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Ming-Qing
Xu, Wei Wang, Lv-Nan Yan, Department of General Surgery, West China
(Huaxi) Hospital, Sichuan University, Chengdu 610041, Sichuan
Province, China
Lan Xue, 208 PLA Hospital, Changchun 130021, Jilin Province, China
Correspondence to: Dr Ming-Qing Xu, Department of General
Surgery, West China Hospital, Sichuan University, Chengdu 610041,
Sichuan Province, China. xumingqing@hotmail.com
Telephone: +86-28-85582968
Received: 2002-12-22
Accepted: 2003-02-16
Abstract
AIM: To investigate the role of NF-kB activation and zinc finger protein A20 expression in the
regulation of maturation of dendritic cells (DCs) derived from liver
allografts undergoing acute rejection.
METHODS: Sixty donor male SD rats and sixty recipient male LEW rats
weighing 220-300 g were randomly divided into whole liver
transplantation group and partial liver transplantation group.
Allogeneic (SD rat to LEW rat) whole and 50 % partial liver
transplantation were performed. DCs from liver grafts 0 hour and 4
days after transplantation were isolated and propagated in the
presence of GM-CSF in vitro. Morphological characteristics
and phenotypical features of DCs propagated for 10 days were
analyzed by electron microscopy and flow cytometry, respectively.
NF-kB binding activity, IL-12p70 protein and zinc finger protein A20
expression in these DCs were measured by EMSA and Western blotting,
respectively. Histological grading of rejection was determined.
RESULTS: Allogeneic whole liver grafts showed no signs of rejection
on day 4 after the transplantation. In contrast, allogeneic partial
liver grafts demonstrated moderate to severe rejection on day 4
after the transplantation. After propagation for 10 days in the
presence of GM-CSF in vitro, DCs from allogeneic whole liver
grafts exhibited features of immature DC with absence of CD40
surface expression, these DCs were found to exhibit detectable but
very low level of NF-kB activity, IL-12 p70 protein and zinc finger protein A20
expression. Whereas, DCs from allogeneic partial liver graft 4 days
after transplantation displayed features of mature DC, with high
level of CD40 surface expression, and as a consequence, higher
expression of IL-12p70 protein, higher activities of NF-kB and higher expression of zinc finger protein A20 compared with
those of DCs from whole liver grafts (P<0.001).
CONCLUSION: These results suggest that A20 expression is
up-regulated in response to NF-kB activation in mature DCs derived from allogeneic liver grafts
undergoing acute rejection. Given the NF-kB inhibition function of this gene, it is suggested that their
expression survives to limit NF-kB activation and maturation of DCs, and consequently inhibits the
acute rejection and induces acceptance of liver graft.
Xu MQ, Wang W, Xue L, Yan LN. NF-kB activation and zinc finger protein A20 expression in mature
dendritic cells derived from liver allografts undergoing acute
rejection. World J Gastroenterol
2003; 9(6): 1296-1301
http://www.wjgnet.com/1007-9327/9/1296.asp
INTRODUCTION
Dendritic cells (DCs) are specialized antigen-presenting cells (APCs)
that play an essential role in the activation of lymphocytes[1-10].
Among APCs, which also include macrophages and B cells, only DCs are
believed to be capable of activating naive T cells. DC function is
regulated by their state of maturation. Immature DCs resident in
nonlymphoid tissues such as normal liver are deficient at antigen
capture and progressing processing[11, 12]. "Maturation"
of DC can be induced by microbial stimuli, proinflammatory
cytokines, as well as through interaction with CD40L-CD40
cross-linking[13-20]. The control of DC maturation and
activation plays an important role in regulating their T cell
priming functions[21]. Significantly, engagement of CD40
expressed on DCs with CD40L expressed on T cells not only stimulates
maturation and cytokine production but also enhances DC survival and
activation[19, 22, 23]. Mature DCs are highly immunogenic
due to high levels of expression of MHC I and II, costimulatory and
adhesion molecules, including B7-1, B7-2, CD40, and ICAM-1[11-19].
In the case of experimental skin, heart, or kidney allografts,
mature dendritic cells resident in donor tissue have been implicated
as the principal instigators of rejection. Whereas, DCs derived from
normal liver display an immature phenotype with absence of
costimulatory molecules (CD40, CD80 and CD86) surface expression,
low levels of MHC class I and II, and as a consequence, low
stimulatory capacity for naive allogeneic T cells. Unlike mature DC,
these liver-derived immature DCs do not induce detectable levels of
intracytoplasmic IFN-g in allogeneic CD4+ cells in 72-h MLR, and elicite
very low levels of CTLs in vitro[11, 12]. It has
been observed that liver-derived[11, 24] or bone
marrow-derived immature DCs[25], propagated in vitro
and lacking surface costimulatory molecules, can prolong heart or
pancreatic islet allograft survival. Whereas, marked
augmentation of DCs numbers and maturation of DCs in liver
allografts by donor treatment with the hematopoietic growth factor
fms-like tyrosine kinase 3 (Flt3) ligand (FL) results in acute liver
graft rejection[26, 27].
