bims-hummad Biomed News
on Humanised mouse models of autoimmune disorders
Issue of 2024–08–11
two papers selected by
Maksym V. Kopanitsa, Charles River Laboratories
  1. Psoriatic arthritis subtypes are phenocopied in humanized mice.
  2. A Novel Immunodeficient Hyperglycemic Mouse Carrying the Ins1 Akita Mutation for Xenogeneic Islet Cell Transplantation.
  1. JCI Insight. 2024 Jul 02. pii: e178213. [Epub ahead of print]9(15):
    Psoriatic arthritis subtypes are phenocopied in humanized mice.
    Christopher T Ritchlin, Javier Rangel-Moreno, Delaney Martino, Brian Isett, Ananta Paine, Soumyaroop Bhattacharya, Jeffrey Fox, Ernest M Meyer, Riyue Bao, Tullia Bruno, Francisco Tausk, Maria de la Luz Garcia-Hernandez.
      Psoriatic arthritis (PsA) is a complex inflammatory disease that challenges diagnosis and complicates the rational selection of effective therapies. Although T cells are considered active effectors in psoriasis and PsA, the role of CD8+ T cells in pathogenesis is not well understood. We selected the humanized mouse model NSG-SGM3 transgenic strain to examine psoriasis and PsA endotypes. Injection of PBMCs and sera from patients with psoriasis and PsA generated parallel skin and joint phenotypes in the recipient mouse. The transfer of human circulating memory T cells was followed by migration and accumulation in the skin and synovia of these immunodeficient mice. Unexpectedly, immunoglobulins were required for recapitulation of the clinical phenotype of psoriasiform lesions and PsA domains (dactylitis, enthesitis, bone erosion). Human CD8+ T cells expressing T-bet, IL-32 and CXCL14 were detected by spatial transcriptomics in murine synovia and by immunofluorescence in the human PsA synovia. Importantly, depletion of human CD8+ T cells prevented skin and synovial inflammation in mice humanized with PsA peripheral blood cells. The humanized model of psoriasis and PsA represents a valid platform for accelerating the understanding of disease pathogenesis, improving the design of personalized therapies, and revealing psoriatic disease targets.
    Keywords:  Arthritis; Autoimmune diseases; Dermatology; Inflammation
    DOI:  https://doi.org/10.1172/jci.insight.178213
  2. Transplantation. 2024 Aug 06.
    A Novel Immunodeficient Hyperglycemic Mouse Carrying the Ins1 Akita Mutation for Xenogeneic Islet Cell Transplantation.
    Kenta Nakano, Motohito Goto, Satsuki Fukuda, Rieko Yanobu-Takanashi, Shigeharu G Yabe, Yukiko Shimizu, Tetsushi Sakuma, Takashi Yamamoto, Masayuki Shimoda, Hitoshi Okochi, Riichi Takahashi, Tadashi Okamura.
       BACKGROUND: For patients who have difficulty controlling blood glucose even with insulin administration, xenogeneic islet cells, including human stem cell-derived pancreatic islets (hSC-islet) and porcine islets, have garnered attention as potential solutions to challenges associated with donor shortages. For the development of diabetes treatment modalities that use cell transplantation therapy, it is essential to evaluate the efficacy and safety of transplanted cells using experimental animals over the long term.
    METHODS: We developed permanent diabetic immune-deficient mice by introducing the Akita (C96Y) mutation into the rodent-specific Insulin1 gene of NOD/Shi-scid IL2rγcnull (NOG) mice (Ins1C96Y/C96Y NOG). Their body weight, nonfasting blood glucose, and survival were measured from 4 wk of age. Insulin sensitivity was assessed via tolerance tests. To elucidate the utility of these mice in xenotransplantation experiments, we transplanted hSC-islet cells or porcine islets under the kidney capsules of these mice.
    RESULTS: All male and female homozygous mice exhibited persistent severe hyperglycemia associated with β-cell depletion as early as 4 wk of age and exhibited normal insulin sensitivity. These mice could be stably engrafted with hSC-islets, and the mice that received porcine islet grafts promptly exhibited lowered blood glucose levels, maintaining blood glucose levels below the normal glucose range for at least 52 wk posttransplantation.
    CONCLUSIONS: The Ins1C96Y/C96Y NOG mouse model provides an effective platform to assess both the efficacy and safety of long-term xenograft engraftment without the interference of their immune responses. This study is expected to contribute essential basic information for the clinical application of islet cell transplantation.
    DOI:  https://doi.org/10.1097/TP.0000000000005152
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