Gomi Masaki, Nakayama Yuka, Sakurai Yu, Oyama Ryotaro, Iwasaki Koki, Doi Mizuki, Liu Yi, Hori Mizuho, Watanabe Himeka, Hashimoto Kohei, Tanaka Hiroki, Tange Kota, Nakai Yuta, Akita Hidetaka
Laboratory of DDS Design and Drug Disposition, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-0856, Japan.
Laboratory of DDS Design and Drug Disposition, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
Pharmaceuticals (Basel). 2023 Sep 7;16(9):1270. doi: 10.3390/ph16091270.
Multiple sclerosis is a disease caused by autoantigen-responsive immune cells that disrupt the myelin in the central nervous system (CNS). Although immunosuppressive drugs are used to suppress symptoms, no definitive therapy exists. As in the experimental autoimmune encephalitis (EAE) model of multiple sclerosis, a partial sequence of the myelin oligodendrocyte glycoprotein (MOG) was identified as a causative autoantigen. This suggests that the induction of immune tolerance that is specific to MOG would be a fundamental treatment for EAE. We previously reported that lipid nanoparticles (LNPs) containing an anionic phospholipid, phosphatidylserine (PS), in their lipid composition, can be used to deliver mRNA and that this leads to proteins of interest to be expressed in the spleen. In addition to the targeting capability of PS, PS molecules avoid activating the immune system. Physiologically, the recognition of PS on apoptotic cells suppresses immune activation against these cells by releasing cytokines, such as interleukin-10 (IL-10) and transforming growth factor (TGF)-β that negatively regulate immunity. In this study, we tested whether mRNA delivery of autoantigens to the spleen by PS-LNPs causes the expression of MOG antigens with minimal immune stimulation and whether this could be used to treat an EAE model by inducing immune tolerance.
多发性硬化症是一种由自身抗原反应性免疫细胞引起的疾病，这些细胞会破坏中枢神经系统（CNS）中的髓磷脂。尽管使用免疫抑制药物来抑制症状，但尚无确切的治疗方法。与多发性硬化症的实验性自身免疫性脑脊髓炎（EAE）模型一样，髓鞘少突胶质细胞糖蛋白（MOG）的部分序列被确定为致病性自身抗原。这表明诱导对MOG特异的免疫耐受将是EAE的一种基本治疗方法。我们之前报道过，脂质纳米颗粒（LNPs）在其脂质组成中含有阴离子磷脂磷脂酰丝氨酸（PS），可用于递送mRNA，这会导致目的蛋白在脾脏中表达。除了PS的靶向能力外，PS分子还能避免激活免疫系统。在生理上，对凋亡细胞上PS的识别通过释放白细胞介素-10（IL-10）和转化生长因子（TGF）-β等对免疫有负调节作用的细胞因子来抑制针对这些细胞的免疫激活。在本研究中，我们测试了通过PS-LNPs将自身抗原的mRNA递送至脾脏是否会在最小程度的免疫刺激下导致MOG抗原的表达，以及这是否可用于通过诱导免疫耐受来治疗EAE模型。
