Zusammenfassung
Die Leber ist ein Organ mit einzigartigem immunregulatorischen Potenzial. In dieser Arbeit wird die experimentelle Evidenz dargestellt, die für die Beteiligung hepatischer Zellpopulationen an der Induktion von oraler Toleranz spricht. Obwohl die Induktion von Immuntoleranz gegenüber oralen Antigenen vor allem im lymphatischen Gewebe des Gastrointestinaltraktes erfolgt, besteht ein weiterer Bedarf für die Aufrechterhaltung peripherer Immuntoleranz außerhalb des Gastrointestinaltraktes, da orale Antigene innerhalb von Minuten nach Aufnahme schnell über den Blutstrom systemisch verteilt werden. Neben hepatischen dendritischen Zellen sind vor allem sinusoidale Endothelzellen der Leber an der Aufnahme von oralem Antigen aus portalvenösem Blut und der Kreuzpräsentation dieser Antigene auf MHC-I-Molekülen für CD8-T-Zellen beteiligt. Die Folge der Kreuzpräsentation oraler Antigene durch sinusoidale Endothelzellen der Leber ist die Induktion von CD8-T-Zell-Immuntoleranz. Diese Befunde unterstreichen die Bedeutung der Leber in der Aufrechterhaltung peripherer Immuntoleranz auch gegenüber oralen Antigenen.
Abstract
The liver is an organ with unique immune regulatory potential. This review highlights the experimental evidence for the involvement of hepatic cell populations in the induction of oral tolerance. Although immune tolerance towards oral antigens is mainly induced in the gastrointestinal tract within gut associated lymphatic tissue via generation of regulatory CD4 T cells, there is a further need for tolerance induction outside the gastrointestinal tract, because oral antigens rapidly distribute within minutes systemically through the blood stream. Besides hepatic dendritic cells, liver sinusoidal endothelial cells are active in the uptake and cross-presentation of oral antigens from portal venous blood and engage in the induction of CD8 T cell tolerance towards these antigens. These reports strengthen the notion that the liver participates in the induction of oral tolerance.
Schlüsselwörter
Sinusoidale Endothelzellen der Leber - hepatische dendritische Zellen - Antigenaufnahme - Kreuzpräsentation - Immuntoleranz
Key words
Liver sinusoidal endothelial cells - hepatic dendritic cells - antigen uptake - cross-presentation - immune tolerance
References
-
1
Cantor H, Dumont A.
Hepatic suppression of sensitization to antigen absorbed into the portal system.
Nature.
1967;
44
744
-
2
Callery M P, Kamei T, Flye M W.
The effect of portacaval shunt on delayed-hypersensitivity responses following antigen feeding.
J Surg Res.
1989;
44
391-394
-
3
Yang R, Liu Q, Grosfeld J L. et al .
Intestinal venous drainage through the liver is a prerequisite for oral tolerance induction.
J Pediatr Surg.
1994;
44
1145-1148
-
4
Calne R Y.
Induction of immunological tolerance by porcine liver allografts.
Nature.
1969;
44
472-476
-
5
Dahmen U, Qian S, Rao A S. et al .
Split tolerance induced by orthotopic liver transplantation in mice.
Transplantation.
1994;
44
1-8
-
6
Barker C F, Corriere J N Jr.
Canine renal homotransplantation with venous drainage via the portal vein.
Ann Surg.
1967;
44
279-282
-
7
Boeckx W, Sobis H, Lacquet A. et al .
Prolongation of allogeneic heart graft survival in the rat after implantation on portal vein.
Transplantation.
1975;
44
145-149
-
8
Gorczynski R M, Chan Z, Chung S. et al .
Prolongation of rat small bowel or renal allograft survival by pretransplant transfusion and/or by varying the route of allograft venous drainage.
Transplantation.
1994;
44
816-820
-
9
Yu S, Nakafusa Y, Flye M W.
Portal vein administration of donor cells promotes peripheral allospecific hyporesponsiveness and graft tolerance.
