外泌体介导的肠道黏膜免疫靶向调节在IgA肾病中的作用及可能机制

Recent studies suggest a tempting new hypothesis for a major role of gut-associated lymphoid tissue (GALT) and a strong intestine–kidney connection in the development of immunoglobulin A nephropathy (IgAN). A dysregulated intestinal mucosal immune system is believed to be a promising target for IgAN intervention. Interestingly, our previous work verified that citrus sinensis-derived exosomes exhibited excellent stability at wide ranges of pH values and in the presence of gastrointestinal fluids in vitro. Moreover, they were selectively taken up by lymphocytes in Peyer’s patches and luminia propria via intragastric administration. This lead us to further develop a novel exosomes-based oral delivery system incorporating a small dose of dexamethasone sodium phosphate（Dex）as a therapeutic nano-agent，which is expected to prevent side effects of corticosteroid in light of its lower serum concentration. We intend to evaluate the effectiveness and safety of Exo-Dex in IgAN, and investigate the potential mechanism, both in vivo and in vitro, involving lymphocyte immunophenotypes modulation and the role of LIGHT/LT-βR in T lymphocytes activation in intestinal Peyer’s patches and luminia propria. Our study is expected to provide evidence for “intestine–kidney axis” mechanism and offer new targeted treatment options for IgAN.

近年发现“肠-肾轴”是IgA肾病（IgAN）重要致病机制，肠黏膜免疫细胞有望成为IgAN治疗新靶点。课题组前期研究发现，脐橙来源外泌体（Exo）在近似人体消化道环境中稳定存在，口服后直接被肠黏膜局部淋巴细胞摄取，故推测Exo负载糖皮质激素可直接经“肠-肾轴”有效减轻IgAN病理损伤；因较少进入血循环，遂能切实减少激素的副作用。本项目拟构建负载低剂量地塞米松磷酸钠外泌体（Exo-Dex），通过建立黏膜免疫源性IgAN小鼠模型，研究Exo-Dex靶向调控肠道Peyer’s结（免疫诱导区）及固有层（免疫效应区）T、B淋巴细胞功能，减轻IgA肾小球内沉积等病变的可行性及其机制；通过分离纯化IgAN小鼠Peyer’s结T细胞，体外探讨Exo-Dex抑制T细胞活化与LIGHT/LT-βR通路的关联。课题的实施将为阐明肠黏膜免疫在IgAN发病机制中的作用提供理论新依据，为IgAN肠道靶向治疗提供新手段。

近年发现“肠-肾轴”是IgA肾病（IgAN）重要致病机制，肠黏膜免疫细胞有望成为IgAN治疗新靶点。本研究旨在构建负载低剂量地塞米松磷酸钠外泌体（Exo-DexP），通过口服途径给药，探讨其对肠道免疫功能的影响以及对IgA肾病小鼠的疗效。研究者首先利用超高速差速离心法从橙汁中获得数量丰富的外泌体，通过电穿孔使其包载地塞米松磷酸钠，在酸碱环境中验证其稳定性。口服给药后，Exo-DexP可被小鼠小肠淋巴细胞摄取。体外实验证实，相比DexP，Exo-DexP可明显抑制淋巴细胞的增殖和活化。体内实验发现，Exo-DexP可有效减少IgA肾病小鼠肠道IgA分泌、减少IgA在肾脏沉积、减轻肾脏病理损伤程度、减少蛋白尿。本研究为阐明肠黏膜免疫在IgAN发病机制中的作用提供理论新依据，为IgAN肠道靶向治疗提供新手段。