Nature Biomedical Engineering ( IF 28.1 ) Pub Date : 2020-10-12 , DOI: 10.1038/s41551-020-00627-3 Ako Ishihara 1 , Jun Ishihara 1, 2 , Elyse A Watkins 1 , Andrew C Tremain 1, 3 , Mindy Nguyen 1 , Ani Solanki 4 , Kiyomitsu Katsumata 1 , Aslan Mansurov 1 , Erica Budina 1 , Aaron T Alpar 1 , Peyman Hosseinchi 1 , Lea Maillat 1 , Joseph W Reda 1 , Takahiro Kageyama 5 , Melody A Swartz 1, 3, 6 , Eiji Yuba 1 , Jeffrey A Hubbell 1, 3
Interleukin-4 (IL-4) suppresses the development of multiple sclerosis in a murine model of experimental autoimmune encephalomyelitis (EAE). Here, we show that, in mice with EAE, the accumulation and persistence in the lymph nodes and spleen of a systemically administered serum albumin (SA)–IL-4 fusion protein leads to higher efficacy in preventing disease development than the administration of wild-type IL-4 or of the clinically approved drug fingolimod. We also show that the SA–IL-4 fusion protein prevents immune-cell infiltration in the spinal cord, decreases integrin expression in antigen-specific CD4+ T cells, increases the number of granulocyte-like myeloid-derived suppressor cells (and their expression of programmed-death-ligand-1) in spinal cord-draining lymph nodes and decreases the number of T helper 17 cells, a pathogenic cell population in EAE. In mice with chronic EAE, SA–IL-4 inhibits immune-cell infiltration into the spinal cord and completely abrogates immune responses to myelin antigen in the spleen. The SA–IL-4 fusion protein may be prophylactically and therapeutically advantageous in the treatment of multiple sclerosis.
中文翻译:
白蛋白-IL-4 融合蛋白在次级淋巴器官中的长期驻留可改善实验性自身免疫性脑脊髓炎
在实验性自身免疫性脑脊髓炎 (EAE) 的小鼠模型中,白细胞介素 4 (IL-4) 抑制多发性硬化症的发展。在这里,我们表明,在患有 EAE 的小鼠中,全身施用的血清白蛋白 (SA)-IL-4 融合蛋白在淋巴结和脾脏中的积累和持久性比施用野生- IL-4 型或临床批准的药物芬戈莫德。我们还表明 SA-IL-4 融合蛋白可防止脊髓中的免疫细胞浸润,降低抗原特异性 CD4 + 中的整联蛋白表达T 细胞,增加脊髓引流淋巴结中粒细胞样髓源性抑制细胞(及其程序性死亡配体 1 的表达)的数量,并减少 T 辅助 17 细胞的数量,这是一种致病细胞群EAE。在患有慢性 EAE 的小鼠中,SA-IL-4 抑制免疫细胞浸润到脊髓中,并完全消除对脾脏髓鞘抗原的免疫反应。SA-IL-4 融合蛋白在多发性硬化症的治疗中可能具有预防和治疗优势。