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，如在气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。在这里，我们最近发现了淀粉酶胰蛋白酶抑制剂（ATI），小麦和相关谷物中的水溶性非麸质蛋白，作为髓系先天免疫细胞的常见营养激活剂和肠道生态失调的诱导剂。在第一个项目期间，我们证明了ATI在体外作为过敏原特异性免疫反应的佐剂，并在体内的人源化过敏小鼠模型中促进过敏性气道和肠道炎症。在这个人源化小鼠模型中，我们还可以证明表达cd56的不变性自然杀伤T （iNKT）和可能下游激活的先天淋巴样2 （ILC2）细胞在过敏原诱导的肠道和肺部炎症的发展中起关键作用。用益生菌制剂BactoFlor®10/20或短链脂肪酸治疗人源化小鼠时，微生物群的变化可预防过敏性炎症。有趣的是，在无菌小鼠的肠道和肺部发现iNKT细胞数量增加，表明微生物信号对调节它们的发育很重要。因此，在本项目的扩展中，我们希望研究以BactoFlor®10/20为代表的有益菌与选择性免疫调节代谢物的相互作用，这可能在预防过敏性疾病中发挥重要作用，与移植的人类先天细胞群，特别是iNKT细胞。

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.