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Ai-Bin
Zhang, Shu-Sen Zheng, Chang-Ku Jia, Yan Wang, Department of
Hepatobiliary Pancreatic Surgery, The First Affiliated Hospital of
Medicine School, Zhejiang University, Key Lab of Combined
Multi-Organ Transplantation, Ministry of Public Health, Hangzhou
310003, Zhejiang Province, China
Correspondence to: Ai-Bin Zhang, Department of Hepatobiliary
Pancreatic Surgery, The First Affiliated Hospital of Medicine
School, Zhejiang University, Hangzhou 310003, Zhejiang Province,
China. cheung163@163.com
Telephone: +86-571-87236570
Received: 2002-11-06
Accepted: 2002-12-16
Abstract
AIM: To study the mechanism and the preventive role of
1,25-dihydroxyvitamin D3 in acute rejection following orthotopic
liver transplantation.
METHODS:
Rats were randomly divided as donors or recipients for orthotopic
liver allotransplantation model. Four groups were designed in the
study, Group I: syngenic control (Wistar to Wistar); Group II: acute
rejection (SD to Wistar); Group III: acute rejection treated with
cyclosporine A, and Group IV: acute rejection treated with
1,25-(OH)2D3. Liver function, rejection activity index and mRNA of
IFN-g,
IL-10 intragraft in recipients were measured on day 1, 5, 7, 15, 30
posttransplant for assessing graft function, severity of acute
rejection and immune state of recipients.
RESULTS:
Survival time of recipients in Group IV was
significantly prolonged (4/6 recipients survived for over 100
days. vs Group II, P<0.001; vs Group III, P>0.05). After
treatment with 1,25-(OH)2 D3, mean value of all the assay tested on
each experimental time was compared, liver function in group IV was
significantly improved (AST 127±41 U/L-360±104 U/L, BIL 13±5 mmol/l-3811 mmol/l; vs Group II, P<0.05; vs Group III,
P>0.05. Rejection activity index was significantly decreased
(0-3.3±1.6; vs Group II, P<0.05; vs Group III, P>0.05). Level of
hepatic IFN-g
mRNA in group IV was decreased, while level of hepatic IL-10 mRNA
was increased (vs Group II, P<0.05; vs Group III, P>0.05).
CONCLUSION: Our results indicated that 1,25-(OH)2D3
induced the secretion of cytokine toward to Th2 type, which
would alleviate acute rejection, protect liver function and prolong
survival of recipient after orthotopic liver transplantation.
Zhang AB, Zheng SS, Jia CK, Wang Y. Effect of 1,25-dihydroxyvitamin
D3 on preventing allograft from acute rejection following rat
orthotoic liver transplantation. World J Gastroenterol
2003; 9(5): 1067-1071
http://www.wjgnet.com/1007-9327/9/1067.asp
INTRODUCTION
1,25-dihydroxyvitamin D3 (1,25-(OH)2 D3), the
functional metabolite of vitamin D, is a key regulator of calcium
and phosphorus[1], has important immunomodulatory action[2,3],
and was demonstrated to be able to prevent graft from acute
rejection after transplantation of heart and renal, and prolong the
survival of graft significantly[4-7]. In previous study,
we demonstrated that 1,25-(OH)2 D3 played
important role in preventing the rejection of allograft after liver
transplantation. The kinetic characteristic of 1,25-dihydroxyvitamin
D3 on liver allograft viability and rejection after liver
transplantation was explored in present study with orthotopic rat
liver transplantation model. Furthermore, expression of IFN and
IL-10 was determined to examine the immunomodulatory effect of
1,25-dihydroxyvitamin D3.
