Characterization and validation of a mouse model for colitis ulcerosa based on NOD-scid IL2R γnull mice reconstituted with peripheral blood mononuclear cells from patients.

Abstract

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 by challenge with toxins such as oxazolone, DSS or TNBS have been instrumental in understanding inflammatory processes of UC, however, they neither reflect the heterogeneous patient population observed in UC nor can they be used when inhibitors require high homology between ligands and receptors. In an attempt to overcome these problems we have developed a mouse model which relies on NOD-SCID IL2rγnull mice reconstituted with peripheral blood mononuclear cells derived from patients suffering from UC. Upon challenge with ethanol mice developed colitis-like symptoms and changes of 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, TGFß1 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 colon of challenged mice identified CD14+ monocytes and CD11b+ monocytes as predominant populations. RTPCR analysis from distal parts of the colon indicated that IFNγ might be one cytokine 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 translatability between animal- and clinical studies.