Although the
significance of DCs as regulators of transplantation immunity is
beyond doubt, little is known about intracellular mechanisms
specifically responsible for regulation of DC activation and
maturation. Previous studies have suggested that NF-kB may play a key role in DC maturation[20, 28-30], and
NF-kB inhibition could impair the maturation and function of DC[28,
29].
A20
is a zinc finger protein originally identified as a TNF- inducible
gene product in endothelial cells (EC), and has been shown to be
dependent upon NF-kB for its expression. A20 is expressed in a variety of cell types
including fibroblasts, B, T, and b-cells in response to different stimuli including LPS, IL-1 and
CD40 cross-linking[31-36]. A20 is itself a NF-kB- dependent gene and is part of a negative regulatory loop
critical for modulation of cell activation[37, 38]. A20
serves a broad cytoprotective function in EC by protecting EC from
apoptosis and down-regulating inflammatory responses via NF-kB inhibition[39]. A20-/- knock-out mice are born
cachectic and die within 3 weeks from severe and uncontrolled
inflammation that further confirms the potent anti-inflammatory
function of A20[40]. A20 is also part of the physiologic
NF-kB-dependent survival response of hepatocytes to injury, limited
expression of A20 in hepatocytes drastically improves the fate of
mice in the D-gal/LPS model of toxic FHF where A20 protects
hepatocytes from apoptosis and promotes the liver regeneration[37].
In addition, investigation has shown that A20 expression is
up-regulated in human renal allografts in response to immune injury
inferred by acute rejection, and the result suggests that A20 could
limit graft injury[41].
Although
A20 is a very effective inhibitor of NF-kB activation induced by LPS, IL-1 and CD40 cross-linking, little
is known about the role of A20 in the regulation of maturation of
DCs derived from allogeneic liver grafts accompanied by acute
rejection.
The
purpose of the present study was to investigate the binding activity
of NF-kB DNA and A20 expression in mature DCs derived from allogeneic
partial liver grafts undergoing acute rejection in rats. Attempts
were made also to correlate A20 expression in DCs derived from liver
grafts with the acceptance of allogeneic liver grafts.
MATERIALS AND METHODS
Animals
Sixty donor male SD rats and sixty recipient male LEW rats weighing
220-300 g were randomly divided into whole liver transplantation
group and partial liver transplantation group. Allogeneic whole and
50 % partial liver transplantation were performed using a SD to LEW
combination. The animals were purchased from Chinese Academy of
Sciences and Sichuan University. They were maintained with a 12-hour
light/dark cycle in a conventional animal facility with water and
commercial chow provided ad libitum, with no fasting before the
transplantation.
Liver transplantation
All operations were performed under ether anesthesia in
clean but not sterile conditions. All surgical procedures were
performed from 8 a.m to 5 p.m . Donors and recipients of similar
weight (±10 g) were chosen. Liver reduction was
achieved by removing the left lateral lobe and the two caudate
lobes, which resulted in a 50 % reduction of the liver mass. Whole
liver transplantation (WLT) and partial liver transplantation (PLT)
were performed according to the method described in our previous
study[42].
Histology
Part of liver tissues was sectioned and preserved in 10 %
formalin, embedded in paraffin, cut with microtome, and stained with
hematoxylin and eosin. The histological grading of rejection was
determined according to the criteria described by Williams.
Propagation
and purification of liver graft-derived DC populations
DCs from liver graft 0 hour and 4 days after the
transplantation were propagated in GM-CSF from nonparenchymal cells
(NPC) isolated from collagenase-digested liver graft tissue, as
described by Lu et al[24]. Nonadherent cells,
released spontaneously from proliferating cell clusters, were
collected after culture for 10 days, and purified by centrifugation
500 ×g, for 10
minutes at room temperature on a 16 % w/v metrizamide gradient (DC
purity 80-85 %).