MATERIALS
AND METHODS
Animals, surgical procedure and experimental groups
Male Sparague-Dawley (SD) and Wistar rats (200-250 g, purchased from
Shanghai Animal Center, Academy of Science, Shanghai) were selected
randomly as transplant donors or recipients. Under ether inhalation,
orthotopic rat liver transplantation was performed according to
Kamada's two-cuff
technique[8]. Four experimental groups were designed in
this study, Group I: syngenic control (Wistar-to-Wistar); Group II:
acute rejection (SD-to-Wistar); Group III: acute rejection treated
with cyclosporine A 3.0 mg.kg-1.d-1
intramuscularly, from day 0 to 13 posttransplant (SD-to-Wistar+CsA);
Group IV: acute rejection treated with 1,25-(OH)2 D3 1.0 mg.kg-1.d-1
intraperitoneally, from day 0 to day 13 posttransplant
(SD-to-Wistar+1,25-(OH)2 D3). Recipient animals had an experimental
diet containing 0.47 % calcium 7 days before transplantation; only
recipients in Group IV received experimental diet for15 days
following transplantation.
Sample
harvesting
On day 1, 5, 7, 15, and 30 posttransplant, three rats were selected
from each group for sample harvesting. Serum calcium levels were
measured to study the effect of 1,25-(OH)2 D3
on calcium metabolism. Serum aspartate aminotransferase (AST) and
total bilirubin (BIL) were measured to study the effect of 1,25-(OH)2
D3 on liver functions. Liver allografts were taken for
histology and cytokine determination. Another 6 rats in each group
were bred for observing survival time. Rocaltrolâ,
1,25-dihydroxyvitamin D3 product of Roche Pharma, and Sandimmuneâ,
Cyclosporine A product of Novartis Pharma were used in this
study.
Histopathologic
examination
Grafted liver samples were fixed in 10 % buffered formalin and embed
in paraffin. Five-micrometer-think sections were affixed on slides,
deparaffinized, and stained with hematoxylin and eosin. Morphologic
change of graft was observed and severity of acute rejection was
assessed with Rejection Activity Index according to Banff 97 working
classification of hepatic allograft pathology[9].
Cytokine
reverse transcription-polymerase chain reaction
Primer sequences and reaction conditions
The sequences of primers, synthesized by Bioengine-ering Corp
at Shanghai are as follow, IFN-g
sense primer 5'-ACT GCC AAG GCA CAC TCA TT-3', antisense primer
5'-AGG TGC GAT TCG ATG ACA CT-3'(size 235bp); IL-10 sense primer
5'-TGC TCT TAC TGG CTG GAG TG-3', IL-10 antisense primer 5'-GTC GCA
GCT GTA TCC AGA GG-3'(size 345bp). b-actin
sense primer, 5'-TCG TAC CAC TGG CAT TGT GA-3', b-actin
antisense primer, 5'-TCC TGC TTG CTG ATC CAC AT-3' (size 645bp).
Amplification were performed using an initial denaturation step of
95 ℃
for 2 minutes, followed by 32 cycles consisting of 94 ℃
for 45 seconds, 56 ℃
for 45 seconds and 72 ℃
for 45 seconds. The final extension step was one cycle at 72 ℃
for 10 minutes.
RT-PCR
Total RNA was prepared from grafted liver with TRIzol Reagent
(Gibco, BRL) according to the manufacturer's recommendations.
For cDNA synthesis, 4 mg
total RNA was reverse transcribed with MuLV (MBI, Fermentas) reverse
transcriptase according to the manufacturer's recommendations.
Two microliters from the resulting cDNA solution were then amplified
in a volume of 25 ml
PCR buffer using specific oligonucleotides under the conditions
aforementioned. Reaction products were run on a 1.5 % agarose gel
for 20-30 min at 100 V, and visualized with ethidium bromide under
UV light. Relative expression of cytokines was defined as optical
density ratio (cytokine/b-actin)
analyzed by Kodak science scanning system.
Statistics
All data were expressed as mean values and standard deviations and
analyzed using SPSS software (version 10.0 for windows). Difference
in mean value between the groups was tested by Independent-Samples t
test. Differences in pathological Reject Activity Index score
between the groups were tested with the Mann-Whitney U nonparametric
test. Recipient's survival
was estimated with the Kaplan-Mier product limit estimator.
