bims-hummad Biomed News
on Humanised mouse models of autoimmune disorders
Issue of 2025–08–31
two papers selected by
Maksym V. Kopanitsa, Charles River Laboratories
  1. Basophil-derived exosomes exacerbate systemic lupus erythematosus by regulating B-cell proliferation via miR-24550.
  2. Genetically modified CD19-targeting IL-15 secreting NK cells for the treatment of systemic lupus erythematosus.
  1. BMC Med. 2025 Aug 22. 23(1): 490
    Basophil-derived exosomes exacerbate systemic lupus erythematosus by regulating B-cell proliferation via miR-24550.
    Jiaxuan Chen, Shuzhen Liao, Jiaqi Lun, Xing Lu, Bitang Huang, Xiaoxian Liu, Xiaowei Xu, Lawei Yang, Fengbiao Guo, Liuyong You, Haiyan Xiao, Hua-Feng Liu, Qingjun Pan.
       BACKGROUND: Systemic lupus erythematosus (SLE) is a complex autoimmune disease where B-cell proliferation and activation play a pivotal role in pathogenesis. While the role of basophils in SLE is recognized, the impact of basophil-derived exosomes on B-cell proliferation and activation has not been thoroughly investigated.
    METHODS: Exosomes from human basophils in both resting and activated states were isolated and characterized. These exosomes were then co-cultured with B cells to assess their effects on B-cell survival and proliferation. To investigate the in vivo roles, a Pristane-induced lupus model in Mcpt8flox/flox CAGGCre-ERTM mice was utilized. The Pristane-Mcpt8flox/flox, CAGGCre-ERTM mice were analyzed for basophil-derived exosome accumulation in the spleen and kidneys, and the effects on immune cell proliferation and plasma cell-plasmablast balance were assessed. Transcriptomic analysis was conducted on basophil-derived exosomes to identify key non-coding RNAs. Lupus mice were humanized by transplanting peripheral blood mononuclear cells (PBMCs) from patients with SLE into immunodeficient mice to evaluate the effects of intervening miR-24550 in B cells.
    RESULTS: Activated basophil-derived exosomes were found to enhance B-cell survival and proliferation in patients with SLE. In the lupus mouse model, basophil-derived exosomes accumulated primarily in the spleen and kidneys, inducing excessive immune cell proliferation and disrupting the plasma cell-plasmablast balance, which worsened kidney damage. Transcriptomic analysis revealed key non-coding RNAs within basophil-derived exosomes. Activated basophil-derived exosomes were internalized by B cells, releasing miR-24550, which promoted B-cell proliferation. In humanized SLE mice, inhibiting miR-24550 in B cells reduced immune hyperactivation and improved renal function, similar to the effects of inhibiting basophil-derived exosomes release in Pristane-Mcpt8flox/flox, CAGGCre-ERTM mice. Ultimately, basophil-derived exosomal miR-24550 promotes B-cell proliferation and activation by targeting Krüppel-like factor 5 (KLF5), which exacerbates SLE progression.
    CONCLUSIONS: Basophil-derived exosomal miR-24550 promotes B-cell proliferation and activation by targeting KLF5, thereby exacerbating SLE progression. This study presents a novel strategy for SLE prevention and treatment.
    Keywords:  B cells; Basophils; Exosomes; Systemic lupus erythematosus; miR-24550
    DOI:  https://doi.org/10.1186/s12916-025-04324-3
  2. Ann Rheum Dis. 2025 Aug 25. pii: S0003-4967(25)04298-0. [Epub ahead of print]
    Genetically modified CD19-targeting IL-15 secreting NK cells for the treatment of systemic lupus erythematosus.
    Yakai Fu, Zupeng Xu, Chunmei Wu, Fangjie Gao, Pengyu Huang, Fuwei Jiang, Chuxuan Hu, Nick Patsoukis, Yiyang Wang, Zejin Cui, Limin Wen, Peiying Li, Chong Wang, Shuang Ye, Zhuoxiao Cao, Qiong Fu.
       OBJECTIVES: Given the efficacy of B-cell depletion therapy in systemic lupus erythematosus (SLE) treatment and the capacity of engineered natural killer (NK) cells in B-cell elimination, we explored the potential of genetically modified NK cells to target CD19 for the treatment of SLE.
    METHODS: Peripheral blood-derived NK cells were engineered with CAR.CD19/interleukin (IL)-15 (XB-19.15) or CAR.CD19 alone. In vitro assays tested cytotoxicity, proliferation (Ki-67), and cytokine release (IL-15/interferon-gamma [IFN-γ]] against CD19+ cells (Raji, Nalm6, SLE B-cell). In vivo models included Nalm6-luc xenografts, humanised CD34+ mice, and SLE peripheral blood mononuclear cells xenografts to assess efficacy, persistence, and safety. A phase 1 trial enrolled 3 patients with refractory SLE receiving XB-19.15 as a proof-of-concept study.
    RESULTS: XB-19.15 showed superior cytotoxicity, sustained IL-15 secretion, and enhanced proliferation in vitro. In the mouse model, XB-19.15 showed significant dose-dependent tumour regression of Nalm-6 and B-cell depletion of humanised mice with long-term persistence in various lymphoid organs. The total levels of hIgG and anti-dsDNA antibodies were decreased in XB-19.15-treated groups with deep clearance of B-cell and plasma cells of bone marrow and spleen in the SLE xenograft model, indicating potential attenuation of SLE. Three patients received XB-19.15 achieved improvement in disease activity and reset of B-cell repertoires without severe adverse events.
    CONCLUSIONS: XB-19.15 enables potent, durable B-cell depletion and immune resetting in SLE with off-the-shelf utility and favourable safety. Preclinical and early clinical data support further trials to optimise dosing and confirm long-term efficacy.
    DOI:  https://doi.org/10.1016/j.ard.2025.07.028
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