Humanized NSG mice ‒ a modern approach to modelling systemic lupus erythematosus in preclinical research
DOI:
https://doi.org/10.15584/ejcem.2026.1.10Keywords:
hematopoietic stem cell, humanized mouse model, immunopathogenesis, NSG mice, SLEAbstract
Introduction and aim. Systemic lupus erythematosus (SLE) is a complex autoimmune illness characterized by widespread immune dysregulation and involvement of several organ systems. Conventional mouse models, although crucial for understanding basic immunopathogenic pathways, inadequately mimic human-specific immunological responses, hence constraining translational relevance. This review offers a comprehensive understanding of humanized NSG mice in systemic lupus erythematosus research, outlining techniques for engraftment, model-specific immune reconstitution characteristics, and their respective applications in simulating acute and chronic disease phenotypes.
Material and methods. A comprehensive analysis of studies published between 2017 to 2025 was conducted in PubMed, Scopus, Web of Science and Google Scholar database. After removing the duplicates, a total of 87 articles were employed to finalize this study.
Analysis of literature. Humanized NSG mice successfully recapitulate major immunopathological features of systemic lupus erythematosus. Among numerous approaches, CD 34+ hemopoietic stem cell models best mimic chronic phenotype, while PBMC and pristane-based systems mimic acute and environmentally triggered forms. Recent advances include cytokine knock-in and HLA transgenic derivatives improving immune reconstitution and translational dependability.
Conclusion. This review provides the first integrative synthesis of humanized NSG mouse models applied to systemic lupus erythematosus, highlighting their translational potential and methodological advancements from 2017–2025. Collectively, these innovations establish humanized NSG mice as essential preclinical tools bridging experimental immunology with precision medicine in lupus research and therapy development.
Downloads
References
Arnaud L, Chasset F, Martin T. Immunopathogenesis of systemic lupus erythematosus: an update. Autoimmun Rev. 2024;23(10):103648. doi:10.1016/j.autrev.2024.103648
Ahmed AB, Chetia P. Selegiline modulates inflammatory indicators in RAW 264.7 macrophages and LPS-aggravated CFA-induced rheumatoid arthritis in rats. Eur J Clin Exp Med. 2024;22(1):6-16. doi:10.15584/ejcem.2024.1.12
Su X, Yu H, Lei Q, et al. Systemic lupus erythematosus:pathogenesis and targeted therapy. Mol Biomed. 2024;5(1):54. doi:10.1186/s43556-024-00217-8
Benseler SM, Silverman ED. Systemic Lupus Erythematosus. Rheum Dis Clin North Am. 2007;33(3):471-498. doi:10.1016/j.rdc.2007.07.008
Lin SY, Huang YW, Błochowiak K. Autoimmune diseases and their various manifestations in the oral cavity: a systematic review. Eur J Clin Exp Med. 2023;21(3):627-638. doi:10.15584/ejcem.2023.3.16
Gaballah H, Abd-Elkhalek R, Hussein O, El-Wahab SA. Association of TNFAIP3 gene polymorphism (rs5029939) with susceptibility and clinical phenotype of systemic lupus erythematosus. Arch Rheumatol. Published online October 16, 2021. doi:10.46497/ArchRheumatol.2022.8769
Laurynenka V, Harley JB. The 330 risk loci known for systemic lupus erythematosus (SLE): a review. Front Lupus. 2024;2. doi:10.3389/flupu.2024.1398035