Statistically significance was defined at P<0.05.
RESULTS
Survival of recipient posttransplantation
All the recipients in Group I survived for over 100 days; all the
recipients in Group II died at day 7 to day 19 posttransplantation
and median survival time was 12.3±4.0 days. Five out of 6 recipients in Group III, and
4 out of 6 recipients in Group IV survived for long term.
Difference between Group IV and II was statistically significant,
but not for that between group IV and III. Kaplan-Mier Survival
Curve was showed in Figure 1.
Figure
1(PDF) Effect of
1,25-(OH)2 D3 on survival of rat recipients of
an othtopic liver allograft (Kaplan-Meier Survival Curve). When
Group III was compared with Grou II: P=0.0005. When Group IV was
compared with Grou II: P=0.0005. When Group IV was compared with
Group III: P=0.70.
Effect of 1,25-(OH)2D3 on serum calcium and
liver function
An obvious limitation to the use of vitamin D3 derivatives in
transplantation was hypercalcemia. Serum calcium in Group I on day 7
posttransplant was defined as basal value. If value was not
significant in comparison with basal value, no significant effect of
1,25-(OH)2 D3 or CsA on calcium metabolism was considered
(Table 1). Level of AST and BIL in Group I increased slightly within
7 days posttransplant and then gradually restored to normal after 7
days posttransplant. In Group II, liver function deteriorated
dramatically on day 5 posttransplant, and levels of bilirubin and AST
increased steadily
until the death of recipients. In contrast, administration of either
CsA or 1,25-(OH)2 D3 prevented deterioration of the graft
function during the first 30 days after transplantation. The average
values of AST were 146±33 U/L-241±107 U/L, and BIL 17±6 mmol/l-25±9 mmol/l in Group III, while mean level of
AST, BIL in Group IV posttransplant was 127±41 U/L-360±104 U/L and 13±5 mmol/l-38±11 mmol/l, respectively. Difference
of these values between Group II and IV was statistically
significant while difference between group III and IV was not
(Figure 2).
Table 1 Serum calcium
assessment (mmol/l, x±s)a
| Group |
Time
posttransplant (d) |
| 7 |
15 |
30 |
| I |
2.29±0.13 |
2.16±0.05 |
2.22±0.16 |
| II |
2.34±0.04 |
|
|
| III |
2.25±0.11 |
2.32±0.07 |
2.12±0.09 |
| IV |
2.60±0.31 |
2.47±0.27 |
2.33±0.31 |
a:
Serum calcium of Group I on 7 d posttransplant was supposed as basal
values, each value was not significant in comparison with basal
values (P>0.05).
Figure 2(PDF)
Effect of 1,25-(OH)2 D3 on graft
function (x±s). aP<0.05, vs Group I; bP<0.05, vs
Group II.
Histological assessment of graft rejection
In Group I no signs of rejection were found all the time, on day 5
posttransplant, minimal inflammation on portal area
was found, average RAI score was 0.3±0.6. On all other experimental times, RAI score was 0; In group II, a few
lymphocytes infiltrated in portal area with minimal vein
endothelialitis on day 1 posttransplant. Lymphocytes
infiltrated in portal area obviously with degeneration of
hepatic parenchyma in all cases on day 5 posttransplant with average
RAI 8.3±1.1 Marked mononuclear infiltration, severe vein
subendothelialitis with bridging hepatocellular necrosis can be
found on day 7 posttransplant with average RAI 8.7±0.6. Rejection reaction was greatly inhibited in Group III due
to the immunosuppressive effect of CsA. No evidence of rejection was
found on day 1 and day 5 posttransplant. But both inflammatory
infiltration and endothelialitis can be found on day 7 with RAI at
2.3±0.6 was evaluated. Infiltration in portal area and bile duct
hyperplasia in some cases were detected on day 15 and day 30
postransplant. As for Group IV, RAI was 0 on day 1 posttransplant.
