Magnetic Particle Imaging of liver tumors in small animal models

In vivo liver visualization can be realized with Magnetic Particle Imaging (MPI) since a major part of the iron oxide nanoparticles – intravenously injected and imaged with MPI – is finally taken up by the mononuclear phagocytic system (MPS) of the liver. In this study, the possibility to detect and characterize liver tumors with MPI was analyzed. Genetically modified mice developing hepatocellular carcinoma (HCC) were continuously screened with high-field MRI. In case of liver lesions with diameters larger 5 mm, the mice were sequentially imaged with MRI and MPI after the intravenous injection of ferucarbotran (Resovist®). For comparison of liver morphologies represented by MPI and MRI, image data of both modalities were fused assisted by external MPI and MRI fiducial markers. A good correlation between MPI and MRI images was found with image analysis-based 2-D correlation coefficients of around 0.7. Liver lesions – characterized by a missing accumulation of ferucarbotran – led to signal gaps or drops in the MPI signal depending on their actual size and location. While lesions with diameters larger than 5 mm caused visible effects in the MPI signal, smaller sized lesions could not be detected. This was mainly attributed to the comparable low MPI resolution of a few millimeters in this study. The principle feasibility of liver tumor visualizations with MPI was demonstrated motivating more detailed studies on liver MPI for diagnostic and interventional applications

Oxysterol 7-α Hydroxylase (CYP7B1) Attenuates Metabolic-Associated Fatty Liver Disease in Mice at Thermoneutrality

Ambient temperature is an important determinant of both the alternative bile acid synthesis pathway controlled by oxysterol 7-α hydroxylase (CYP7B1) and the progression of metabolic-associated fatty liver disease (MAFLD). Here, we investigated whether CYP7B1 is involved in the etiology of MAFLD under conditions of low and high energy expenditure. For this, Cyp7b1−/− and wild type (WT) mice were fed a choline-deficient high-fat diet and housed either at 30 °C (thermoneutrality) or at 22 °C (mild cold). To study disease phenotype and underlying mechanisms, plasma and organ samples were analyzed to determine metabolic parameters, immune cell infiltration by immunohistology and flow cytometry, lipid species including hydroxycholesterols, bile acids and structural lipids. In WT and Cyp7b1−/− mice, thermoneutral housing promoted MAFLD, an effect that was more pronounced in CYP7B1-deficient mice. In these mice, we found higher plasma alanine aminotransferase activity, hyperlipidemia, hepatic accumulation of potentially harmful lipid species, aggravated liver fibrosis, increased inflammation and immune cell infiltration. Bile acids and hydroxycholesterols did not correlate with aggravated MAFLD in Cyp7b1−/− mice housed at thermoneutrality. Notably, an up-regulation of lipoprotein receptors was detected at 22 °C but not at 30 °C in livers of Cyp7b1−/− mice, suggesting that accelerated metabolism of lipoproteins carrying lipotoxic molecules counteracts MAFLD progression

Dysfunction of hepatic regulatory T cells in experimental sclerosing cholangitis is related to IL-12 signaling

Background & Aims: Reduced numbers of regulatory T cells (Treg) have been reported in patients with primary sclerosing cholangitis (PSC); therefore, Treg expansion might serve as a therapeutic approach. Here, we explored whether treatment with IL-2/IL-2 monoclonal antibody complex (IL-2/IL-2Ab complex) could provide in vivo Treg expansion and treatment of experimental sclerosing cholangitis. Methods: Treg were expanded by repeated injection of IL-2/IL2Ab complex in mouse models of cholangitis (Mdr2(-/-), DDC) or colitis (dextran sulfate sodium [DSS]) as control. In vitro suppressive capacity and gene expression were analyzed in isolated hepatic and splenic Treg. Results: In vivo expansion resulted in a 5-fold increase in hepatic Treg, which localized within the inflamed portal tracts. However, although Treg expansion was associated with reduced proinflammatory IL-17 and increased anti-inflammatory IL-10 production by hepatic lymphocytes, the severity of cholangitis was not reduced. In contrast, DSS-induced colitis could be improved by Treg expansion, suggesting a selectively reduced functionality of intrahepatic Treg. Indeed, hepatic Treg manifested reduced Foxp3 expression and reduced suppressive capacity compared to splenic Treg. Hepatic Treg dysfunction could be linked to increased IL-12 signaling due to an upregulation of the IL-12 receptor. Accordingly, IL-12 receptor beta 2 knockout mice (IL12rb2(-/-)) were able to maintain hepatic Treg functionality. Conclusions: Hepatic Treg expanded in vivo failed to improve the course of cholangitis, which was related to the effects of hepatic IL-12 on Treg. Therefore, neutralization of IL-12 should be considered as part of treatment strategies targeting Treg in sclerosing cholangitis. Lay summary: Primary sclerosing cholangitis (PSC) is associated with a paucity of regulatory T cells (Treg) that have a particular ability to control immune responses; therefore, in vivo expansion of Treg might serve as a treatment of cholangitis. However, in a mouse model of PSC, we show that Treg enrichment in the liver was not sufficient to provide effective control of cholangitis, as the suppressive functionality of hepatic Treg was significantly limited by IL-12 signals. Thus, neutralization of IL-12 should be considered as part of treatment strategies to improve the efficacy of Treg-based treatments for liver diseases