Crow MK. Pathogenesis of systemic lupus erythematosus: risks, mechanisms and therapeutic targets. Ann Rheum Dis. 2023;82(8):999-1014. doi:10.1136/ard-2022-223741
Vieira AA, Almada-Correia I, Inácio J, Costa-Reis P, da Rocha ST. Female-bias in systemic lupus erythematosus: How much is the X chromosome to blame? Biol Sex Differ. 2024;15(1):76. doi:10.1186/s13293-024-00650-y
Dai X, Fan Y, Zhao X. Systemic lupus erythematosus: updated insights on the pathogenesis, diagnosis, prevention and therapeutics. Signal Transduct Target Ther. 2025;10(1):102. doi:10.1038/s41392-025-02168-0
Londe AC, Fernandez-Ruiz R, Julio PR, Appenzeller S, Niewold TB. Type I Interferons in Autoimmunity: Implications in Clinical Phenotypes and Treatment Response. J Rheumatol. 2023;50(9):1103-1113. doi:10.3899/jrheum.2022-0827
Katikaneni D, Morel L, Scindia Y. Animal models of lupus nephritis: the past, present and a future outlook. Autoimmunity. 2024;57(1). doi:10.1080/08916934.2024.2319203
Polis B, Cuda CM, Putterman C. Animal models of neuropsychiatric systemic lupus erythematosus: deciphering the complexity and guiding therapeutic development. Autoimmunity. 2024;57(1). doi:10.1080/08916934.2024.2330387
Bin Y, Ren J, Zhang H, et al. Against all odds: The road to success in the development of human immune reconstitution mice. Anim Model Exp Med. 2024;7(4):460-470. doi:10.1002/ame2.12407
Moore E, Reynolds JA, Davidson A, et al. Promise and complexity of lupus mouse models. Nat Immunol. 2021;22(6):683-686. doi:10.1038/s41590-021-00914-4
Campilan B, Schroeder C, Sagaityte E, et al. Animal model considerations for chordoma research: reproducing the tumor microenvironment in vivo with humanized mice. Front Oncol. 2024;14. doi:10.3389/fonc.2024.1330254
Chen J, Liao S, Zhou H, et al. Humanized Mouse Models of Systemic Lupus Erythematosus: Opportunities and Challenges. Front Immunol. 2022;12. doi:10.3389/fimmu.2021.816956
Chen J, Liao S, Xiao Z, et al. The development and improvement of immunodeficient mice and humanized immune system mouse models. Front Immunol. 2022;13. doi:10.3389/fimmu.2022.1007579
Chupp DP, Rivera CE, Zhou Y, et al. A humanized mouse that mounts mature class-switched, hypermutated and neutralizing antibody responses. Nat Immunol. 2024;25(8):1489-1506. doi:10.1038/s41590-024-01880-3
Li H, Zhang Y, Zhang B, Chen D. A novel PRKDC mutation caused B lymphocytes V(D)J rearrangement disorder in the SLE-DAH like symptoms patient. Pediatr Rheumatol. 2023;21(1):84. doi:10.1186/s12969-023-00840-9
Aryee K, Shultz LD, Burzenski LM, Greiner DL, Brehm MA. NOD- scid IL2rγnull mice lacking TLR4 support human immune system development and the study of human-specific innate immunity. J Leukoc Biol. 2023;113(5):418-433. doi:10.1093/jleuko/qiac020
Shan L, Flavell RA, Herndler-Brandstetter D. Development of humanized mouse models for studying human NK cells in health and disease. In: Herndler-Brandstetter D, Flavell RA, eds. Human NK Cells: Methods and Protocols. New York, NY: Springer; 2022:53-66. doi:10.1007/978-1-0716-2160-8_5
Long JE, Jankovic M, Maddalo D. Drug discovery oncology in a mouse: concepts, models and limitations. Futur Sci OA. 2021;7(8). doi:10.2144/fsoa-2021-0019
Karnik I, Her Z, Neo SH, Liu WN, Chen Q. Emerging preclinical applications of humanized mouse models in the discovery and validation of novel immunotherapeutics and their mechanisms of action for improved cancer treatment. Pharmaceutics. 2023;15(6):1600. doi:10.3390/pharmaceutics15061600