Morphological
and phenotypical features of DCs
Morphological characteristics of DCs derived from liver
graft were observed by electron microscopy. Expression of cell
surface molecules was quantitated by flow cytometry as described in
our previous study[42]. Aliquots of 2×105
DCs propagated for 10 days in vitro were incubated with the
following primary mouse anti - rat mAbs against OX62, CD40 (Serotec,
USA), or rat IgG as an isotype control for 60 minutes on ice (1 mg/ml diluted in PBS/1.0 % FCS). The cells were washed with
PBS/1.0 % FCS and labeled with FITC-conjugated goat anti-mouse IgG,
diluted 1/50 in PBS/1.0 % FCS for 30 minutes on ice. At the end of
this incubation, cells were washed, propidium iodide/PBS were added,
and the cells were subsequently analyzed in an FACS-4200 flow
cytometer (Becton-Dikison, USA).
Isolation
of nuclear proteins
Nuclear proteins were isolated from DCs extract by placing
the sample in 0.9 ml of ice-cold hypotonic buffer [10 mM.l-1
HEPES (pH7.9), 10 mM.l-1
KCl, 0.1 mM.l-1
EDTA, 0.1 mM.l-1
ethylene glycol tetraacetic acid, 1 mM.l-1
DTT; Protease inhibitors (aprotinin, pepstatin, and leupeptin, 10 mg.l-1
each)]. The homogenates were incubated on ice for 20 minutes,
vortexed for 20 seconds after adding 50 ml of 10 % Nonide-P40, and then centrifuged for 1 minutes at 4 °C in an Eppendorf centrifuge. Supernatants were decanted, the
nuclear pellets after a single wash with hypotonic buffer without
Nonide-P40 were suspended in an ice-cold hypertonic buffer [20 mM.l-1
HEPES(pH7.9), 0.4 M.l-1
NaCl, 1 mM.l-1
EDTA,1 mM.l-1
DTT; Protease inhibitors], incubated on ice for 30 minutes at 4 °C, mixed frequently, and centrifuged for 15 minutes at 4 °C. The supernatants were collected as nuclear extracts and stored
at -70 °C. Concentrations of total proteins in the samples were determined
according to the method of Bradford.
Electrophoretic
mobility shift assay (EMSA) for NF-kB activation of DCs
NF-kB binding activity was performed in a 10-?l binding reaction
mixture containing 1×binding buffer [50 mg.l-1
of double-stranded poly (dI-dC), 10 mM.l-1
Tris-HCl (pH7.5), 50 mM.l-1
NaCl, 0.5 mM.l-1
EDTA, 0.5 mM.l-1DTT,
1 mM.l-1
MgCl2, and 100 ml.l-1
glycerol], 5 mg of nuclear protein, and 35 fmol of double-stranded NF-kB consensus oligonucleotide (5'-AGT TGA GGG GAC TTT CCC AGG-3')
that was endly labeled with g-32P (111TBq mM-1 at 370 GBq-1) using T4
polynucleotide kinase. The binding reaction mixture was incubated at
room temperature for 20 minutes and analyzed by electrophoresis on 7
% nondenaturing polyacrylamide gels. After electrophoresis, the gels
were dried by Gel-Drier (Biol-Rad Laboratories, Hercules, CA) and
exposed to Kodak X-ray films at -70 °C.
Western
blotting for IL-12 p70 and zinc finger protein A20 expression in DCs
DCs cultured for 10 days in vitro were starved in
serum-free medium for 4 hours at 37 °C. These cells were washed twice in cold PBS, resuspended in 100 ml lysis buffer (1 % Nonidet -P40, 20 mM Tris-HCl, pH8.0, 137 mM
NaCl, 10 % glycerol, 2 mM EDTA, 10 mg.L-1
leupeptin, 10 mg.L-1
aprotinin, 1mM PMSF, and 1 mM sodium orthovanadate), and total cell
lysates were obtained. The homogenates were centrifuged at 10 000×g for
10 minutes at 4 °C. Cell lysates (20 mg) were electrophoresed on SDS-PAGE gels, and transferred to PVDC
membranes for Western blot analysis. Briefly, PVDC membranes were
incubated in a blocking buffer for 1 hour at room temperature, then
incubated for 2 hours with Abs raised against IL-12 p70 and A20
(Santa Cruz, CA). The membranes were washed and incubated for 1 hour
with HRP-labeled IgG. Immunoreactive bands were visualized by ECL
detection reagent. The binding bands were quantified by scanning
densitometer of a Bio-Image Analysis System. The results were
expressed as relative optical density.
Statistics
analysis
Statistic analysis of data was performed using the Student's
t-test; P<0.05 was
considered statistically significant.
