Nishidate Akiko, Takemoto Kana, Imura Yuki, Murase Mikako, Yamanaka Ryu, Kikuchi Manami, Anan Junpei, Kato Sayuka, Akatsuka Airi, Mochizuki Sachiko, Koda Yuzo
Oncology & Immunology Unit, Research Division, Mitsubishi Tanabe Pharma Corporation, Kanagawa, 227-0033, Japan.
Discovery Technology Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation, Kanagawa, 227-0033, Japan.
Inflamm Regen. 2025 Jan 15;45(1):1. doi: 10.1186/s41232-025-00365-6.
Idiopathic inflammatory myopathies (IIMs) are a group of autoimmune disorders characterized by immune cell infiltration of muscle tissue accompanied by inflammation. Treatment of IIMs is challenging, with few effective therapeutic options due to the lack of appropriate models that successfully recapitulate the features of IIMs observed in humans. In the present study, we demonstrate that immunodeficient mice transplanted with human peripheral blood mononuclear cells (hPBMCs) exhibit the key pathologic features of myositis observed in humans and develop graft-versus-host disease. The hPBMC mice exhibit elevated serum levels of creatine kinase and aspartate transaminase, markers of myositis, and increased expression levels of myositis-related genes, such as vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and serum amyloid A1, in muscle tissues. Histopathologic and flow cytometric analyses reveal the infiltration of CD8 T cells in the muscle tissue of hPBMC mice, similar to that observed in patients with myositis, particularly in those with polymyositis. Transplantation of CD8 T cell-depleted hPBMC leads to a significant reduction in polymyositis-like symptoms, in agreement with previous studies demonstrating CD8 T cells as the main pathologic drivers of polymyositis. Furthermore, the transcriptome analysis of muscle tissue from hPBMC mice reveal extensive upregulation of characteristic genes of polymyositis, providing further support that hPBMC mice accurately reflect the pathophysiology of myositis in humans. Finally, administration of prednisolone or tacrolimus, which are commonly used for IIM treatment, leads to significant alleviation of myositis findings. Therefore, we propose that hPBMC mice should be considered as a model that accurately reflects the pathophysiology of myositis in human patients.
特发性炎症性肌病（IIMs）是一组自身免疫性疾病，其特征是免疫细胞浸润肌肉组织并伴有炎症。IIMs的治疗具有挑战性，由于缺乏能够成功重现人类IIMs特征的合适模型，有效的治疗选择很少。在本研究中，我们证明移植了人外周血单核细胞（hPBMCs）的免疫缺陷小鼠表现出人类肌炎的关键病理特征，并发展为移植物抗宿主病。hPBMC小鼠血清中肌酸激酶和天冬氨酸转氨酶水平升高，这是肌炎的标志物，并且肌肉组织中肌炎相关基因如血管细胞黏附分子1、细胞间黏附分子1和血清淀粉样蛋白A1的表达水平增加。组织病理学和流式细胞术分析显示hPBMC小鼠肌肉组织中有CD8 T细胞浸润，类似于肌炎患者，特别是多发性肌炎患者中观察到的情况。移植去除CD8 T细胞的hPBMC可导致多发性肌炎样症状显著减轻，这与先前证明CD8 T细胞是多发性肌炎主要病理驱动因素的研究一致。此外，对hPBMC小鼠肌肉组织的转录组分析显示多发性肌炎特征基因广泛上调，进一步支持hPBMC小鼠准确反映人类肌炎的病理生理学。最后，给予常用于IIMs治疗的泼尼松龙或他克莫司可显著减轻肌炎表现。因此，我们建议hPBMC小鼠应被视为一种准确反映人类患者肌炎病理生理学的模型。