Mihaylova N, Chipinski P, Bradyanova S, et al. Suppression of autoreactive T and B lymphocytes by anti-annexin A1 antibody in a humanized NSG murine model of systemic lupus erythematosus. Clin Exp Immunol. 2020;199(3):278-293. doi:10.1111/cei.13399
Yu CI, Maser R, Marches F, Banchereau J, Palucka K. Engraftment of adult hematopoietic stem and progenitor cells in a novel model of humanized mice. iScience. 2024;27(3):109238. doi:10.1016/j.isci.2024.109238
Dinh B, Hoeksema MA, Spann NJ, et al. Isolation and cryopreservation of highly viable human peripheral blood mononuclear cells from whole blood: A guide for beginners. J Vis Exp. 2024;(212). doi:10.3791/66794
Sykes M, Sachs DH. Progress in xenotransplantation: overcoming immune barriers. Nat Rev Nephrol. 2022;18(12):745-761. doi:10.1038/s41581-022-00624-6
Wang W, Li Y, Lin K, Wang X, Tu Y, Zhuo Z. Progress in building clinically relevant patient‐derived tumor xenograft models for cancer research. Anim Model Exp Med. 2023;6(5):381-398. doi:10.1002/ame2.12349
Lee JY, Hong SH. Hematopoietic stem cells and their roles in tissue regeneration. Int J Stem Cells. 2020;13(1):1-12. doi:10.15283/ijsc19127
Zhang Y, Shen B, Guan X, et al. Safety and efficacy of ex vivo expanded CD34+ stem cells in murine and primate models. Stem Cell Res Ther. 2019;10(1):173. doi:10.1186/s13287-019-1275-0
Brendel C, Rio P, Verhoeyen E. Humanized mice are precious tools for evaluation of hematopoietic gene therapies and preclinical modeling to move towards a clinical trial. Biochem Pharmacol. 2020;174:113711. doi:10.1016/j.bcp.2019.113711
Miner Xie, Shanshan Zhang, Fang Dong, et al. Granulocyte colony-stimulating factor directly acts on mouse lymphoid-biased but not myeloid-biased hematopoietic stem cells. Haematologica. 2020;106(6):1647-1658. doi:10.3324/haematol.2019.239251
Sanchez-Petitto G, Rezvani K, Daher M, et al. Umbilical cord blood transplantation: connecting its origin to its future. Stem Cells Transl Med. 2023;12(2):55-71. doi:10.1093/stcltm/szac086
Sefik E, Xiao T, Chiorazzi M, et al. Engineering mice to study human immunity. Annu Rev Immunol. 2025;43(1):451-487. doi:10.1146/annurev-immunol-082523-124415
Chen W, Hong SH, Jenks SA, et al. Distinct transcriptomes and autocrine cytokines underpin maturation and survival of antibody-secreting cells in systemic lupus erythematosus. Nat Commun. 2024;15(1):1899. doi:10.1038/s41467-024-46053-w
Ménoret S, Ouisse LH, Tesson L, et al. In vivo analysis of human immune responses in immunodeficient rats. Transplantation. 2020;104(4):715-723. doi:10.1097/TP.0000000000003047
Akama-Garren EH, Carroll MC. Lupus susceptibility loci predispose mice to clonal lymphocytic responses and myeloid expansion. J Immunol. 2022;208(10):2403-2424. doi:10.4049/jimmunol.2200098
Wakiya R, Ueeda K, Nakashima S, et al. Effect of add-on hydroxychloroquine therapy on serum proinflammatory cytokine levels in patients with systemic lupus erythematosus. Sci Rep. 2022;12(1):10175. doi:10.1038/s41598-022-14571-6
Ktena YP, Koldobskiy MA, Barbato MI, et al. Donor T cell DNMT3a regulates alloreactivity in mouse models of hematopoietic stem cell transplantation. J Clin Invest. 2022;132(13). doi:10.1172/JCI158047
