Validation of a model of rheumatoid arthritis using mice reconstituted with patient peripheral blood mononuclear cells

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and joint destruction. Replicating human manifestations of RA in animal models remains challenging, however, owing to heterogeneity of the disease. In this study, a humanized mouse model for RA was developed and validated using NOD-scid IL2Rγnull (NSG) mice engrafted with peripheral blood mononuclear cells (PBMCs) from patients with RA (NSG-RA). RA symptoms were induced using lipopolysaccharide and a cocktail of antibodies against type II collagen. Pathological manifestations were assessed through clinical scoring of hind paw swelling, histological analysis, and evaluation of RA-specific markers in plasma and joints using Luminex, RT-PCR and RNA sequencing. NSG-RA mice exhibited increased levels of RA-specific markers, an influx of inflammatory cells into the synovium, bone erosion and elevated levels of human autoantibodies. Enriched RNA-sequencing pathway analysis revealed activation of the RA disease pathway, along with the TNF and IL-17 signalling pathways. Treatment with prednisolone or infliximab ameliorated disease symptoms and decreased levels of inflammatory markers. These findings indicate that the NSG-RA model offers a translational tool for studying RA pathogenesis and testing novel therapeutic approaches.