在预防过敏性疾病中发挥重要作用。

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.