负载TNF-α抑制剂的骨髓基质干细胞在类风湿性关节炎治疗中的协同作用及机制

Rheumatoid arthritis (RA) is a kind of refractory autoimmune disease with high morbidity. Our previous project revealed that the local transplantation of BMSCs in the joint exhibited a clear therapeutic efficacy toward RA model. However, it was reported that TNF-α could reverse the immunomodulatory effect of BMSCs and reduce their efficacy in RA therapy. TNF-α inhibitor is a remarkable agent in RA therapy, while exhibits some side effects, including reduced systemic immunity, upregulated opportunistic infections, and so on. It is meaningful that if TNF-α inhibitor could selectively accumulate in the inflammation sites. In this project, TNF-α inhibitor will be linked to BMSCs through a matrix metalloproteinase-2 (MMP-2)-sensitive peptide, and specifically delivered to the the inflammation sites of RA through the homing effect of BMSCs. With this strategy, TNF-α inhibitor provides a suitable immune microenvironment for BMSCs, and also, the selectivity of TNF-α inhibitor toward inflammation site is enhanced. In addition, through the research on the influence of TNF-α inhibitor on the immunomodulatory and cartilage differentiation capacity of BMSCs, the synergistic effect and mechanisms of the combined applications of BMSCs and TNF-α inhibitor are investigated. The project provides a new idea for the immunotherapy of RA.

类风湿性关节炎（RA）是发病率很高的难治愈的自身免疫性疾病。我们上一个面上项目证实骨髓基质干细胞（BMSCs）移植对RA有明确的疗效。但RA病灶区存在的肿瘤坏死因子-α（TNF-α）可逆转BMSCs的免疫抑制作用，同时降低其分化能力，从而影响疗效。TNF-α抑制剂在RA治疗中具有显著疗效，但存在全身免疫力降低及机会性感染增加等副作用。因此，实现TNF-α抑制剂在炎症区特异性聚集有重要意义。本研究拟通过基质金属蛋白酶-2敏感的短肽将TNF-α抑制剂连接于BMSCs表面，通过BMSCs归巢特性，使其特异地到达病灶区并酶切释放；这样在TNF-α抑制剂为BMSCs提供适宜的免疫微环境的同时，也增强了其对炎症局部的选择性，最大限度地减少不良反应的发生。通过研究TNF-α抑制剂对BMSCs治疗效果的影响，阐明BMSCs与TNF-α抑制剂联合应用在RA治疗中的协同作用及机制，为RA免疫治疗提供新的思路。

类风湿性关节炎（RA）是一种发病率很高，难以彻底治愈的自身免疫性疾病。骨髓基质干细胞（BMSCs）移植对RA有明确的治疗效果。但RA关节损伤区域存在的肿瘤坏死因子-α（TNF-α）可逆转BMSCs的免疫抑制作用，降低其分化能力，从而影响疗效。TNF-α抑制剂在RA治疗中具有显著疗效，但存在造成患者全身免疫力降低及机会性感染增加等副作用。为了解决上述问题，本项目应用基质金属蛋白酶-2敏感的短肽将TNF-α抑制剂连接于BMSCs表面，通过BMSCs归巢特性，使其特异地到达关节损伤的区域，并特异性酶切释放；这样，TNF-α抑制剂在为BMSCs提供适宜的免疫微环境的同时，也增强了其对炎症局部的选择性，最大限度地减少不良反应的发生。体外和体内实验证实BMSCs可以作为TNF-α抑制剂的载体，将TNF-α抑制剂运载到RA炎症关节局部并特异性酶切释放，减少TNF-α抑制剂系统应用的副作用。BMSCs与TNF-α抑制剂的抗炎作用协同，有效发挥了调节局部免疫微环境、软骨修复等作用，显著提高了RA免疫治疗的效果，为应用BMSCs治疗RA提供了实验室依据和理论基础。