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Background & Aims: T cells are central mediators of liver inflammation and represent potential treatment targets in cholestatic liver disease. Whereas emerging evidence shows that bile acids (BAs) affect T cell function, the role of T cells for the regulation of BA metabolism is unknown. In order to understand this interplay, we investigated the influence of T cells on BA metabolism in a novel mouse model of cholangitis., Methods: Mdr2 -/- mice were crossed with transgenic K14-OVAp mice, which express an MHC class I restricted ovalbumin peptide on biliary epithelial cells (Mdr2 -/- xK14-OVAp). T cell-mediated cholangitis was induced by the adoptive transfer of antigen-specific CD8+ T cells. BA levels were quantified using a targeted liquid chromatography-mass spectrometry-based approach., Results: T cell-induced cholangitis resulted in reduced levels of unconjugated BAs in the liver and significantly increased serum and hepatic levels of conjugated BAs. Genes responsible for BA synthesis and uptake were downregulated and expression of the bile salt export pump was increased. The transferred antigen-specific CD8+ T cells alone were able to induce these changes, as demonstrated using Mdr2 -/- xK14-OVAp recipient mice on the Rag1 -/- background. Mechanistically, we showed by depletion experiments that alterations in BA metabolism were partly mediated by the proinflammatory cytokines TNF and IFN-γ in an FXR-dependent manner, a process that in vitro required cell contact between T cells and hepatocytes., Conclusion: Whereas it is known that BA metabolism is dysregulated in sepsis and related conditions, we have shown that T cells are able to control the synthesis and metabolism of BAs, a process which depends on TNF and IFN-γ. Understanding the effect of lymphocytes on BA metabolism will help in the design of combined treatment strategies for cholestatic liver diseases., Lay Summary: Dysregulation of bile acid metabolism and T cells can contribute to the development of cholangiopathies. Before targeting T cells for the treatment of cholangiopathies, it should be determined whether they exert protective effects on bile acid metabolism. Herein, we demonstrate that T cell-induced cholangitis resulted in decreased levels of harmful unconjugated bile acids. T cells were able to directly control synthesis and metabolism of bile acids, a process which was dependent on the proinflammatory cytokines TNF and IFN-γ. Understanding the effect of lymphocytes on bile acid metabolism will help in the design of combined treatment strategies for cholestatic liver diseases., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

To enable causal analysis of port catheter failure, this study aimed to develop an experimental setup for uniaxial tensile tests that addresses the specific requirements of highly elastic medical catheters; and to quantify parameters of the catheters' mechanical competence with respect to effects of artificial aging. Segments of 6F-polyurethane catheters were tested in their native status, after chemical and after mechanical aging. Tension experiments were performed with a rate of 220 mm/min until catheter failure. Material behavior was analyzed based on load cell measurements of the universal test system and an additional optical distance registration. The Young's modulus, the ultimate stress and the ultimate strain were determined. Chemical aging significantly decreased Young's modulus (84%; p = 0.001) and ultimate stress (83%; p < 0.001), whereas mechanical aged samples demonstrated similar results for the Young's modulus (p = 0.772) and a non-significant rise of ultimate stress (13%; p = 0.128). Ultimate strain did not differ significantly regardless of the pretreatment. The results proof reliability, reproducibility and sensitivity to quantify artificial aging induced variations and also promise to detect deviations in material features caused by long-term clinical usage of catheters., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background & Aims: The IL-23/IL-17 axis plays an important role in the pathogenesis of autoimmune diseases and the pathological consequences of infection. We previously showed that immunopathologic mechanisms mediated by inflammatory monocytes underlie the severe focal liver damage induced by the protozoan parasite, Entamoeba histolytica. Here, we analyze the contribution of the IL-23/IL-17 axis to the induction and subsequent recovery from parasite-induced liver damage., Methods: IL-23p19(-/-), IL-17A/F(-/-), CCR2(-/-), and wild-type (WT) mice were intra-hepatically infected with E. histolytica trophozoites and disease onset and recovery were analyzed by magnetic resonance imaging. Liver-specific gene and protein expression during infection was examined by qPCR, microarray, FACS analysis and immunohistochemistry. Immuno-depletion and substitution experiments were performed in IL-23p19(-/-) and WT mice to investigate the role of IL-13 in disease outcome., Results: Liver damage in infected IL-23p19(-/-), IL-17A/F(-/-), and CCR2(-/-) mice was strongly attenuated compared with that in WT mice. IL-23p19(-/-) mice showed reduced accumulation of IL-17 and CCL2 mRNA and proteins. Increased numbers of IL-13-producing CD11b(+)Ly6C(lo) monocytes were associated with disease attenuation in IL-23p19(-/-) mice. Immuno-depletion of IL-13 in IL-23p19(-/-) mice reversed this attenuation and treatment of infected WT mice with an IL-13/anti-IL-13-mAb complex supported liver recovery., Conclusions: The IL-23/IL-17 axis plays a critical role in the immunopathology of hepatic amebiasis. IL-13 secreted by CD11b(+)Ly6C(lo) monocytes may be associated with recovery from liver damage. An IL-13/anti-IL13-mAb complex mimics this function, suggesting a novel therapeutic option to support tissue healing after liver damage., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: It is well-known that the liver can induce immune tolerance, yet this knowledge could, thus far, not be translated into effective treatments for autoimmune diseases. We have previously shown that liver sinusoidal endothelial cells (LSECs) could substantially contribute to hepatic tolerance through their ability to induce CD4+ Foxp3+ regulatory T cells (Tregs). Here, we explored whether the Treg-inducing potential of LSECs could be harnessed for the treatment of autoimmune disease., Methods: We engineered a polymeric nanoparticle (NP) carrier for the selective delivery of autoantigen peptides to LSECs in vivo. In the well-characterized autoimmune disease model of experimental autoimmune encephalomyelitis (EAE), we investigated whether administration of LSEC-targeting autoantigen peptide-loaded NPs could protect mice from autoimmune disease., Results: We demonstrate that NP-based autoantigen delivery to LSECs could completely and permanently prevent the onset of clinical EAE. More importantly, in a therapeutic approach, mice with already established EAE improved rapidly and substantially following administration of a single dose of autoantigen peptide-loaded NPs, whereas the control group deteriorated. Treatment efficacy seemed to depend on Tregs. The Treg frequencies in the spleens of mice treated with autoantigen peptide-loaded NPs were significantly higher than those in vehicle-treated mice. Moreover, NP-mediated disease control was abrogated after Treg depletion by repeated administration of Treg-depleting antibody., Conclusion: Our findings provide proof of principle that the selective delivery of autoantigen peptides to LSECs by NPs can induce antigen-specific Tregs and enable effective treatment of autoimmune disease. These findings highlight the importance of Treg induction by LSECs for immune tolerance., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