Surgery.
1994;
44
229-234; discussion 234 - 235
-
10
Bertolino P, Bowen D G, McCaughan G W. et al .
Antigen-specific primary activation of CD8 + T cells within the liver.
J Immunol.
2001;
44
5430-5438
-
11
Bertolino P, McCaughan G W, Bowen D G.
Role of primary intrahepatic T-cell activation in the “liver tolerance effect”.
Immunol Cell Biol.
2002;
44
84-92
-
12
Bowen D G, Zen M, Holz L. et al .
The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity.
J Clin Invest.
2004;
44
701-712
-
13
Richman L K, Klingenstein R J, Richman J A. et al .
The murine Kupffer cell. I. Characterization of the cell serving accessory function in antigen-specific T cell proliferation.
J Immunol.
1979;
44
2602-2609
-
14
Rubinstein D, Roska A K, Lipsky P E.
Antigen presentation by liver sinusoidal lining cells after antigen exposure in vivo.
J Immunol.
1987;
44
1377-1382
-
15
Knolle P, Schlaak J, Uhrig A. et al .
Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge.
J Hepatol.
1995;
44
226-229
-
16
Bissell D M, Wang S S, Jarnagin W R. et al .
Cell-specific expression of transforming growth factor-beta in rat liver. Evidence for autocrine regulation of hepatocyte proliferation.
J Clin Invest.
1995;
44
447-455
-
17
Callery M P, Kamei T, Flye M W.
Kupffer cell blockade inhibits induction of tolerance by the portal venous route.
Transplantation.
1989;
44
1092-1094
-
18
Kamei T, Callery M P, Flye M W.
Kupffer cell blockade prevents induction of portal venous tolerance in rat cardiac allograft transplantation.
J Surg Res.
1990;
44
393-396
-
19
Steinman R M, Hawiger D, Liu K. et al .
Dendritic cell function in vivo during the steady state: a role in peripheral tolerance.
Ann N Y Acad Sci.
2003;
44
15-25
-
20
Goddard S, Youster J, Morgan E. et al .
Interleukin-10 secretion differentiates dendritic cells from human liver and skin.
Am J Pathol.
2004;
44
511-519
-
21
Jomantaite I, Dikopoulos N, Kroger A. et al .
Hepatic dendritic cell subsets in the mouse.
Eur J Immunol.
2004;
44
355-365
-
22
Pillarisetty V G, Shah A B, Miller G. et al .
Liver dendritic cells are less immunogenic than spleen dendritic cells because of differences in subtype composition.
J Immunol.
2004;
44
1009-1017
-
23
Lau A H, Thomson A W.
Dendritic cells and immune regulation in the liver.
Gut.
2003;
44
307-314
-
24
Matsuno K, Ezaki T, Kudo S. et al .
A life stage of particle-laden rat dendritic cells in vivo: their terminal division, active phagocytosis, and translocation from the liver to the draining lymph [see comments].
J Exp Med.
1996;
44
1865-1878
-
25
Kudo S, Matsuno K, Ezaki T. et al .
A novel migration pathway for rat dendritic cells from the blood: hepatic sinusoids-lymph translocation.
J Exp Med.
1997;
44
777-784
-
26
Steinbrink K, Wolfl M, Jonuleit H. et al .
Induction of tolerance by IL-10-treated dendritic cells.
J Immunol.
1997;
44
4772-4780
-
27
Lutz M B, Schuler G.
Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity?.
Trends Immunol.
2002;
44
445-449
-
28
Steinman R M, Hawiger D, Nussenzweig M C.
Tolerogenic dendritic cells.
Annu Rev Immunol.
2003;
44
685-711
-
29
Smedsrod B.
Clearance function of scavenger endothelial cells.
Comp Hepatol.
2004;
44
S22
-
30
Lohse A W, Knolle P A, Bilo K. et al .