On day 5 posttransplant, RAI was 2.3±0.6. Inflammatory was mild. Vein subendothelial tissue and bile
duct were cuffed by lymphocytic infiltrate occasionally. Necrosis of
hepatocytes was not detected. On day 7 and 15, mild to moderate
portal inflammatory was continuously mild to moderate. Various
degree endothelialitis or hepatocyte necrosis existed in some cases.
On day 30 posttransplant, mild to moderate portal infiltrate was
still existed. Mild bile duct hyperplasia was found in 2/3 cases.
RAI in Group IV was lower than in Group II significantly (P<0.05)
on each time point. In comparison with Group III, RAI in group IV
was slightly higher without any significance (P>0.05) on each
time point (Figure 3).
Figure 3(PDF)
Effect of 1,25-(OH)2 D3 on Rejection
Activity Index(RAI). (x±s). aP<0.05, vs Group I; bP<0.05 vs
Group II.
Figure 4(PDF)
Effect of 1,25-(OH)2 D3 on IFN-g
and IL-10 gene transcription (x±s, analyzed by RT-PCR). aP<0.05, vs Group I; bP<0.05
vs Group II.
Effect
of 1,25-(OH)2 D3 on IFN-g
mRNA and IL-10 mRNA
On each defined time posttransplant, the expression of IFN-g
mRNA intragraft was little in Group I and strong in Group II. After
administration of CsA, the expressed level of IFN-g
mRNA decreased significantly (P<0.05, vs Group II). After
treatment with 1,25-(OH)2 D3 1.0 mg.kg-1.d-1,
the expressed level of IFN-g
mRNA decreased significantly (P<0.05, vs Group I; P>0.05, vs
Group III).
In contrast, expression of IL-10 mRNA intragraft was strong
and obvious in Group, but very weak in Group II. The expression
level increased significantly (P<0.05, vs Group II) after
treatment with CsA. As for Group IV, the expression level increased
markedly (P<0.05, vs Group II; P>0.05, vs Group III) (Figure
4).
DISCUSSION
As a newly recognized hormone, 1,25-(OH)2 D3
has immune activity in vitro and its role in organ transplantation
has been highlighted last decade. For instance, MC1288, a analogue
of 1,25-(OH)2 D3, could prolong survival of
cardiac and small-bowel allografts in rats[4]. 1,25-(OH)2
D3 was demonstrated to inhibit neonatal as well as
vascularized heart transplantation rejection much effectively than a
high-dose CsA regimen[5].
However, no effect was observed in graft survival in a
neonatal nonvascularized murine heart transplantation model in
another report[10]; Jordan et al[11] reported
a marginal effect of vitamin D on rat cardiac allograft survival. In
all cases, significant toxicity of hypercalcium was observed. In our
study, we showed that 1,25-(OH)2 D3 can
effectively inhibit acute rejection following liver transplantation,
and prolong recipients survival markedly. Our study also showed that
hypercalcemic effect of 1,25-(OH)2 D3 can be
mitigated by a low-calcium diet. The major differences between these
studies were the administrative route of 1,25-(OH)2 D3.
It was given every
other day intraperitoneally in previous study. Since the half-life
of 1,25-(OH)2 D3 is few hours[1],
the administration of this compound every other day would not be
sufficient. Furthermore, several studies used various analogues of
vitamin D such as KH1060, MC1288. These analogues had varied side
effect of hypercalmia by changing its stereochemistry at C-20[12-14],
and allowed to take higher dosage of this agents and thus increased
its immune effect in therapy.
