Human PBMC-based humanized mice exhibit myositis features and serve as a drug evaluation model.

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.