Pere Ginès

Human hepatic stellate cells show features of antigen‐presenting cells and stimulate lymphocyte proliferation

Following cell activation, hepatic stellate cells (HSCs) acquire proinflammatory and profibrogenic properties. We investigated whether activated HSCs also display immune properties. Here we show that cultured human HSCs express membrane proteins involved in antigen presentation, including members of the HLA family (HLA-I and HLA-II), lipid-presenting molecules (CD1b and CD1c), and factors involved in T-cell activation (CD40 and CD80). Exposure of HSCs to proinflammatory cytokines markedly up-regulates these molecules. Importantly, cells freshly isolated from human cirrhotic livers (in vivo activated HSCs) highly express HLA-II and CD40, suggesting that HSCs can act as antigen-presenting cells (APCs) in human fibrogenesis. We also explored whether human HSCs can efficiently process exogenous antigens. Activated HSCs internalize low- and high-molecular-weight dextran and transferrin, indicating that they can perform fluid-phase and receptor-mediated endocytosis. Moreover, HSCs can perform phagocytosis of macromolecules because they internalize latex particles as well as bacteria. Interestingly, both culture-activated and in vivo activated HSCs express high levels of CD68, a protein involved in antigen trafficking. Finally, we studied whether HSCs modulate T-lymphocyte proliferation. In basal conditions, coculture of irradiated HSCs barely induces allogeneic T-lymphocyte proliferation. However, cytokine-stimulated HSCs stimulate the allogeneic T-lymphocyte response in an HLA-II-dependent manner. In conclusion, human activated HSCs express molecules for antigen presentation, internalize macromolecules, and modulate T-lymphocyte proliferation. These results suggest that HSCs may play a role in the immune function of the liver.

Management of hepatorenal syndrome: another piece of the puzzle.

Knowledge on the hepatorenal syndrome (HRS) has substantially improved in recent years. These advances relate to all aspects of the syndrome, including a widely accepted definition, a consensus-based diagnostic criteria that help differentiate HRS from other causes of renal failure also present in patients with cirrhosis, an improved understanding of the pathogenic mechanisms, successful methods of prevention in specific settings, and, more importantly, the introduction of effective therapies, mainly vasoconstrictor drugs.1–3 The administration of vasoconstrictor drugs to patients with cirrhosis and renal dysfunction was first reported in the 1950s.4,5 However, due to limited success, the treatment was abandoned for many decades. The main reason for the reappraisal of vasoconstrictors in the management of HRS was the growing pathophysiological evidence that renal vasoconstriction responsible for renal failure in HRS was the final consequence of a marked vasodilation of the splanchnic circulation.6–8 This vasodilation impairs the effective arterial blood volume and gives rise to a remarkable activation of vasoconstrictor systems aimed at maintaining effective arterial blood volume and arterial pressure by means of vasoconstriction of several arterial beds, particularly the kidneys. Phase 2 studies in patients with HRS have demonstrated that the administration of vasoconstrictors (mainly vasopressin analogues, particularly terlipressin, but also -adrenergic agonists, such as noradrenaline or midodrine) improves renal function in approximately two-thirds of patients with HRS, with relatively low incidence of severe side effects (less than 10% of patients).9–17 Moreover, and most importantly, it appears that patients in whom renal function improves after therapy have a longer survival compared to nonresponders.14,15 Although exciting, these results should be interpreted with caution due to the small number of patients included in most studies and the lack of large randomized prospective controlled investigations. This type of study is absolutely necessary to put the usefulness of vasoconstrictors for HRS into clinical perspective. In the current issue of HEPATOLOGY, Wong et al. have explored the use of sequential treatments in patients with HRS—i.e., vasoconstrictor therapy followed by transjugular intrahepatic portosystemic shunt (TIPS).18 TIPS has previously been shown to have beneficial effects on renal function in HRS.19 In this prospective study, 14 patients with cirrhosis and type 1 HRS were treated with a combination of midodrine, octreotide, and albumin, followed by insertion of TIPS in selected patients with a relatively preserved liver function (INR lower than 2, bilirubin lower than 5 mg/dL, and Child-Turcotte-Pugh score lower than 12). The main finding of this study was the improvement of renal function achieved by the pharmacological therapy being further enhanced by TIPS. In fact, after the sequential treatment, there was an almost complete normalization of renal function and a remarkable improvement of circulatory function with normalization of effective arterial blood volume. Although the low number of evaluated patients and lack of randomization limit to some extent the relevance of the study, the information provided is of interest from both a pathogenic and a clinical perspective. One of the intriguing issues surrounding the treatment of HRS with vasoconstrictors is the observation that, despite the improvement, renal function does not reach normal levels in the majority of patients, with persistence of mild-to-moderate renal failure after therapy, as indicated by low renal plasma flow and glomerular filtration rate values.9–12,16,17 This observation has been confirmed in the study of Wong et al.18 The reason for this lack of normalization of renal function is unknown but could be the result of the existence of a component of renal failure unresponsive to changes in circulatory function, or that the effective arterial blood volume, although improved, is not normalized with pharmacological therapy. The results of Wong et al.18 support this latter option. Abbreviations: HRS, heatorenal syndrome; TIPS, transjugular intra hepatic portal systemic shunt. From the 1Liver Unit, Institut de Malalties Digestives, and the 2Cardiology Unit, Hospital Clı́nic de Barcelona, Institut d’Investigacions Biomèdiques August PiSunyer, Instituto Reina Sofı́a de Investigación Nefrológica, Universitat de Barcelona, Barcelona, Spain. Supported, in part, by grants from Marato Fundació TV3 (U-2000-TV2710), Fondo de Investigaciones Sanitarias de la Seguridad Social (FISS 02/0701), Dirección General de Investigación Cientı́fı́co y Técnica (SAF 2001/0300), Instituto Reina Sofı́a de Investigación Nefrológica, and Instituto de Salud Carlos III (C03/2). Address reprint requests to: Pere Ginès, M.D., Liver Unit, Hospital Clı́nic de Barcelona, Villarroel 170, 08036 Barcelona, Catalunya, Spain. E-mail: gines@medicina.ub.es; fax: 34 73 451 5522. Copyright