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01.12.2017 | Research | Ausgabe 1/2017 Open Access

Journal of Translational Medicine 1/2017

Design and validation of a disease network of inflammatory processes in the NSG-UC mouse model

Zeitschrift:
Journal of Translational Medicine > Ausgabe 1/2017
Autoren:
Henrika Jodeleit, Pia Palamides, Florian Beigel, Thomas Mueller, Eckhard Wolf, Matthias Siebeck, Roswitha Gropp
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12967-017-1368-4) contains supplementary material, which is available to authorized users.
Henrika Jodeleit and Pia Palamides contributed equally to this work

Abstract

Background

Ulcerative colitis (UC) is a highly progressive inflammatory disease that requires the interaction of epithelial, immune, endothelial and muscle cells and fibroblasts. Previous studies suggested two inflammatory conditions in UC-patients: ‘acute’ and ‘remodeling’ and that the design of a disease network might improve the understanding of the inflammatory processes. The objective of the study was to design and validate a disease network in the NOD-SCID IL2rγnull (NSG)-UC mouse model to get a better understanding of the inflammatory processes.

Methods

Leukocytes were isolated from the spleen of NSG-UC mice and subjected to flow cytometric analysis. RT-PCR and RNAseq analysis were performed from distal parts of the colon. Based on these analyses and the effects of interleukins, chemokines and growth factors described in the literature, a disease network was designed. To validate the disease network the effect of infliximab and pitrakinra was tested in the NSG-UC model. A clinical- and histological score, frequencies of human leukocytes isolated from spleen and mRNA expression levels from distal parts of the colon were determined.

Results

Analysis of leukocytes isolated from the spleen of challenged NSG-UC mice corroborated CD64, CD163 and CD1a expressing CD14+ monocytes, CD1a expressing CD11b+ macrophages and HGF, TARC, IFNγ and TGFß1 mRNA as inflammatory markers. The disease network suggested that a proinflammatory condition elicited by IL-17c and lipids and relayed by cytotoxic T-cells, Th17 cells and CD1a expressing macrophages and monocytes. Conversely, the remodeling condition was evoked by IL-34 and TARC and promoted by Th2 cells and M2 monocytes. Mice benefitted from treatment with infliximab as indicated by the histological- and clinical score. As predicted by the disease network infliximab reduced the proinflammatory response by suppressing M1 monocytes and CD1a expressing monocytes and macrophages and decreased levels of IFNγ, TARC and HGF mRNA. As predicted by the disease network inflammation aggravated in the presence of pitrakinra as indicated by the clinical and histological score, elevated frequencies of CD1a expressing macrophages and TNFα and IFNγ mRNA levels.

Conclusions

The combination of the disease network and the NSG-UC animal model might be developed into a powerful tool to predict efficacy or in-efficacy and potential mechanistic side effects.
Zusatzmaterial
Additional file 1: Figure S1. Gating strategy for human leukocytes isolated from mouse spleen. Table S1. Cellular markers used to define immune cells. Table S2. Monoclonal antibodies used in labelling of surface markers of leukocytes. Table S3. Data set of variables changed upon challenge with ethanol in the NSG-UC mouse model. Table S4. Data set of variables changed upon challenge with ethanol and treated with infliximab. Table S5. Data set of variables changed upon challenge with ethanol and treated with pitrakinra.
Literatur
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