In present study, it has been confirmed that the beneficial
of 1,25-(OH)2 D3 on survival was due to a
marked inhibition of rejection and amelioration of graft function. At the cellular level,
1,25-(OH)2 D3 interferes with function of
antigen-presenting cells by decreasing MHC class II expression, and
blocks mitogen stimulated T-cell proliferation[15-17]. As a result,
1,25-(OH)2 D3 reduces the immunogenicity of
allograft and the cytotoxicity of CTL, prevents the allograft from
immune attack. In present study, the allografts of rats that did not
receive 1,25-(OH)2 D3 demonstrated moderate to
severe acute rejection. Marked lymphocytic infiltration, severe bile
duct injury, subendothelialitis and hepatic necrosis were observed.
The RAI score and bilirubin concentration, AST activity increased
continuously until the death of recipients. In contrast, allografts
of rats receiving 1,25-(OH)2 D3 showed
significant improvement.
Lymphocytic infiltration intragraft and hepatocellular necrosis were
mild, and the rejection activity was inhibited. On each time point
observed, the differences in values of RAI, BIL and AST between
Group III and IV were not significant statistically. It suggested
that the effect of 1,25-(OH)2 D3 and CsA in
protecting graft function was equal.
Some studies[18-21] showed that in allografting
Th1 cells launched rejection by priming the cytotoxicity of CTL and
delayed-type hypersensitivity reaction through cytokine, and Th2
cells induced allografts tolerance by receding the activity of Th1
cells through cytokine. 1,25-(OH)2 D3
interacted with a nuclear receptor (VDR). In nuclear, VDR combined
with RXR to form a heterodimer, then bound to the target gene. Once
1,25-(OH)2 D3 combined with the VDR, DNA
bending occurs. Ultimately it affected the RNA polymerase activity
for either stimulation or suppression of transcription[22-24].
The present study has demonstrated that 1,25-(OH)2 D3
can inhibit transcription of IFN-g,
and stimulate transcription of IL-10. Thus, our results provide
further evidence that a high IL-10 and low IFN-g
expression state may protect allografts[25,26]. It was
manifested in vitro that 1,25-(OH)2 D3 could
inhibit interleukin 12[27] which was produced by
myelomonocytic cells and played a pivotal role in the development of
Th1 cells, as well as inhibition the excretion of cytokine such as
IFN-g[28,29]
and IL-2[30,31]. In the other hand, 1,25-(OH)2
D3 can directly stimulate Th2 cells to excrete cytokine
such as IL-4, IL-5 and IL-10[32-34]. The effect of
vitamin D3 on cytokine may shift the immune response from the Th1
pathway, which leads to allograft rejection to the Th2 pathway,
which can induce allograft tolerance.
In kinetic surveillance, some common characteristic can be
found in all groups. In isograft, variation of each index was
relatively gentle. The allografts of rats that did not take
1,25-(OH)2 D3 demonstrated a obvious tidemark
of rejection on day 5 posttransplant. In Group III and IV, the
rejection reaction was inhibited markedly due to the
immunosuppressive effect of 1,25-(OH)2 D3
and CsA. The kinetic in the two groups and IFN-g
mRNA and RAI were similar, that is, the severe rejection reaction
appeared on day 7 posttransplant, meanwhile expression of IL-10 mRNA
and liver function were very low. Previous studies[35,36]
showed that high immunoresponses occurred day 3 to day 5
posttransplantation and thus called
a transient "rejection
crisis". It may be due to the strong immunosuppressive effect
of 1,25-(OH)2 D3 and CSA that rejection crisis
phase in Group III and IV was postponed.
Interesting, although majority of recipients in group III and
IV survived for long-term, all of grafts in these two groups were
demonstrated various degree of rejection activity. Further studies[37,38]
have confirmed that majority of this rejection was self-limited, and
it could resolve spontaneously by day 50 posttransplant without
immunosuppressive agents.
In conclusion, our study proved that 1,25-(OH)2 D3
could effectively
modulate the cytokine net, induce TH1/TH2 shifting, and thus
postpone the "rejection
crisis", inhibit the acute rejection and protect the graft
function.
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Edited
by
Ren SY
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