Abstract

Introduction: Preclinical testing of novel therapeutic approaches for rheumatoid arthritis (RA) requires amouse model that imitates the human disease. To circumvent limitations due to differences between murineand human immune systems, we intended to establish a humanized mouse model of RA by transferringperipheral blood mononuclear cells (PBMCs) from healthy or RA subjects into immunodeficient mice.Methods: PBMCs were injected intravenously into 5-8-week old female NOD-scid IL2rgnull (NSG) mice.Human cell engraftment was monitored weekly and reactivity of human cells, recovered from spleens,towards synovial fluid (SF) and polyclonal stimulation, was assessed by flow cytometry. Humanimmunoglobulins (Ig) were quantified in serum by ELISA. Joint sections were stained with H&E. Results:Engraftment of human cells reached 36±5% in spleen, 77±4% in lymph nodes, 6±2% in bone marrow, and22±4% in blood of NSG mice at six weeks after PBMC injection, regardless of whether PBMC from healthy orRA donors were used. The human graft consisted predominantly of activated CD4+ T cells which preservedtheir capacity to express IFN-γ in response to SF or polyclonal stimulation. Engrafted B cells continuedproducing IgM and IgG. Injection of RA patient-derived PBMC alone failed to generate histologicalalterations, however, in pilot experiments, additional intraarticular administration of SF, or injection of RA-derived CD4+ T cells together with SF-pulsed dendritic cells, resulted in cellular infiltrates and cartilagedegradation. Conclusion: Although requiring further investigation, this chimeric human-mouse model of RAmight provide an experimental system for preclinical testing of new therapies. Funded byFONDECYT3150453 and FONDECYT1140553.