Abstract
ABSTRACTAnimal 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.
Highlights
Animal models present one of the biggest scientific challenges in exploring the etiology of complex inflammatory diseases
Characterization of inflammatory response in ethanolchallenged mice In order to gain a better understanding of the inflammatory responses evoked by the challenge with ethanol in NSG mice reconstituted with peripheral blood mononuclear cells (PBMCs) derived from ulcerative colitis (UC)-affected individuals and to elucidate whether this model is reflective of the human disease, the response to challenge was analyzed with regard to the development of a clinical and histological score, macroscopic changes of the colon, the frequency of leucocytes isolated from the spleen and colon, and cytokine and growth factor expression in the colon
The first aim of this study was to characterize the inflammatory response mounted in NSG mice that had been reconstituted with PBMCs derived from donors with UC upon challenge with ethanol
Summary
Animal models present one of the biggest scientific challenges in exploring the etiology of complex inflammatory diseases. Mice are the preferred animals in which cases of ulcerative colitis (UC) are usually induced with toxins such as oxazolone, dextran sodium sulphate (DSS) or 2,4,6trinitrobenzenesulfonic acid (TNBS), leading to the development of colitis-like symptoms (Kiesler et al, 2015) These models differ substantially from the human disease because they poorly reflect the pathophysiological mechanisms of a genetically heterogeneous population of affected individuals that are often diseased for decades. Similar, albeit milder, effects were observed with ethanol as the solvent for oxazolone when a UC individual served as donor This observation prompted us to assume that the inflammatory cells of UC individuals increase the susceptibility of mice to develop colitis and might be more reflective of the human disease. Treatment resulted in an increase of CD8+ cells and central memory
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