Z Gastroenterol 2007; 45(1): 63-70
DOI: 10.1055/s-2006-927397
Übersicht

© Karl Demeter Verlag im Georg Thieme Verlag KG Stuttgart · New York

Cellular and Cytokine-Mediated Mechanisms of Inflammation and its Modulation in Immune-Mediated Liver Injury

Zelluläre und zytokinvermittelte Mechanismen der Entzündungsantwort und ihrer Regulation bei LeberschädigungG. Tiegs1
  • 1Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Erlangen, Germany
Further Information

Publication History

manuscript received: 21.11.2006

manuscript accepted: 21.12.2006

Publication Date:
19 January 2007 (online)

Zusammenfassung

Bei Hepatitisvirusinfektion oder Autoimmunhepatitis wird eine Leberschädigung durch die Immunantwort gegenüber den Fremd- oder Autoantigenen ausgelöst. In letzter Zeit mehren sich Hinweise, dass auch bei toxischer Leberschädigung, bei der die Immunantwort gegen spezifische Leberantigene zunächst nicht im Vordergrund steht, Immunzellen der angeborenen und adaptiven Immunantwort an der Schadensvermittlung beteiligt sind. Zu diesen Erkrankungen gehören unter anderem die Alkoholhepatitis, die nichtalkoholische Steatohepatitis sowie Ischämie/Reperfusionsschäden bei Lebertransplantationen. Hier kann es zu einer Funktionseinbuße der gastrointestinalen Barriere und damit zu einer Zunahme von Bakterien und ihren Toxinen im Pfortaderblut kommen. Bakterielle Toxine können Zellen der angeborenen Immunabwehr wie die Kupfferzellen oder auch konventionelle T-Zellen aktivieren. Vor kurzem konnte gezeigt werden, dass bei Fettleber die invarianten natürlichen Killer-T-Zellen (NKT-Zellen), die spezifisch Glykolipidantigene erkennen, beim Fortschreiten der Erkrankung involviert sind. Sowohl bei nichtalkoholischer Steatohepatitis als auch bei Ischämie/Reperfusionsschädigung beobachtet man das Zytokinprofil einer sogenannten Th1-Immunantwort, die insbesondere durch erhöhte IFNγ- und TNFα-Spiegel gekennzeichnet ist. An der Auslösung dieser Zytokinantwort scheinen NKT-Zellen sowie konventionelle CD4+-T-Lymphozyten beteiligt zu sein. Detaillierte Studien der pathophysiologischen Mechanismen einer immunvermittelten Leberschädigung wurden im Modell der Concanavalin A-induzierten Hepatitis durchgeführt. Hierbei wurden nicht nur Immuneffektormechanismen und Zytokinsignaltransduktionswege, die zu Organschädigung, hepatozellulärer Apoptose, Apoptosehemmung und Regeneration führen, sondern seit kurzem auch Mechanismen der Immuntoleranz untersucht. Die tolerogene Funktion der Leber scheint deshalb von besonderer Bedeutung zu sein, da das Organ kontinuierlich Abwehr- und Scavengerfunktionen gegenüber Fremdmaterial aus dem Darm ausüben muss, ohne dass eine chronische Entzündung entsteht.

Abstract

The immune response to foreign or self antigens mediates liver damage during viral or autoimmune hepatitis. However, it now appears that also specific antigen-independent liver diseases, where liver damage has been attributed to occur from oxygen radical formation, seem to be mediated by cells of the innate and adaptive immune response. These liver disorders include alcoholic liver disease, non-alcoholic fatty liver disease or non-alcoholic steatohepatitis, and ischemia/reperfusion injury that impairs the function of liver grafts. Here it seems that breakdown of the gastrointestinal barrier might increase the concentration of bacterial toxins in the portal blood, which then activate cells of the innate immune system, e. g., Kupffer cells, but, depending on the nature of the toxin, probably also conventional T cells. Invariant NKT cells which specifically recognize glycolipid antigens were supposed to become activated during metabolic disorders related to obesity. However, both steatohepatitis as well as ischemia/reperfusion injury are associated with a Th1 cytokine response characterized by IFNγ and TNFα elevation, that might reflect an NKT cell response on the one hand, but also conventional T lymphocytes, in particular CD4+ T cells, are critical for the pathophysiology of these disorders. In 1992 we described a model of T cell-dependent liver injury inducible by the T cell-mitogenic lectin concanavalin A. This model of immune-mediated liver injury was intensively used to study pathophysiological immune effector mechanisms as well as cytokine signaling important for hepatocellular apoptosis, inhibition of apoptosis and regeneration. Recently it became evident that the inflammatory response in this model is regulated by specific cytokine signals as well as by immune regulator cells. The immune-regulatory functions of the liver are of particular interest with respect to the scavenger function of this organ, being continuously exposed to foreign antigenic material from the gut which should be eliminated without causing chronic disease.

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Gisa Tiegs

Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg

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