RESULTS
Histological rejection
Histological rejection features of allografted livers were compared
between the whole and partial groups on day 4 after the
transplantation, allogeneic whole liver grafts demonstrated no
rejection. In contrast, partial liver grafts demonstrated moderate
to severe rejection, including inflammatory cellular infiltration in
the portal tract, endotheliitis, bile duct damage and hepatocytes
necrosis.
Phenotypic
characteristics of liver graft-derived DCs propagated in vitro
As shown in our previous study[42], after
cultured for 10 days in the presence of GM-CSF, DCs both from whole
and partial liver grafts displayed typical morphological features of
DC, including anomalous shape, bigger body, and numerous longer
dendrites. Flow cytometry showed 80-85 % of these DCs strongly
expressed rat DC - specific OX62 antigen molecule, which suggested
that high purity DCs were obtained. Flow cytometric analysis showed
that DCs from whole liver grafts and from partial liver grafts 0
hour after the transplantation were negative for the costimulatory
molecule CD40 expression, which was an immature phenotype (CD40-),
whereas DCs from partial liver graft 4 days after the
transplantation showed high level of CD40 expression, which was a
mature phenotype(CD40+). These results suggested
maturation of DCs resident in allogeneic partial liver graft
undergoing acute rejection.
IL-12
p70 protein expression in DCs derived from allogeneic partial liver
grafts
Our previous study showed that IL-12 p35 and IL-12 p40
subunit expressions were significantly up-regulated in mature DCs
derived from allogeneic partial liver grafts undergoing acute
rejection[42]. In the present study, we evaluated IL-12
p70 expression in DCs from allogeneic liver grafts. As shown in
Figure 1, DCs derived from both whole and partial liver grafts 0
hour after the transplantation expressed detectable but very low
level of IL-12 p70, and expression level of IL-12 p70 in DCs from
whole liver graft 4 days after transplantation was not elevated
compared with those of DCs from whole liver graft 0 hour after the
transplantation (P>0.05). However, expression of IL-12 p70
in DCs from partial liver graft 4 days after transplantation was
markedly increased, and their expression levels were significantly
higher than those of DCs both from partial liver graft 0 hour and
whole liver graft 4 days after transplantation (P<0.001).
Figure
1(PDF) Expression of
IL-12 p70 in liver graft - derived DCs by Western blotting. Lanes 1,
2: Expression of IL-12 p70 in DCs from partial liver graft and whole
liver graft 0 hour after transplantation. Lanes 3, 4: Expression of
IL-12 p70 in DCs from partial liver graft and whole liver graft 4
days after transplantation. aP<0.001 vs 4d WLT
group ; bP<0.001 vs 0 hour PLT group.
Electrophoretic
mobility shift assay (EMSA) for NF-kB activation of DCs
As shown in Figure 2, EMSA analysis showed detectable but very low
level of NF-kB activity of DCs derived from both whole and partial liver
grafts 0 hour after transplantation, and NF-kB activity of DCs from whole liver graft 4 days after
transplantation was not increased compared with those of DCs from
liver graft 0 hour after transplantation (P>0.05).
However, NF-kB activity of DCs from partial liver graft 4 days after
transplantation was significantly elevated compared with those of
DCs from partial liver graft 0 hour and whole liver graft 4 days
after transplantation (P<0.001).
Figure 2(PDF)
NF-kB activation of DCs derived from allogeneic liver grafts. Lanes
1, 2: NF-kB activation of DCs from partial liver graft and whole liver
graft 0 hour after transplantation. Lanes 3, 4: NF-kB activation of DCs from partial liver graft and whole liver
graft 4 days after transplantation. aP<0.001 vs
4 d WLT group; bP<0.001 vs 0 hour PLT group.
A20 protein expression in DCs derived from partial liver
allografts
In order to investigate the intracellular mechanisms
specifically responsible for regulation of DC activation and
maturation, we evaluated NF-kB inhibitor zinc finger protein A20 expression in DCs derived
from allogeneic liver grafts. As shown in Figure 3, DCs from both
whole and partial liver grafts 0 hour after the transplantation
expressed detectable but very low level of A20, and expression level
of A20 in DCs derived from whole liver graft 4 days after
transplantation was not increased compared with those of DCs from
whole liver graft 0 hour after transplantation (P>0.05).
However, expression of A20 in DCs from partial liver graft 4 days
after transplantation was markedly up-regulated, and its expression
level was significantly higher than those of DCs both from partial
liver graft 0 hour and whole liver graft 4 days after
transplantation (P<0.001).