We report the case of a 65-year-old patient with esophageal necrosis that developed after thoracic endovascular aortic repair (TEVAR) of a previously stented, ruptured chronic type B aortic dissection. The cause of this complication may have been related to an infected mediastinal hematoma causing esophageal compression. Emergent esophagectomy was performed with success., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: To detect anti-CEACAM5 targeted superparamagnetic iron oxide (SPIO) particles in vitro on the cell surface by quantitative magnetic resonance (MR) imaging and to compare with flow cytometry., Materials and Methods: The monoclonal mouse antibody T84.1 and an appropriate IgG isotype antibody were conjugated to dextran-coated SPIO particles. HT29 cells expressing carcinoembryonic antigen (CEACAM5) were treated with antibody-conjugated SPIO particles. Purified cell samples were examined on a 3.0-T MR scanner using a multi-echo spin-echo sequence for MR relaxometry. Aliquots of the cell samples were further treated with a fluorescein isothiocyanate (FITC) anti-dextran antibody and an Alexa Fluor 488 anti-mouse antibody for the corresponding flow cytometry., Results: MR relaxometry revealed a dose-dependent binding of T84.1-conjugated SPIO particles with a positive correlation between R(2) relaxation rate of cell samples and SPIO particle concentration during incubation (r=0.993, P<.01). Positive correlations were also observed between R(2) relaxation rate and flow cytometry (geometric mean) with both fluorescent antibodies (r=0.972 and r=0.953, both P<.01), respectively., Conclusion: The study revealed the feasibility of quantitative MR imaging of targeted SPIO particles on the cell surface comparable to flow cytometry., (2010 Elsevier Inc. All rights reserved.)

This study aims to investigate the uptake of the experimental ultrasmall superparamagnetic particles of iron oxide (USPIO) contrast agent DDM43/34 (Schering AG, Berlin, Germany) by aortic atherosclerotic plaques using magnetic resonance imaging (MRI) at 3 T. Six Watanabe heritable hyperlipidemic rabbits were injected with USPIO at doses of 0.1-1.0 mmol/kg Fe. Parasagittal magnetic resonance angiography (MRA) scans were acquired using 3D gradient-echo sequences before and after USPIO administration, then again after 6 h, 1 day, 2 days and 5 days. At later time points, when the USPIO concentration was too low to enhance blood signal, additional MRA scans were acquired during the infusion of gadopentate dimeglumine (Magnevist; Schering AG). In the images, widespread susceptibility artifacts demonstrated readily detectable USPIO uptake in the liver, bone marrow and lymphatic vessels. Surprisingly, however, no such effects could be associated specifically with the aortic vessel wall, in contrast to previous studies that showed strong uptake with similar pulse sequences. Histological analysis was performed on aortic slices from two animals, demonstrating that aortic plaques were active but showed very little USPIO uptake, consistent with MRI findings. We conclude that, despite the exciting potential of plaque detection using USPIO, some caution is advised since the absence of susceptibility effects does not necessarily imply the absence of plaque, even at 3 T, which offers increased sensitivity to susceptibility. Future work will investigate the dependence of such results on stage of plaque development, magnetic field strength and choice of contrast agent.

Background: Adult stem cells are promising for the development of novel therapies in regenerative medicine. Acute renal failure (ARF) remains a frequent clinical complication, associated with an unacceptably high mortality rate, in large part due to the ineffectiveness of currently available therapies. The aim of this study was, therefore, to evaluate the therapeutic effectiveness of bone marrow-derived mesenchymal stem cells in a rat model of ischemia/reperfusion (I/R) ARF., Methods: We used a common I/R model in rats to induce ARF by clamping both renal pedicles for 40 minutes. Mesenchymal stem cells were iron-dextran-labeled for in vivo tracking studies by magnetic resonance imaging (MRI) and kidneys were imaged for mesenchymal stem cells immediately after infusion and at day 3 after ARF. Renal injury was scored on day 3 and cells were additionally tracked by Prussian blue staining., Results: We show in I/R-induced ARF in rats, modeling the most common form of clinical ARF, that infusion of mesenchymal stem cells enhances recovery of renal function. Mesenchymal stem cells were found to be located in the kidney cortex after injection, as demonstrated by MRI. Mesenchymal stem cells-treated animals had both significantly better renal function on days 2 and 3 and better injury scores at day 3 after ARF. Histologically, mesenchymal stem cells were predominantly located in glomerular capillaries, while tubules showed no iron labeling, indicating absent tubular transdifferentiation., Conclusion: We conclude that the highly renoprotective capacity of mesenchymal stem cells opens the possibility for a cell-based paradigm shift in the treatment of I/R ARF.