The Combination of Patient Profiling and Preclinical Studies in a Mouse Model Based on NOD/Scid IL2Rγ null Mice Reconstituted With Peripheral Blood Mononuclear Cells From Patients With Ulcerative Colitis May Lead to Stratification of Patients for Treatment With Adalimumab.
Adalimumab
/ pharmacology
Adult
Aged
Animals
Colitis, Ulcerative
/ blood
Colon
/ pathology
Disease Models, Animal
Female
Humans
Inflammation
/ pathology
Leukocytes, Mononuclear
/ drug effects
Longitudinal Studies
Male
Mice
Mice, Inbred NOD
Mice, SCID
Middle Aged
Monocytes
/ drug effects
Spleen
/ pathology
T-Lymphocytes, Helper-Inducer
/ drug effects
Young Adult
NOD/scid IL-2Rγ null
NSG-UC
adalimumab
immunological profiling
inflammatory bowel disease
ulcerative colitis
Journal
Inflammatory bowel diseases
ISSN: 1536-4844
Titre abrégé: Inflamm Bowel Dis
Pays: England
ID NLM: 9508162
Informations de publication
Date de publication:
04 03 2020
04 03 2020
Historique:
received:
06
08
2019
pubmed:
30
11
2019
medline:
7
4
2021
entrez:
30
11
2019
Statut:
ppublish
Résumé
To date, responsiveness to tumor necrosis factor alpha inhibitors in ulcerative colitis (UC) patients is not predictable. This is partially due to a lack of understanding of the underlying inflammatory processes. The aim of this study was to identify immunological subgroups of patients with UC and to test responsiveness to adalimumab in these subgroups in the mouse model of ulcerative colitis (UC), which is based on NOD/scid IL-2Rγ null (NSG) mice reconstituted with peripheral blood mononuclear cells (PBMCs; NSG-UC). The immunological profiles of 40 UC patients and 16 non-UC donors were determined by flow cytometric analysis of PBMCs in a snapshot and longitudinal study and analyzed by principal component, orthogonal partial least square discrimination (oPLS-DA), and hierarchical clustering analysis. NSG mice were reconstituted 5 times at consecutive time points with PBMCs from a single donor and were analyzed for frequencies of human leukocytes and histological phenotype. The response to adalimumab of 2 identified subgroups was tested in the NSG-UC model. We used the clinical, colon, and histological score, serum levels of glutamic and aspartic acid, and IL-6 and IL-1ß. Response was analyzed by oPLS-DA. Analysis revealed a distinction between UC and non-UC donors. Hierarchical clustering identified 2 major subgroups in UC patients. Group I was characterized by TH17 and M1 monocytes, group II by TH2/TH1, and switched B cells. These subgroups reflect the dynamics of inflammation as patients. NSG-UC mice achieved an immunological phenotype reflecting the patient's immunological phenotype. oPLS-DA revealed that NSG-UC mice reconstituted with PBMCs from group II responded better to adalimumab. The combination of profiling and testing of therapeutics in the NSG-UC model may lead to individualized and phase-dependent therapies.
Sections du résumé
BACKGROUND
To date, responsiveness to tumor necrosis factor alpha inhibitors in ulcerative colitis (UC) patients is not predictable. This is partially due to a lack of understanding of the underlying inflammatory processes. The aim of this study was to identify immunological subgroups of patients with UC and to test responsiveness to adalimumab in these subgroups in the mouse model of ulcerative colitis (UC), which is based on NOD/scid IL-2Rγ null (NSG) mice reconstituted with peripheral blood mononuclear cells (PBMCs; NSG-UC).
METHODS
The immunological profiles of 40 UC patients and 16 non-UC donors were determined by flow cytometric analysis of PBMCs in a snapshot and longitudinal study and analyzed by principal component, orthogonal partial least square discrimination (oPLS-DA), and hierarchical clustering analysis. NSG mice were reconstituted 5 times at consecutive time points with PBMCs from a single donor and were analyzed for frequencies of human leukocytes and histological phenotype. The response to adalimumab of 2 identified subgroups was tested in the NSG-UC model. We used the clinical, colon, and histological score, serum levels of glutamic and aspartic acid, and IL-6 and IL-1ß. Response was analyzed by oPLS-DA.
RESULTS
Analysis revealed a distinction between UC and non-UC donors. Hierarchical clustering identified 2 major subgroups in UC patients. Group I was characterized by TH17 and M1 monocytes, group II by TH2/TH1, and switched B cells. These subgroups reflect the dynamics of inflammation as patients. NSG-UC mice achieved an immunological phenotype reflecting the patient's immunological phenotype. oPLS-DA revealed that NSG-UC mice reconstituted with PBMCs from group II responded better to adalimumab.
CONCLUSIONS
The combination of profiling and testing of therapeutics in the NSG-UC model may lead to individualized and phase-dependent therapies.
Identifiants
pubmed: 31782956
pii: 5648003
doi: 10.1093/ibd/izz284
pmc: PMC7054775
doi:
Substances chimiques
Adalimumab
FYS6T7F842
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
557-569Informations de copyright
© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.
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