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...

Overview

Journal Inflamm Bowel Dis

Publisher Oxford University Press

Specialty Gastroenterology

Date 2019 Nov 30

PMID 31782956

Citations 7

Authors

Henrika Jodeleit

Janina Caesar

Christina Villarroel Aguilera

Sebastian Sterz

Lesca Holdt

Florian Beigel

Johannes Stallhofer

Simone Breiteneicher

Eckart Bartnik

Matthias Siebeck

Roswitha Gropp

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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Wess V, Schuster-Winkelmann P, Karatekin Y, Malik S, Beigel F, Kuhn F Int J Mol Sci. 2023; 24(15).

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

Unterweger A, Ruscher A, Seuss M, Winkelmann P, Beigel F, Koletzko L Immun Inflamm Dis. 2021; 9(4):1631-1647.

PMID: 34499803 PMC: 8589348. DOI: 10.1002/iid3.516.

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