NOD/scid IL-2Rγnull mice reconstituted with peripheral blood mononuclear cells from patients with Crohn's disease reflect the human pathological phenotype.

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.

Are we curing one evil with another? A translational approach targeting the role of neoatherosclerosis in late stent failure.

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.

La neoateroesclerosis se define como infiltración de macrófagos espumosos en la zona periprotésica o de la neoíntima tras una implantación de stent, lo cual posiblemente derive en un fracaso tardío del stent mediante cambios ateroescleróticos progresivos, incluidos la calcificación, fibroateromas, fibroateromas de cápsula fina (FACF) y trombosis del stent (TS). Gracias a los estudios de autopsia humana y de imagen intravascular se ha podido comprender la formación de la neoateroesclerosis de una manera fisiopatológica similar a la ateroesclerosis nativa pero significativamente acelerada. Esta aceleración se basa principalmente en la alteración de la integridad endotelial con una función de barrera insuficiente y una mayor transmigración de lípidos a consecuencia de una lesión vascular tras una intervención coronaria y, especialmente, tras la implantación de stents farmacoactivos. En este artículo ofrecemos un resumen de las perspectivas translacionales sobre la fisiopatología de la enfermedad y analizamos los enfoques terapéuticos para abordar esta nueva enfermedad. Presentamos un modelo animal de neoateroesclerosis innovador junto con experimentos in vitro complementarios, en los cuales se pone de manifiesto que la integridad endotelial dañada causa una mayor permeabilidad para el colesterol de las LDL (LDL), lo que da lugar a que los monocitos se transformen en células espumosas. Asimismo, comentamos los criterios indirectos de valoración de imagen intravascular a fin de mejorar el diagnóstico fiable de la neoateroesclerosis en fase inicial. Por último, en un enfoque terapéutico para prevenir la neoateroesclerosis del stent con andamios de magnesio biorreabsorbibles (BRS) y un tratamiento sistémico con estatinas se demostró la posibilidad de mejorar la cicatrización y la reendotelización arteriales, lo que derivó en la formación de neoateroesclerosis significativamente más lenta en un modelo animal de neoateroesclerosis.