bims-hummad Biomed News
on Humanised mouse models of autoimmune disorders
Issue of 2025–06–01
two papers selected by
Maksym V. Kopanitsa, Charles River Laboratories
  1. PBMC-Humanized Mouse Model for Multiple Sclerosis: Studying Immune Changes and CNS Involvement.
  2. Antisense to human CD39 dysregulates immune metabolism in inflammatory bowel disease.
  1. Bio Protoc. 2025 May 20. 15(10): e5312
    PBMC-Humanized Mouse Model for Multiple Sclerosis: Studying Immune Changes and CNS Involvement.
    Anastasia Dagkonaki, Irini Papazian, Vasileios Gouzouasis, Ariadni Karles, Maria Kourouvani, Theodore Tselios, Eirini Fragkiadaki, Lesley Probert.
      Humanized immune system (HIS) mice are powerful tools for studying human immune system function and dysfunction and developing human-specific immunotherapeutics. The availability of sophisticated super immunodeficient mouse strains has allowed immune system humanization using transplants of human peripheral blood mononuclear cells (PBMC) or hematopoietic stem cells. HIS mice are used extensively in immune-oncology, while there are fewer studies in autoimmunity, especially multiple sclerosis (MS). Using the protocol described here, we generated HIS mice that show key features of MS not represented in other widely used MS models [1]. Severely immunodeficient NOD.Cg-B2mem1Tac Prkdcscid Il2rgtm1Sug /JicTac (B2m-NOG) mice, which lack murine B, T, and NK cells and murine major histocompatibility class I molecules and have defective innate immune responses, were transplanted with PBMC from HLA-DRB1-genotyped MS patients and healthy donors. Mice were successfully engrafted with hCD4 and hCD8 T and B lymphocytes and developed both spontaneous and experimental autoimmune encephalomyelitis (EAE)-enhanced T-cell lesions in the central nervous system. B-cell engraftment was highest in mice receiving cells from MS patients with serological evidence for Epstein-Barr virus (EBV) reactivation. This humanized MS model shows advantages over EAE, particularly spontaneous hCD8 T-cell lesions in the brain and spinal cord, mixed hCD8/hCD4 T-cell lesions in EAE-immunized mice, and more severe lesions in mice engrafted with PBMC from MS donors carrying the DRB1*15 MS susceptibility allele compared to DRB1*15-positive healthy and DRB1*13-positive MS donors. MS HIS mice represent simple and rapid tools for investigating human immunopathology and the efficacy of therapeutics at a personalized level. Key features • Humanization of severely immunodeficient B2m-NOG mice with human PBMC. • Engraftment analysis of human immune system in mice using multicolor flow cytometry. • Animal familiarization and handling techniques. • Epstein-Barr virus latency evaluation in human plasma. • Ex vivo characterization of engrafted T-cell cytokine responses.
    Keywords:  B2m-NOG mice; Epstein–Barr virus infection status; Experimental autoimmune encephalomyelitis; Humanized mice; Multiple sclerosis; PBMC engraftment
    DOI:  https://doi.org/10.21769/BioProtoc.5312
  2. Cell Mol Immunol. 2025 May 26.
    Antisense to human CD39 dysregulates immune metabolism in inflammatory bowel disease.
    Lina Zhang, Cortney Cagle, Du Hanh Nguyen, Graziela Scheuer Gomes, Barbora Gromova, Eva Csizmadia, Arian Karimitar, Ghee Rye Lee, Guanqing Chen, Efi Kokkotou, Laurie Grossberg, Sizun Jiang, Adam S Cheifetz, Satya K Kota, Maria Serena Longhi.
      Defective CD39 levels contribute to an imbalance between Tregs and Th17 effectors in inflammatory bowel disease (IBD). CD39 initiates an ATP hydrolysis cascade that culminates with the generation of adenosine, an immune metabolite that is key to tissue homeostasis. Human CD39 is regulated by an endogenous antisense RNA (CD39-AS) that is markedly elevated in IBD Tregs and Th17 cells. In this study, we investigated how CD39-AS affects the function of Tregs and Th17 cells in healthy subjects and IBD patients. We report that CD39-AS RNA is present in two main splice variants that are specifically expressed by Tregs or Th17 cells. Blockade of CD39-AS via self-delivering oligonucleotides targeting the splice variant expressed in Tregs results in a decrease of glucose transport and glycolysis and in enhanced Treg function and stability in IBD. In Th17 cells, silencing of CD39-AS limits oxidative responses and ameliorates mitochondrial health. These metabolic effects are also noted in a model of experimental colitis in humanized mice, along with reduced disease activity. Thus, in vivo administration of oligonucleotides targeting the Treg or Th17 cell CD39-AS variant limits disease activity, decreases the expression of GLUT1 and improves mitochondrial health in gut-derived CD4 lymphocytes. Mechanistically, activation of HIF-1α and STAT3 results in the upregulation of CD39-AS in IBD cells. In conclusion, CD39-AS is an important modulator of Treg and Th17 cell metabolism. Interference with this antisense RNA, or the factors favoring its upregulation, might contain inflammation and halt disease progression in IBD by restoring immune metabolism and Treg functional stability.
    Keywords:  CD39 antisense; Immune metabolism; Inflammatory bowel disease; Th17 cell; Treg
    DOI:  https://doi.org/10.1038/s41423-025-01295-6
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