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

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 p...

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Autores principales: Unterweger, Anna‐Lena, Rüscher, Alena, Seuß, Marietta, Winkelmann, Paula, Beigel, Florian, Koletzko, Leandra, Breiteneicher, Simone, Siebeck, Matthias, Gropp, Roswitha, Aszodi, Attila
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589348/
https://www.ncbi.nlm.nih.gov/pubmed/34499803
http://dx.doi.org/10.1002/iid3.516
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author Unterweger, Anna‐Lena
Rüscher, Alena
Seuß, Marietta
Winkelmann, Paula
Beigel, Florian
Koletzko, Leandra
Breiteneicher, Simone
Siebeck, Matthias
Gropp, Roswitha
Aszodi, Attila
author_facet Unterweger, Anna‐Lena
Rüscher, Alena
Seuß, Marietta
Winkelmann, Paula
Beigel, Florian
Koletzko, Leandra
Breiteneicher, Simone
Siebeck, Matthias
Gropp, Roswitha
Aszodi, Attila
author_sort Unterweger, Anna‐Lena
collection PubMed
description 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‐2Rγ(null) (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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spelling pubmed-85893482021-11-19 NOD/scid IL‐2Rγ(null) mice reconstituted with peripheral blood mononuclear cells from patients with Crohn's disease reflect the human pathological phenotype Unterweger, Anna‐Lena Rüscher, Alena Seuß, Marietta Winkelmann, Paula Beigel, Florian Koletzko, Leandra Breiteneicher, Simone Siebeck, Matthias Gropp, Roswitha Aszodi, Attila Immun Inflamm Dis Original Articles 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‐2Rγ(null) (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. John Wiley and Sons Inc. 2021-09-09 /pmc/articles/PMC8589348/ /pubmed/34499803 http://dx.doi.org/10.1002/iid3.516 Text en © 2021 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Unterweger, Anna‐Lena
Rüscher, Alena
Seuß, Marietta
Winkelmann, Paula
Beigel, Florian
Koletzko, Leandra
Breiteneicher, Simone
Siebeck, Matthias
Gropp, Roswitha
Aszodi, Attila
NOD/scid IL‐2Rγ(null) mice reconstituted with peripheral blood mononuclear cells from patients with Crohn's disease reflect the human pathological phenotype
title NOD/scid IL‐2Rγ(null) mice reconstituted with peripheral blood mononuclear cells from patients with Crohn's disease reflect the human pathological phenotype
title_full NOD/scid IL‐2Rγ(null) mice reconstituted with peripheral blood mononuclear cells from patients with Crohn's disease reflect the human pathological phenotype
title_fullStr NOD/scid IL‐2Rγ(null) mice reconstituted with peripheral blood mononuclear cells from patients with Crohn's disease reflect the human pathological phenotype
title_full_unstemmed NOD/scid IL‐2Rγ(null) mice reconstituted with peripheral blood mononuclear cells from patients with Crohn's disease reflect the human pathological phenotype
title_short NOD/scid IL‐2Rγ(null) mice reconstituted with peripheral blood mononuclear cells from patients with Crohn's disease reflect the human pathological phenotype
title_sort nod/scid il‐2rγ(null) mice reconstituted with peripheral blood mononuclear cells from patients with crohn's disease reflect the human pathological phenotype
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589348/
https://www.ncbi.nlm.nih.gov/pubmed/34499803
http://dx.doi.org/10.1002/iid3.516
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