Antigen-presenting function and B7 expression of murine sinusoidal endothelial cells and Kupffer cells.
Gastroenterology.
1996;
44
1175-1181
-
31
Knolle P A, Schmitt E, Jin S. et al .
Induction of cytokine production in naive CD4(+) T cells by antigen-presenting murine liver sinusoidal endothelial cells but failure to induce differentiation toward Th1 cells.
Gastroenterology.
1999;
44
1428-1440
-
32
Limmer A, Ohl J, Kurts C. et al .
Efficient presentation of exogenous antigen by liver endothelial cells to CD8 + T cells results in antigen-specific T-cell tolerance.
Nat Med.
2000;
44
1348-1354
-
33
Rescigno M, Urbano M, Valzasina B. et al .
Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria.
Nat Immunol.
2001;
44
361-367
-
34
Niess J H, Brand S, Gu X. et al .
CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance.
Science.
2005;
44
254-258
-
35
Mowat A M.
Anatomical basis of tolerance and immunity to intestinal antigens.
Nat Rev Immunol.
2003;
44
331-341
-
36
Karlsson M, Lundin S, Dahlgren U. et al .
“Tolerosomes” are produced by intestinal epithelial cells.
Eur J Immunol.
2001;
44
2892-2900
-
37
Blanas E, Carbone F R, Allison J. et al .
Induction of autoimmune diabetes by oral administration of autoantigen.
Science.
1996;
44
1707-1709
-
38
Hanninen A, Braakhuis A, Heath W R. et al .
Mucosal antigen primes diabetogenic cytotoxic T-lymphocytes regardless of dose or delivery route.
Diabetes.
2001;
44
771-775
-
39
Peng H J, Turner M W, Strobel S.
The kinetics of oral hyposensitization to a protein antigen are determined by immune status and the timing, dose and frequency of antigen administration.
Immunology.
1989;
44
425-430
-
40
Gutgemann I, Fahrer A M, Altman J D. et al .
Induction of rapid T cell activation and tolerance by systemic presentation of an orally administered antigen.
Immunity.
1998;
44
667-673
-
41
Smith K M, Davidson J M, Garside P.
T-cell activation occurs simultaneously in local and peripheral lymphoid tissue following oral administration of a range of doses of immunogenic or tolerogenic antigen although tolerized T cells display a defect in cell division.
Immunology.
2002;
44
144-158
-
42
Watanabe T, Katsukura H, Shirai Y. et al .
A liver tolerates a portal antigen by generating CD11c+ cells, which select Fas ligand+ Th2 cells via apoptosis.
Hepatology.
2003;
44
403-412
-
43
Watanabe T, Yoshida M, Shirai Y. et al .
Administration of an antigen at a high dose generates regulatory CD4 + T cells expressing CD95 ligand and secreting IL-4 in the liver.
J Immunol.
2002;
44
2188-2199
-
44
Regnault A, Lankar D, Lacabanne V. et al .
Fcgamma receptor-mediated induction of dendritic cell maturation and major histocompatibility complex class I-restricted antigen presentation after immune complex internalization.
J Exp Med.
1999;
44
371-380
-
45
Limmer A, Ohl J, Wingender G. et al .
Cross-presentation of oral antigens by liver sinusoidal endothelial cells leads to CD8 T cell tolerance.
Eur J Immunol.
2005;
44
2970-2981
-
46
Campos R A, Szczepanik M, Itakura A. et al .
Cutaneous immunization rapidly activates liver invariant Valpha14 NKT cells stimulating B-1 B cells to initiate T cell recruitment for elicitation of contact sensitivity.
J Exp Med.
2003;
44
1785-1796
MD Percy A. Knolle
Institute for Molecular Medicine and Experimental Immunology, Friedrich-Wilhelms-University Bonn, University Hospital
Sigmund-Freud-Str. 25
53105 Bonn
Telefon: ++ 49/2 28/2 87-10 50
eMail: Percy.Knolle@ukb.uni-bonn.de