Morvan MG, Teque F, Ye L, et al. Genetically edited CD34 + cells derived from human iPS cells in vivo but not in vitro engraft and differentiate into HIV-resistant cells. Proc Natl Acad Sci. 2021;118(20). doi:10.1073/pnas.2102404118
Chuprin J, Buettner H, Seedhom MO, et al. Humanized mouse models for immuno-oncology research. Nat Rev Clin Oncol. 2023;20(3):192-206. doi:10.1038/s41571-022-00721-2
Garcia-Perez L, van Roon L, Schilham MW, Lankester AC, Pike-Overzet K, Staal FJT. Combining mobilizing agents with busulfan to reduce chemotherapy-based conditioning for hematopoietic stem cell transplantation. Cells. 2021;10(5):1077. doi:10.3390/cells10051077
Gutierrez-Barbosa H, Medina-Moreno S, Perdomo-Celis F, et al. A Comparison of lymphoid and myeloid cells derived from human hematopoietic stem cells xenografted into NOD-derived mouse strains. Microorganisms. 2023;11(6):1548. doi:10.3390/microorganisms11061548
Liu Y, Wu W, Cai C, Zhang H, Shen H, Han Y. Patient-derived xenograft models in cancer therapy: technologies and applications. Signal Transduct Target Ther. 2023;8(1):160. doi:10.1038/s41392-023-01419-2
Khosravi-Maharlooei M, Li HW, Sykes M. T Cell development and responses in human immune system mice. Annu Rev Immunol. 2025;43(1):83-112. doi:10.1146/annurev-immunol-082223-041615
Gunawan M, Her Z, Liu M, et al. A novel human systemic lupus erythematosus model in humanised mice. Sci Rep. 2017;7(1):16642. doi:10.1038/s41598-017-16999-7
von Hofsten S, Fenton KA, Pedersen HL. Human and murine toll-like receptor-driven disease in systemic lupus erythematosus. Int J Mol Sci. 2024;25(10):5351. doi:10.3390/ijms25105351
Zare Moghaddam M, Mousavi MJ, Ghotloo S. Stem cell-based therapy for systemic lupus erythematous. J Transl Autoimmun. 2024;8:100241. doi:10.1016/j.jtauto.2024.100241
Song Y, Li J, Wu Y. Evolving understanding of autoimmune mechanisms and new therapeutic strategies of autoimmune disorders. Signal Transduct Target Ther. 2024;9(1):263. doi:10.1038/s41392-024-01952-8
Teshima T, Boelens JJ, Matsuoka KI. Novel insights into GVHD and immune reconstitution after allogeneic hematopoietic cell transplantation. Blood cell Ther. 2023;6(2):42-48. doi:10.31547/bct-2022-023
Yun Y, Wang X, Xu J, et al. Pristane induced lupus mice as a model for neuropsychiatric lupus (NPSLE). Behav Brain Funct. 2023;19(1):3. doi:10.1186/s12993-023-00205-y
Pannu N, Bhatnagar A. Oxidative stress and immune complexes: Pathogenic mechanisms in pristane induced murine model of lupus. Immunobiology. 2020;225(1):151871. doi:10.1016/j.imbio.2019.11.006
Xu D, Reilly CM. HDAC6 knockout alleviates pristane-induced lupus. J Immunol. 2022;208(Supplement_1):104.13-104.13. doi:10.4049/jimmunol.208.Supp.104.13
Zhou Y, Yang B, Long H, et al. Immune cell alterations in a pristane‐induced lupus model in C57BL/6J mice. Rheumatol Autoimmun. Published online January 21, 2025. doi:10.1002/rai2.12164
Mizui M, Tsokos GC. Animal models: systemic autoimmune diseases. In: The Autoimmune Diseases. Elsevier; 2020:533-551. doi:10.1016/B978-0-12-812102-3.00029-4
O’Brien LJ, Walpole CM, Leal-Rojas IM, et al. Characterization of human engraftment and hemophagocytic lymphohistiocytosis in NSG-SGM3 neonate mice engrafted with purified CD34+ hematopoietic stem cells. Exp Hematol. 2024;130:104134. doi:10.1016/j.exphem.2023.11.008
