12/23/2023 0 Comments Nod scid gamma![]() The severity of disease symptoms and pathological manifestations were donor dependent. Colon architecture was characterized by the development of edema, fibrosis, crypt abscesses and hemorrhage. Challenge with ethanol resulted in a mixed infiltrate of immune cells into the lamina propria that comprised CD4+, CD8+ T-cells, CD11b+ macrophages and CD14+ monocytes. Here, we report that NSG mice reconstituted with PBMCs derived from UC individuals developed similar symptoms to those previously observed in oxazolone-challenged mice ( Nolte et al., 2013a). This observation prompted us to assume that the inflammatory cells of UC individuals increase the susceptibility of mice to develop colitis and thus might be more reflective of the human disease. Unexpectedly, similar, albeit milder, effects were observed with ethanol as the solvent for oxazolone when a UC individual served as donor. In this model, UC-like symptoms were induced through rectal challenge with oxazolone. Therefore, we have developed a model that is based on immunocompromised NOD- scid IL2R γ null (NSG) mice reconstituted with peripheral blood mononuclear cells (PBMCs) derived from UC-affected individuals ( Nolte et al., 2013a). In addition, they cannot be used when species-specific responses are involved, or when high sequence and/or structural similarity between inhibitors and ligands across species is required in order to interact with receptors of interest. However, 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. For practical reasons, 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 2,4,6-trinitrobenzenesulfonic acid (TNBS), leading to the development of colitis-like symptoms ( Kiesler et al., 2015). Thus, this model is partially reflective of the human disease and might help to increase the translation of animal and clinical studies.Īnimal models present one of the biggest scientific challenges in exploring the etiology of complex inflammatory diseases. Treatment with infliximab ameliorated symptoms and pathological manifestations, whereas pitrakinra had no therapeutic benefit. Quantitative real-time PCR (RT-PCR) analysis from distal parts of the colon indicated that IFNγ might be one of the cytokines driving inflammation. Analysis of human leucocytes from the colon of challenged mice identified CD14+ monocytes and CD11b+ monocytes as the predominant populations. 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. TARC, TGFβ1 and HGF expression increased in distal parts of the colon. 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. In an attempt to overcome these problems, we have developed a mouse model that relies on NOD- scid IL2R γ null mice reconstituted with peripheral blood mononuclear cells derived from UC-affected individuals. 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. 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. 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.
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