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.

Animal models reflective of ulcerative colitis (UC) remain a major challenge, and yet are crucial to understand mechanisms underlying the onset of disease and inflammatory characteristics of relapses and remission. Mouse models in which colitis-like symptoms are induced through challenge with toxins such as oxazolone, dextran sodium sulfate (DSS) or 2,4,6-trinitrobenzenesulfonic acid (TNBS) have been instrumental in understanding the inflammatory processes of UC. However, these neither reflect the heterogeneous symptoms observed in the UC-affected population nor can they be used to test the efficacy of inhibitors developed against human targets where high sequence and structural similarity of the respective ligands is lacking. In an attempt to overcome these problems, we have developed a mouse model that relies on NOD-scid IL2R γnull mice reconstituted with peripheral blood mononuclear cells derived from UC-affected individuals. Upon challenge with ethanol, mice developed colitis-like symptoms and changes in the colon architecture, characterized by influx of inflammatory cells, edema, crypt loss, crypt abscesses and epithelial hyperplasia, as previously observed in immune-competent mice. TARC, TGFβ1 and HGF expression increased in distal parts of the colon. Analysis of human leucocytes isolated from mouse spleen revealed an increase in frequencies of CD1a+, CD64+, CD163+ and TSLPR+ CD14+ monocytes, and antigen-experienced CD44+ CD4+ and CD8+ T-cells in response to ethanol. Analysis of human leucocytes from the colon of challenged mice identified CD14+ monocytes and CD11b+ monocytes as the predominant populations. Quantitative real-time PCR (RT-PCR) analysis from distal parts of the colon indicated that IFNγ might be one of the cytokines driving inflammation. Treatment with infliximab ameliorated symptoms and pathological manifestations, whereas pitrakinra had no therapeutic benefit. Thus, this model is partially reflective of the human disease and might help to increase the translation of animal and clinical studies.

BackgroundUlcerative 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.MethodsLeukocytes 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.ResultsAnalysis 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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (10.1186/s12967-017-1368-4) contains supplementary material, which is available to authorized users.

support-information-section). Adipose browning Normalization of adipokinesCardiometabolic health Adipose whitening Hypertrophy and inflammation AtherosclerosisAbstract Obesity is a medical disorder caused by multiple mechanisms of dysregulated energy balance. A major consequence of obesity is an increased risk to develop diabetes, diabetic Maude Giroud has been working on adipose tissue metabolism and obesity since 2012, when she started her PhD on adipose tissue plasticity in the team of Zoubir Amri at the university of Nice Sophia Antipolis in France. She pursued her scientific career as a postdoc at the Helmholtz Centre Munich in the team of Stefan Herzig where she studied novel transcription factors in adipogenesis as well as the role of long non-coding RNAs in thermogenic adipocytes. In 2020-2021, Maude was a senior postdoc in the lab of Alexander Bartelt and gained expertise in the field of obesity-related cardiovascular diseases. After her degree in veterinary medicine, Henrika Jodeleit received her doctoral degree from LMU Munich for her work on autoimmune responses in chronic inflammatory diseases. She continued this work during her postdoc and was also involved in the development of preclinical models for IBD and other inflammatory diseases. She joined Alexander Bartelt's lab in 2019 as a senior postdoc working on cardiovascular diseases. Her work mainly focuses on adaptive mechanisms in models of myocardial infarction.

CD1a-expressing monocytes might act as sensors and mediators of inflammation in UC. Mice benefitted from treatment with anti-CD1a antibodies.