Gavish A, Chain B, Salame TM, et al. From pseudo to real-time dynamics of T cell thymic differentiation. iScience. 2023;26(1):105826. doi:10.1016/j.isci.2022.105826
Zoshima T, Hara S, Yamagishi M, et al. Possible role of complement factor H in podocytes in clearing glomerular subendothelial immune complex deposits. Sci Rep. 2019;9(1):7857. doi:10.1038/s41598-019-44380-3
Haque M, Boardman D, Lam A, et al. Modelling graft-versus-host disease in mice using human peripheral blood mononuclear cells. BIO-PROTOCOL. 2022;12(23). doi:10.21769/BioProtoc.4566
Darguzyte M, Antczak P, Bachurski D, et al. Long-term human immune reconstitution, T-cell development, and immune reactivity in mice lacking the murine major histocompatibility complex: validation with cellular and gene expression profiles. Cells. 2024;13(20):1686. doi:10.3390/cells13201686
Kitsera M, Brunetti JE, Rodríguez E. Recent developments in NSG and NRG humanized mouse models for their use in viral and immune research. Viruses. 2023;15(2):478. doi:10.3390/v15020478
Saito Y, Shultz LD, Ishikawa F. Understanding normal and malignant human hematopoiesis using next-generation humanized mice. Trends Immunol. 2020;41(8):706-720. doi:10.1016/j.it.2020.06.004
Adams DE, Shao WH. Epigenetic alterations in immune cells of systemic lupus erythematosus and therapeutic implications. Cells. 2022;11(3):506. doi:10.3390/cells11030506
Tsokos GC. The immunology of systemic lupus erythematosus. Nat Immunol. 2024;25(8):1332-1343. doi:10.1038/s41590-024-01898-7
Walsh NC, Kenney LL, Jangalwe S, et al. Humanized mouse models of clinical disease. Annu Rev Pathol Mech Dis. 2017;12(1):187-215. doi: 10.1146/annurev-pathol-052016-100332
Kwisda K, White L, Hübner D. Ethical arguments concerning human-animal chimera research: a systematic review. BMC Med Ethics. 2020;21(1):24. doi:10.1186/s12910-020-00465-7
Du EJ, Muench MO. A Monocytic barrier to the humanization of immunodeficient mice. Curr Stem Cell Res Ther. 2024;19(7):959-980. doi:10.2174/011574888X263597231001164351
Greene JT, Brian BF, Senevirathne SE, Freedman TS. Regulation of myeloid-cell activation. Curr Opin Immunol. 2021;73:34-42. doi:10.1016/j.coi.2021.09.004
Alves da Costa T, Lang J, Torres RM, Pelanda R. The development of human immune system mice and their use to study tolerance and autoimmunity. J Transl Autoimmun. 2019;2:100021. doi:10.1016/j.jtauto.2019.100021
Liu J, Zhang X, Cao X. Dendritic cells in systemic lupus erythematosus: from pathogenesis to therapeutic applications. J Autoimmun. 2022;132:102856. doi: 10.1016/j.jaut.2022.102856
Luo S, Long H, Lu Q. Recent advances in understanding pathogenesis and therapeutic strategies of systemic lupus erythematosus. Int Immunopharmacol. 2020;89:107028. doi:10.1016/j.intimp.2020.107028
Araki Y, Mimura T. Epigenetic dysregulation in the pathogenesis of systemic lupus erythematosus. Int J Mol Sci. 2024;25(2):1019. doi:10.3390/ijms25021019
Qin R, Liang Y, Zhou F. Advances in the application of patient-derived xenograft models in acute leukemia resistance. Cancer Drug Resist. Published online May 28, 2025. doi:10.20517/cdr.2025.18
Yan H, Semple KM, Gonzaléz CM, Howard KE. Bone marrow-liver-thymus (BLT) immune humanized mice as a model to predict cytokine release syndrome. Transl Res. 2019;210:43-56. doi:10.1016/j.trsl.2019.04.007
