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Background: Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease characterized by the presence of auto-antibodies against nuclear antigens, deposition of immune complexes, and chronic inflammation of target organs such as the skin, joints, and kidneys. Despite substantial progress in the diagnosis and treatment of systemic lupus erythematosus, the disease burden remains heavy, and there is an urgent need for new drugs and therapies [1]. Animal models play a crucial role in understanding the mechanisms and treatments of human diseases. However, due to significant differences in genetic background and disease-specific characteristics, animal models cannot fully simulate the occurrence and development of human diseases. Recently, newly developed humanized immune system mice based on immunodeficient mice have shown they can partially reconstruct the human immune system and mimic the human in vivo microenvironment [2]. In light of these developments, GemPharmatech has constructed a humanized SLE mouse model by transferring peripheral blood mononuclear cells (PBMC) from SLE patients into immunodeficient mice (NCG mice), causing high levels of human auto-antibodies and renal immune complex deposition. We demonstrated that B-cell directed therapeutic antibodies reversed the SLE phenotype in this model, indicating enormous application value and potential.
Objectives: Develop a humanized SLE mouse model for preclinical efficacy evaluation and research of new drugs.
Methods: SLE model was constructed by intraperitoneal injection of SLE patient-derived PBMC. In case 1, three T cell engagers (TCEs) were administered simultaneously during modeling, with weekly intraperitoneal injections for 4 weeks. The peripheral blood was collected 7, 14, 21, and 28 days after PBMC inoculation for flow cytometry analysis of hCD20+ B cells. The plasma was separated at the same time points for ELISA test of human anti-dsDNA and total IgG. In case 2, the T cell engager under test and positive control, Blincyto, were administered intravenously 7 days after PBMC inoculation, twice a week for three consecutive weeks. The peripheral blood was collected 14 and 28 days after PBMC inoculation for flow cytometry analysis of plasma B cells. The plasma was separated simultaneously for ELISA test of human anti-dsDNA and total IgG. The kidney was collected and freshly embedded for Immunofluorescence staining of human IgG. In case 3, Car-T cells were administered intravenously 6 days after PBMC inoculation. The plasma was collected 3 weeks after PBMC inoculation for ELISA test of human anti-dsDNA and total IgG.
Results: NCG mice showed significant increases in plasma human IgG and anti-dsDNA antibody levels at 2, 3, and 4 weeks after inoculation with SLE patient-derived PBMC. In case 1, the results showed treatment of TCEs can significantly reduce the plasma auto-antibody levels and the number of peripheral hCD20+B cells in SLE PBMC-NCG mice. In case 2, after 1 week and 3 weeks of administration of the T cell engager under test and Blincyto, the level of plasma anti-dsDNA and IgG levels, as well as the number of peripheral plasma B cells, were significantly reduced. IgG deposition in the kidneys was also considerably reduced 3 weeks after the drug dosing. In case 3, it is indicated that Car-T treatment can significantly reduce plasma human IgG levels after 2 weeks.
Conclusion: SLE patient-derived PBMC-induced mouse model exhibits similar pathological features seen in SLE patients such as high levels of autoantibodies and pathogenic B cells. It demonstrates good responses to B-cell directed therapeutic antibodies and cell therapies in pharmacological studies and offers a clinically relevant animal model to accelerate the development of novel therapies .
REFERENCES: [1] Hoi A, et al. Lancet. 2024.
[2] Chen J, et al. Front Immunol. 2022.
Acknowledgements: NIL.
Disclosure of Interests: None declared.
© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (