Introduction Crohn's disease (CD) is characterized by pronounced intestinal fibrosis and severe mucosal damage and conventional animal models are limited to reflect these pathological manifestations. The aim of this study was to examine whether the combination of patient immune‐profiling and preclinical studies in a mouse model based on NOD/scid IL‐2Rγnull (NSG) reconstituted with peripheral blood mononuclear cells (PBMC) from CD patients has the capacity to harmonize ex vivo human and in vivo animal studies. Methods Immunological profiles of CD (n = 24) and ulcerative colitis (UC) patients (n = 47) were established by flow cytometry of subgroups of immune cells and subjected to hierarchical cluster and estimation graphics analyses. Pathological phenotypes of NSG mice, which were reconstituted with PBMC from CD, UC, and non‐IBD donors (NSG‐CD, NSG‐UC, and NSG‐non‐IBD) were compared. Readouts were the clinical, colon, and histological scores; subtypes of immune cells from spleen and colon; and levels of inflammatory markers, such as c‐reactive protein (CRP), monocyte chemotactic protein (MCP)‐3, transforming growth factor‐beta (TGFß), and hepatocyte growth factor (HGF). Fibrocytes were identified by immunohistochemistry in colonic sections. Results CD patients were significantly clustered in a group characterized by increased levels of TH1, TH2 cells, and decreased levels of CD14+ CD163+ monocytes (p = .003). In contrast to NSG‐UC mice, NSG‐CD mice exhibited an immune‐remodeling phenotype characterized by enhanced collagen deposition, elevated levels of CD14+ CD163+ monocytes, HGF, and TGFß. This phenotype was further corroborated by the presence of human fibrocytes as components of fibrotic areas. Conclusion The NSG‐CD model partially reflects the human disease and allows for studying the development of fibrosis.

Neoatherosclerosis is defined as foamy macrophage infiltration into the peri-strut or neointimal area after stent implantation, potentially leading to late stent failure through progressive atherosclerotic changes including calcification, fibroatheroma, thin-cap fibroatheroma, and rupture with stent thrombosis (ST) in advanced stages. Human autopsy as well as intravascular imaging studies have led to the understanding of neoatherosclerosis formation as a similar but significantly accelerated pathophysiology as compared to native atherosclerosis. This acceleration is mainly based on disrupted endothelial integrity with insufficient barrier function and augmented transmigration of lipids following vascular injury after coronary intervention and especially after implantation of drug-eluting stents. In this review, we summarize translational insights into disease pathophysiology and discuss therapeutic approaches to tackle this novel disease entity. We introduce a novel animal model of neoatherosclerosis alongside accompanying in vitro experiments, which show impaired endothelial integrity causing increased permeability for low-density lipoprotein cholesterol resulting in foam cell transformation of human monocytes. In addition, we discuss novel intravascular imaging surrogates to improve reliable diagnosis of early stage neoatherosclerosis. Finally, a therapeutic approach to prevent in-stent neoatherosclerosis with magnesium-based bioresorbable scaffolds and systemic statin treatment demonstrated the potential to improve arterial healing and re-endothelialization, leading to significantly mitigated neoatherosclerosis formation in an animal model of neoatherosclerosis.

Background Recently, we have developed a mouse model that relies on NOD-scid IL-2Rγnull (NSG) mice reconstituted with peripheral blood mononuclear cells (PBMC) derived from patients with ulcerative colitis (UC, NSG-UC). In this model, symptoms of UC are induced by rectal challenge with ethanol. The objective of the study was to adapt this model to Crohn’s disease and to compare the phenotypes of the NSG-UC and NSG-CD mouse models. Methods NSG mice were reconstituted with PBMC from UC (n = 4) or CD (n = 3) patients. Mice were separated into two groups: unchallenged control and ethanol challenged mice. Readout were clinical-, colon and histological scores, analysis of frequencies of subgroups of human T cells, monocytes and B cells isolated from spleen and colon by flow cytometry, and the expression levels of the inflammatory markers TGFß, CRP, MCP-3, and IL-6 in the colon or serum by Luminex analysis. Results The pathological phenotype was markedly different in NSG-UC mice as compared with NSG-CD mice. Firstly, histological analysis revealed that NSG-UC mice exhibited more of a pro-inflammatory phenotype as indicated by a severe influx of inflammatory cells, oedema, crypt loss, crypt abscesses and epithelial hyperplasia. In contrast, NSG-CD mice displayed crypt loss and goblet cell atrophy and pronounced fibrosis indicating ongoing wound healing processes. These observations were corroborated by frequencies of splenic and colonic leucocytes. Antigen experienced CD4+ T (CD45RO+) cells and switched B cells (CD19+ CD27+ IgD-) were significantly increased in NSG-UC mice, whereas significantly higher levels of experienced CD8+ T cells and M1 (CD64+), M2 (CD163+) CD14+ monocytes and unswitched B cells (CD19+ CD27+ IgD+) indicated a monocyte driven inflammation in NSG-CD mice. This observation was also reflected in the colon of mice. Inflammation in UC was characterised by increased frequencies of neutrophils, activated CD4+ T cells (CD69+) and increased levels of CRP and MCP-3, whereas NSG-CD mice were signified by increased frequencies of M2 and M1 monocytes and of TGFß levels. In contrast to NSG-CD mice, NSG-UC mice also displayed higher serum levels of IL-6. Secondly, the impact of ethanol was more pronounced in the NSG-UC mice. In NSG-CD mice, the challenge did not evoke significant differences as compared with unchallenged control mice. Conclusion The comparison of pathological phenotypes of the NSG-UC and NSG-CD mouse models revealed differences, some of which reflect the respective human disease. The NSG-UC and NSG-CD mouse models may constitute powerful tools to get a better understanding of the different inflammatory processes in UC and CD.