Shah D, Soper B, Shopland L. Cytokine release syndrome and cancer immunotherapies – historical challenges and promising futures. Front Immunol. 2023;14. doi:10.3389/fimmu.2023.1190379
Justiz-Vaillant AA, Gopaul D, Soodeen S, et al. Neuropsychiatric systemic lupus erythematosus: molecules involved in its imunopathogenesis, clinical features, and treatment. Molecules. 2024;29(4):747. doi:10.3390/molecules29040747
Toumi E, Mezouar S, Plauzolles A, et al. Gut microbiota in SLE: from animal models to clinical evidence and pharmacological perspectives. Lupus Sci Med. 2023;10(1):e000776. doi:10.1136/lupus-2022-000776
Liu JL, Woo JMP, Parks CG, Costenbader KH, Jacobsen S, Bernatsky S. Systemic lupus erythematosus risk. Rheum Dis Clin North Am. 2022;48(4):827-843. doi:10.1016/j.rdc.2022.06.005
Zhang Y, Cui D. Evolving models and tools for microglial studies in the central nervous system. Neurosci Bull. 2021;37(8):1218-1233. doi:10.1007/s12264-021-00706-8
Bouchalova P, Bouchal P. Current methods for studying metastatic potential of tumor cells. Cancer Cell Int. 2022;22(1):394. doi:10.1186/s12935-022-02801-w
Zhang X, Song B, Carlino MJ, et al. An immunophenotype-coupled transcriptomic atlas of human hematopoietic progenitors. Nat Immunol. 2024;25(4):703-715. doi:10.1038/s41590-024-01782-4
Fukuhara T, Ueda Y, Lee SI, et al. Thymocyte development of humanized mice is promoted by interactions with human-derived antigen presenting cells upon immunization. Int J Mol Sci. 2023;24(14):11705. doi:10.3390/ijms241411705
Lim J, Park C, Kim M, Kim H, Kim J, Lee DS. Advances in single-cell omics and multiomics for high-resolution molecular profiling. Exp Mol Med. 2024;56(3):515-526. doi:10.1038/s12276-024-01186-2
Asif A, Rajpoot K, Graham S, Snead D, Minhas F, Rajpoot N. Unleashing the potential of AI for pathology: challenges and recommendations. J Pathol. 2023;260(5):564-577. doi:10.1002/path.6168
Kumari R, Feuer G, Bourré L. Humanized mouse models for immuno‐oncology drug discovery. Curr Protoc. 2023;3(8):e852. doi:10.1002/cpz1.852
Nieto D, Jiménez G, Moroni L, López‐Ruiz E, Gálvez‐Martín P, Marchal JA. Biofabrication approaches and regulatory framework of metastatic tumor‐on‐a‐chip models for precision oncology. Med Res Rev. 2022;42(5):1978-2001. doi:10.1002/med.21914
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 European Journal of Clinical and Experimental Medicine

This work is licensed under a Creative Commons Attribution 4.0 International License.
Our open access policy is in accordance with the Budapest Open Access Initiative (BOAI) definition: this means that articles have free availability on the public Internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from having access to the Internet itself.
All articles are published with free open access under the CC-BY Creative Commons attribution license (the current version is CC-BY, version 4.0). If you submit your paper for publication by the Eur J Clin Exp Med, you agree to have the CC-BY license applied to your work. Under this Open Access license, you, as the author, agree that anyone may download and read the paper for free. In addition, the article may be reused and quoted provided that the original published version is cited. This facilitates freedom in re-use and also ensures that Eur J Clin Exp Med content can be mined without barriers for the research needs.