Figure 3(PDF) Expression
of A20 protein in DCs derived from allogeneic liver grafts. Lanes 1,
2: Expression of A20 protein in DCs from partial liver graft and
whole liver graft 0 hour after transplantation. Lanes 3, 4:
Expression of A20 protein in DCs from partial liver graft and whole
liver graft 4days after transplantation. aP<0.001
vs 4 d WLT group; bP<0.001 vs 0 hour PLT group.
DISCUSSION
Despite the emergence of DCs as key cellular players in the immune
system, the signal transduction events that regulate DC maturation
and function have been poorly understood. This study was conducted
to explore whether NF-kB activation and its inducible expression gene of A20 could be
detected in mature DCs derived from liver allograft undergoing acute
rejection. Our aim was to determine whether A20 gene is involved in
NF-kB inhibition of these mature DCs. In the present study, it has
been shown that engagement of CD40 on DCs derived from allogeneic
partial liver grafts undergoing acute rejection leads to a powerful
NF-kB activation of these mature DCs, and as a consequence, leads to
high level expression of the protective gene A20 in these DCs.
Expression of this gene in mature DCs derived from liver graft
undergoing acute rejection is consistent with their known potential
to be induced in response to NF-kB activation.
It
has been shown that DCs derived from allogeneic partial liver grafts
undergoing acute rejection displayed mature phenotypic high level
CD40 expression and NF-kB activation. Although resting DCs residing in normal liver
tissues display only low levels of CD40, B7, and MHC class II
molecule expression[11, 12, 24]. The ischemia/reperfusion
injury which is consecutive to the transplantation procedure will
rapidly activate them. In addition, partial hepatectomy has been
reported to induce the expression of MHC II on Kupffer cell.
Interstitial dendritic cells and sinusoidal endothelium in rats,
together with the up-regulated TNF-a
production after partial hepatectomy would induce the expression of
B7 and CD40 molecules on DCs[16]. These factors could
stimulate maturation of DCs derived from partial liver grafts. These
mature DCs may contribute to the allogeneic liver graft rejection
induction. Previously other studies showed that mature DC could
provide signals able to trigger T cell proliferation after TCR
engagement[43, 44]. These accessory, or "costimulatory"
signals, are consecutive to interactions between costimulatory
molecules present on activated DC such as B7, CD40, and OX40-ligand
and their respective counter-receptors, CD28, CD40-ligand, and OX40,
on T cell membranes. Several intracellular signals follow the
engagement of costimulatory molecules. Interactions of CD40L, CD28,
and OX40 with their ligands on DCs activate the transcription factor
NF-kB in both T cells and DCs[29, 30]. In turn, NF-kB initiates the transcription of numerous genes involved in
immune activation, such as chemokines and cytokines[20, 30],
and also of costimulatory molecules themselves. For instance, CD40
ligation on the APC will up-regulate its expression of B7 molecules.
This initiates positive feedback loops ultimately contributing to T
cell expansion[45]. Among the costimulatory molecules,
CD40 and B7 seem to play a crucial role in alloreactive responses.
Indeed, blockade of both CD40 and B7 molecules at the time of
transplantation prevents allograft rejection and induces
alloreactive T cell anergy[46, 47]. In the present study,
DCs derived from allogeneic partial liver grafts undergoing acute
rejection demonstrated high level expression of CD40, which could
interact with the CD40-ligand on T cells, leading to a powerful NF-kB activation and high level of IL-12p70 expression in these
mature DCs. Given an essential role for NF-kB transcription in LPS- and CD40L - induced expression of IL-12
(IL-12 p35, p40 and p70) in DCs[20], IL-12 is a key
inducer of liver graft rejection[26], together with high
level of IL-12 p35 and IL-12 p40 protein expression in the mature
DCs derived from allogeneic liver grafts undergoing acute rejection[42].
Our results suggest that NF-kB may play a key role in the maturation of DCs derived from
allogeneic liver grafts undergoing acute rejection.
To provide
further insights into potential intracellular mechanisms responsible
for maturation regulation of DCs derived from allogeneic liver
grafts undergoing acute rejection, we measured the protective A20
gene expression in these DCs. Zinc finger protein A20 is a potent
inhibitor of NF-kB[31], and although other studies have shown A20 is
mainly expressed in endothelial and infiltrating mononuclear cells
of human renal allografts undergoing acute rejection[41],
little is known about whether it is also involved in the regulation
of DC maturation and activation. Our results first demonstrate that
high level A20 expression is detected in the mature DCs (which
presente significant NF-kB activation) derived from acute rejecting liver allografts, but
few A20 is detected in the immature DCs (which present few NF-kB activation) derived from nonrejecting liver allografts. Given
A20 is itself a NF-kB - dependent gene and is part of a negative regulatory loop
critical for modulation of cell activation[37, 38],
together with NF-kB which may play a key role in the maturation of DCs derived from
liver allografts undergoing acute rejection, it is suggested that
A20 expression in these mature DCs derived from liver allografts
undergoing acute rejection survives to inhibit NF-kB activation and to limit maturation of these DCs, and as a
consequence to limit the graft rejection.
