Background/Purpose: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder characterized by the production of autoantibodies targeting nuclear antigens, immune complex deposition, and chronic inflammation of organs such as the skin, joints, and kidneys. Despite advancements in diagnosis and therapeutic strategies, SLE continues to impose a significant clinical challenge, underscoring the urgent need for novel therapies. While indispensable for elucidating disease mechanisms and evaluating treatments, conventional animal models are limited by interspecies differences in immune systems that hinder translational relevance. To overcome this, we developed a humanized SLE model by engrafting immunodeficient mice with peripheral blood mononuclear cells (PBMCs) derived from SLE patients. This model successfully mimics key pathological features, including elevated autoantibody levels (e.g., anti-dsDNA) and renal immune complex deposition, making it a valuable platform for evaluating B cell-targeted antibody therapies and cell-based interventions.

Methods: SLE model was generated by intraperitoneal injection of SLE patient-derived PBMC. Three therapeutic evaluation cases were conducted: Case 1: Three T cell engagers (TCEs) were administered intraperitoneally once weekly for four weeks, starting on day of PBMC engraftment. Peripheral blood was collected on days 7, 14, 21, and 28 days for flow cytometry analysis of hCD20+ B cells. Plasma was analyzed for human anti-dsDNA antibodies and total IgG. Case 2: T cell engager and Blincyto were administered intravenously 7 days post-PBMC engraftment, twice a week for three consecutive weeks. Peripheral blood was collected 14 and 28 days for flow cytometry analysis of plasma B cells. Plasma was analyzed human anti-dsDNA antibodies and total IgG. Kidneys was collected and freshly embedded for Immunofluorescence staining of human IgG. Case 3: CAR-T cells were administered intravenously on day 6 post- engraftment. Plasma was collected 3 weeks after PBMC inoculation for ELISA test of human total IgG.

Results: Following PBMC engraftment, SLE-PBMC-NCG humanized mice demonstrated elevated levels of total human IgG and anti-dsDNA antibodies. Case 1: Treatment with TCEs reduces auto-antibody levels and the number of peripheral hCD20+B cells in SLE PBMC-NCG mice. Case 2: T cell engager and Blincyto treatment both led to reduction in plasma B cell and anti-dsDNA antibody levels. IgG deposition in the kidneys was also considerably reduced 3 weeks post-treatment. Case 3: CAR-T treatment led to a decrease in total human IgG levels two weeks post-infusion.

Conclusion: The SLE patient-derived PBMC-NCG model effectively reproduces key pathogenic features of SLE and responds to multiple therapeutic modalities, including TCEs and CAR-T. This model offers a translationally relevant platform for preclinical evaluation of B-cell targeted therapies, supporting biomarker identification, dosing optimization, and acceleration of SLE drug development.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-application-of-sle-patient-derived-pbmc-induced-mouse-model-in-preclinical-pharmacological-studies/