ZMBH J.Bericht 2000 - Zentrum für Molekulare Biologie der ...

telt intrazelluläre Signaltransduktion.
Klöcker, Uta (2000): Regulation der hepadnaviralen
Replikation: Untersuchung des Effektes antiviraler
Mediatoren mit Hilfe hepadnaviraler Vektoren.
Sprinzl, Martin Franz (2000): Der adenovirale Genomtransfer
überwindet die Speziesbarriere der Hepatitis-
B-Viren.
Habilitations
Hug, Hubert (1998). Signalübertragung der CD95
(Fas/APO-1)-vermittelten Apoptose.
Knolle, Percy (2000). Die Leber als immunregulatorisches
Organ: Bedeutung der sinusoidalen Endothelzellen
und Kupffer Zellen.
Protzer, Ulrike (2000). Virus-Wirt-Interaktion bei der
Hepatitis B Virus Infektion: vom verbesserten Verständnis
zur Entwicklung neuer Therapien.
Urban, Stephan (2000). Identifizierung des aviären
Hepatitis B Virus Rezeptors und Charakterisierung
seiner Interaktion mit dem viralen Hüllprotein.
STRUCTURE OF THE GROUP
E-mail: hshd@zmbh.uni-heidelberg.de
Group leader Schaller, Heinz, Prof. Dr.
Research associates/
postdoctoral
fellows Knaust, Andreas, Dr. *
Kuhn, Christa, Dr.
Mabit, Hélène, Dr.*
124
Obert, Sabine, Dr.*
Protzer, Ulrike, Dr.
Sirma, Hüseyin, Dr.*
Urban, Stephan, Dr.
Visiting
scientists Wimmer, Eckard, Prof.*
from SUNY at Stony Brook, USA
(Humboldt Awardee)
Grgacic, Elizabeth, Dr.*
from Macfarlane Burnet Centre,
Fairfield, Australia
Ph.D. students Breiner, Klaus, Dipl.Ing.,
MA chem.
Dumortier, Jêrome*
Klöcker, Uta
Rothmann, Kirsten*
Sprinzl, Martin*
Thake, Sandra*
Techn.
assistants Glass, Bärbel, Dipl. Biol.
Götzmann, Martina*
Oberwinkler, Heike*
Zachmann-Brand, Beate
*) part of the time reported
Project Group Percy Knolle
Regulation of the Immune Response in the
Liver
The liver is a unique organ with regard to the induction
of peripheral immune tolerance. Delivery of antigen
into the liver results in tolerance induction towards this
specific antigen as is seen by the increased survival
of organ transplants following portal venous injection
of donor antigens or following portal venous drainage
of the organ transplant. A number of different hepatic
cell populations and the unique hepatic microenvironment
seem to cooperate to induce immune tolerance.
We are studying the contribution to immune tolerance
of the sinusoidal endothelial cells of the liver (LSEC),
which interact constitutively with leukocytes in the
sinusoidal lumen (see Fig. 1) as well as two other
Figure 1. Schematic drawing of the relative position and
cell sizes in the hepatic sinusoid. Leukocytes are in intimate
contact with LSEC during liver passage and constitutively
adhere to LSEC under physiologic conditions.
hepatic sinusoidal cell populations, the Kupffer cells
and the liver associated lymphocytes. Kupffer cells
and LSEC have the capacity to act as antigen-presenting
cells and activate CD4 + T cells suggesting
immune-surveillance function for the liver. However,
antigen-presentation by LSEC and Kupffer cells is
stringently controlled by physiological constituents
of portal venous blood (e.g. endotoxin) and by both,
autocrine and paracrine action of soluble mediators,
which are induced in resident liver cells by endotoxin.
Activation of naive CD4 + T cells by LSEC outside
lymphoid tissue may constitute one mechanism of
hepatic tolerance induction, because antigen-presention
by LSEC leads to the generation of CD4 + T cells
that express immunosuppressive cytokines and act as
regulatory T cells.
I. Functional inactivation of CD8+ T cells
by cross-presenting sinusoidal endothelial
cells
J. Ohl und A. Limmer
Presentation of endocytosed antigens on MHC-class
I molecules on antigen-presenting cells to cytotoxic
CD8 + T cells (cross-presentation) is important for
immunity to intracellular pathogens and was supposed
to be restricted to dendritic cells and macrophages.
Once in the blood, antigen is taken up efficiently by
LSEC, but not significantly by other cell populations
of the liver (Fig. 2). In vitro analysis of isolated
LSEC reveiled that cross-presentation of endocytosed
antigen to a antigen-specific CD8 + T cell hybridoma
occured in LSEC. Cross-presentation in LSEC compared
to other antigen-presenting cells requires only
125