In
summary, we demonstrate for the first time an association between
NF-kB activation and expression of the protective gene A20 and
maturation of DCs derived from liver allografts undergoing acute
rejection. NF-kB binding activity and A20 expression in these mature DCs are
strongly up-regulated in response to acute rejection. NF-kB may play a key role in the maturation of DCs derived from
allogeneic liver grafts undergoing acute rejection, and A20
expression in these mature DCs derived from liver allografts
undergoing acute rejection survives to inhibit NF-kB activation and to limit maturation of these DCs.
REFERENCES
1
Zhang JK, Chen HB, Sun JL, Zhou YQ. Effect of dendritic cells
on LPAK cells induced at different times in killing
hepatoma cells. Shijie Huaren Xiaohua
Zazhi 1999; 7: 673-675
2
Li MS, Yuan
AL, Zhang WD, Chen XQ, Tian XH, Piao YT. Immune response induced by
dendritic cells induce apoptosis
and inhibit proliferation of tumor
cells. Shijie Huaren Xiaohua Zazhi 2000; 8: 56-58
3
Luo ZB, Luo
YH, Lu R, Jin HY, Zhang BP, Xu CP. Immunohistochemical study on
dendritic cells in gastric mucosa of
patients with gastric cancer and
precancerous lesions. Shijie Huaren Xiaohua Zazhi 2000; 8: 400-402
4
Li MS, Yuan AL, Zhang WD, Liu SD, Lu AM, Zhou DY. Dendritic
cells in vitro induce efficient and special anti-tumor
immune response. Shijie Huaren
Xiaohua Zazhi 1999; 7: 161-163
5
Wang FS, Xing LH, Liu MX, Zhu CL, Liu HG, Wang HF, Lei ZY.
Dysfunction of peripheral blood dendritic cells from
patients with chronic hepatitis B
virus infection. World J Gastroenterol 2001; 7: 537-541
6
Zhang JK, Li J, Chen HB, Sun JL, Qu YJ, Lu JJ. Antitumor
activities of human dendritic cells derived from peripheral
and cord blood. World J Gastroenterol
2002; 8: 87-90
7
Tang ZH, Qiu WH, Wu GS, Yang XP, Zou SQ, Qiu FZ. The
immunotherapeutic effect of dendritic cells vaccine
modified with interleukin-18 gene and
tumor cell lysate on mice with pancreatic carcinoma. World J
Gastroenterol 2002; 8: 908-912
8
Zhang J, Zhang JK, Zhuo SH, Chen HB. Effect of a cancer
vaccine prepared by fusions of hepatocarcinoma cells
with dendritic cells. World J
Gastroenterol 2001; 7: 690-694
9
Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ,
Pulendran B, Palucka K. Immunobiology of dendritic
cells. Annu Rev Immunol 2000; 18:
767-811
10
Banchereau J, Steinman RM. Dendritic cells and the control of
immunity. Nature 1998; 392: 245-252
11
Khanna A, Morelli AE, Zhong CP, Takayama T, Lu LN, Thomson
AW. Effects of liver-derived dendritic cell progenitors
on Th1-and Th2-like cytokine
responses in vitro and in vivo. J Immunol 2000; 164:
1346-1354
12
Morelli AE, O'Connell
PJ, Khanna A, Logar AJ, Lu LN,Thomson AW. Preferential induction of
Th1 responses by
functionally mature hepatic (CD8a-
and CD8a+)
dendritic cells: association with conversion from liver
transplant
tolerance to acute rejection.
