Immunity, Inflammation and Disease (Dec 2021)

NOD/scid IL‐2Rγnull mice reconstituted with peripheral blood mononuclear cells from patients with Crohn's disease reflect the human pathological phenotype

  • Anna‐Lena Unterweger,
  • Alena Rüscher,
  • Marietta Seuß,
  • Paula Winkelmann,
  • Florian Beigel,
  • Leandra Koletzko,
  • Simone Breiteneicher,
  • Matthias Siebeck,
  • Roswitha Gropp,
  • Attila Aszodi

DOI
https://doi.org/10.1002/iid3.516
Journal volume & issue
Vol. 9, no. 4
pp. 1631 – 1647

Abstract

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Abstract Introduction Crohn's disease (CD) is characterized by pronounced intestinal fibrosis and severe mucosal damage and conventional animal models are limited to reflect these pathological manifestations. The aim of this study was to examine whether the combination of patient immune‐profiling and preclinical studies in a mouse model based on NOD/scid IL‐2Rγnull (NSG) reconstituted with peripheral blood mononuclear cells (PBMC) from CD patients has the capacity to harmonize ex vivo human and in vivo animal studies. Methods Immunological profiles of CD (n = 24) and ulcerative colitis (UC) patients (n = 47) were established by flow cytometry of subgroups of immune cells and subjected to hierarchical cluster and estimation graphics analyses. Pathological phenotypes of NSG mice, which were reconstituted with PBMC from CD, UC, and non‐IBD donors (NSG‐CD, NSG‐UC, and NSG‐non‐IBD) were compared. Readouts were the clinical, colon, and histological scores; subtypes of immune cells from spleen and colon; and levels of inflammatory markers, such as c‐reactive protein (CRP), monocyte chemotactic protein (MCP)‐3, transforming growth factor‐beta (TGFß), and hepatocyte growth factor (HGF). Fibrocytes were identified by immunohistochemistry in colonic sections. Results CD patients were significantly clustered in a group characterized by increased levels of TH1, TH2 cells, and decreased levels of CD14+ CD163+ monocytes (p = .003). In contrast to NSG‐UC mice, NSG‐CD mice exhibited an immune‐remodeling phenotype characterized by enhanced collagen deposition, elevated levels of CD14+ CD163+ monocytes, HGF, and TGFß. This phenotype was further corroborated by the presence of human fibrocytes as components of fibrotic areas. Conclusion The NSG‐CD model partially reflects the human disease and allows for studying the development of fibrosis.

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