Transplantation 2000; 69: 2647-2657
13
Hertz CJ, Kiertscher SM, Godowski PJ, Bouis DA, Norgard MV,
Roth MD, Modlin RL. Microbial lipopeptides
stimulate dendritic cell maturation
via Toll-like receptor 2. J Immunol 2001; 166: 2444-2450
14
Thoma-Uszynski S, Kiertscher SM, Ochoa MT, Bouis DA, Norgard
MV, Miyake K, Godowski PJ, Roth MD, Modlin
RL. Activation of toll-like receptor
2 on human dendritic cells triggers induction of IL-12, but not
IL-10. J Immunol
2000; 165: 3804-3810
15
Kaisho T, Takeuchi O, Kawai T, Hoshino K, Akira S. Endotoxin-induced
maturation of MyD- 88 deficient dendritic
cells. J Immunol 2001; 166: 5688-5694
16
Kitamura H, Iwakabe K, Yahata T, Nishimura S, Ohta A, Ohmi Y,
Sato M, Takeda K, Okumura K, Van Kaer L, Kawano
T, Taniguchi M, Nishimura T. The
natural killer T (NKT) cell ligand alpha-galactosylceramide
demonstrates
its immunopotentiating effect by
inducing interleukin (IL)-12 production by dendritic cells and IL-12
receptor
expression on NKT cells. J Exp Med
1999; 189: 1121-1128
17
Nagayama H, Sato K, Kawasaki H, Enomoto M, Morimoto C,
Tadokoro K, Juji T, Asano S, Takahashi TA.
IL-12 responsiveness and expression
of IL-12 receptor in human peripheral blood monocyte-derived
dendritic
cells. J Immunol 2000; 165: 59-66
18
Visintin A, Mazzoni A, Spitzer JH, Wyllie DH, Dower SK, Segal
DM. Regulation of Toll-like receptor in human
monocytes and dendritic cells. J
Immunol 2001; 166: 249-255
19
Corinti S, Albanesi C, la Sala A, Pastore S, Girolomoni G.
Regulatory activity of autocrine IL-10 on dendritic cell
functions. J Immunol 2001; 166:
4312-4318
20
Ouaaz F, Arron J, Zheng Y, Choi Y, Beg AA. Dendritic cell
development and survival require distinct NF-kB
subunits. Immunity 2002; 16: 257-270
21 Josien R, Li HL,
Ingulli E, Sarma S, Wong BR, Vologodskaia M, Steinman RM, Choi Y.
TRANCE, a tumor necrosis
factor family member, enhances the
longevity and adjuvant properties of dendritic cells in vivo. J Exp
Med
2000; 191: 495-502
22 Miga AJ, Masters SR,
Durell BG, Gonzalez M, Jenkins MK, Maliszewski C, Kikutani H, Wade
WF, Noelle RJ. Dendritic
cell longevity and T cell persistence
is controlled by CD154-CD40 interactions. Eur J Immunol 2001; 31:
959-965
23 Cella M, Scheidegger
D, Palmer-Lehmann K, Lane P, Lanzavecchia A, Alber G. Ligation of
CD40 on dendritic cells
triggers production of high levels of
interleukin-12 and enhances T cell stimulatory capacity: T-T help
via APC
activation. J Exp Med 1996; 184:
747-752
24
Lu L, Woo J, Rao AS, Li Y, Watkins SC, Qian S, Starzl TE,
Demetris AJ, Thomson AW. Propagation of dendritic
cell progenitors from normal mouse
liver using granulocyte/macrophage colony-stimulating factor and
their
maturational development in the
presence of type-1 collagen. J Exp Med 1994; 179: 1823-1834
25 Khanna A, Steptoe RJ,
Antonysamy MA, Li W, Thomson AW. Donor bone marrow potentiates the
effect of tacrolimus
on nonvascularized heart allograft
survival: association with microchimerism and growth of donor
dendritic
cell progenitors from recipient bone
marrow. Transplantation 1998; 65: 479-485
26 Li W, Lu L, Wang Z,
Wang L, Fung JJ, Thomson AW, Qian S. IL-12 antagonism enhances
apoptotic death of T cells
within hepatic allografts from Flt3
ligand-treated donors and promotes graft acceptance. J Immunol
2001; 166: 5619-5628
27
Steptoe RJ, Fu F, Li W, Drakes ML, Lu L, Demetris AJ, Qian S,
McKenna HJ, Thomson AW. Augmentation of dendritic
cells in murine organ donors by Flt3
ligand alters the balance between transplant tolerance and immunity.
J
Immunol 1997; 159: 5483-5491
28
Rescigno M, Martino M, Sutherland CL, Gold MR,
Ricciardi-Castagnoli P. Dendritic cell survival and maturation
are regulated by different signaling
pathways. J Exp Med 1998; 188: 2175-2180
29
Verhasselt V, Vanden
Berghe W, Vanderheyde N, Willems F,Haegeman G, Goldman M.
N-acetyl-L-cysteine inhibits
primary human T cell responses at the
dendritic cell level: association with NF-kB inhibition. J Immunol
1999; 162: 2569-2574
30
Mann J, Oakley F,
Johnson PW, Mann DA. CD40 induces interleukin-6 gene transcription
in dendritic cells. J Biol
Chem 2002; 277: 17125-17138
31
Zetoune FS, Murthy AR, Shao Z, Hlaing T, Zeidler MG, Li Y,
Vincenz C. A20 inhibits NF-kappa B activation downstream
of multiple Map3 kinases and
interacts with the I kappa B signalosome. Cytokine 2001; 15: 282-298
32 Klinkenberg M, Van-Huffel
S, Heyninck K, Beyaert R. Functional redundancy of the zinc fingers
of A20 for inhibition
of NF-kappaB activation and
protein-protein interactions. FEBS Lett 2001; 498: 93-97
33 Hofer-Warbinek R,
Schmid JA, Stehlik C, Binder BR, Lipp J, de-Martin R. Activation of
NF-kappa B by XIAP, the
X chromosome-linked inhibitor of
apoptosis, in endothelial cells involves TAK1. J Biol Chem
2000; 275: 22064-22068
34 Beyaert R, Heyninck K,
Van-Huffel S. A20 and A20-binding proteins as cellular inhibitors of
nuclear factor-
kappa B-dependent gene expression and
apoptosis. Biochem Pharmacol 2000; 60: 1143-1151
35
Sarma V, Lin Z, Clark
L, Rust BM, Tewari M, Noelle RJ, Dixit VM. Activation of the B-cell
surface receptor CD40
induces A20, a novel zinc finger
protein that inhibits apoptosis. J Biol Chem 1995; 270: 12343-12346
36
Kupfner JG, Arcaroli JJ, Yum HK , Nadler SG, Yang KY, Abraham
E. Role of NF-kappaB in endotoxemia-induced
alterations of lung neutrophil
apoptosis. J Immunol 2001; 167: 7044-7051
37
Heyninck K, De Valck D, Vanden Berghe W, Van Criekinge W,
Contreras R, Fiers W, Haegeman G, Beyaert R. The
zinc finger protein A20 inhibits TNF-induced
NF-kB-dependent gene expression by interfering with an RIP- or
TRAF2-mediated transactivation signal
and directly binds to a novel NF-kB-inhibiting protein ABIN. J Cell Biol
1999; 145: 1471-1482
38 Arvelo MB, Cooper JT,
Longo C, Daniel S, Grey ST, Mahiou J, Czismadia E, Abu-Jawdeh G,
Ferran C. A20 protects
mice from D-galactosamine/LPS acute
toxic lethal hepatitis. Hepatology 2002; 35: 535-543
39 Ferran C, Stroka DM,
Badrichani AZ, Cooper JT, Wrighton CJ, Soares M, Grey ST, Bach FH.
A20 inhibits NF-kB
activation in endothelial cells
without sensitizing to tumor necrosis factor- mediated apoptosis.
Blood
1998; 91: 2249-2258
40 Lee EG, Boone DL, Chai
S, Libby SL, Chien M, Lodolce JP, Ma A. Failure to regulate TNF-induced
NF-kappaB and
cell death responses in A20-deficient
mice. Science 2000; 289: 2350-2354
41 Avihingsanon Y, Ma N,
Csizmadia E, Wang C, Pavlakis M, Giraldo M, Strom TB, Soares MP,
Ferran C. Expression
of protective genes in human renal
allografts: a regulatory response to injury associated with
graft rejection. Transplantation
2002; 73:1079-1085
42 Xu MQ, Yao ZX.
Functional changes of dendritic cells derived from allogeneic
partial liver graft undergoing acute
rejection in rats. World J
Gastroenterol 2003; 9: 141-147
43 Lechler R, Ng WF,
Steinman RM. Dendritic cells in transplantation: friend or foe?
Immunity 2001; 14: 357-368
44 Matzinger P. Graft
tolerance: a duel of two signals. Nat Med 1999; 5: 616-617
45
Stout RD, Suttles J.
The many roles of CD40 in cell-mediated inflammatory responses.
Immunol Today
1996; 17: 487- 492
46 Larsen CP, Elwood ET,
Alexander DZ, Ritchie SC, Hendrix R, Tucker-Burden C, Cho HR, Aruffo
A, Hollenbaugh O,
Linsley PS, Winn KJ, Pearson TC.
Long-term acceptance of skin and cardiac allografts after blocking
CD40 and
CD28 pathways. Nature 1996; 381:
434-438
47 Kirk AD, Harlan DM,
Armstrong NN, Davis TA, Dong Y, Grag GS, Hong X, Thomas D, Fechner
JH Jr, Knechtle SJ.
CTLA4-Ig and anti-CD40 ligand prevent
renal allograft rejection in primates. Proc Natl Acad Sci USA
1997; 94: 8789-8794
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