|
Constantin
Fotiadis, Paraskevi Xekouki, Pantelis T Antonakis, George Zografos,
3rd
Department of Surgery, Athens University Medical School, Athens,
Greece
Apostolos E Papalois, Eleutheria Karampela,
Experimental-Research Unit ELPEN Pharma, Athens, Greece
Ioannis Sfiniadakis, Dimitrios Flogeras,
Department of Pathology, Naval Hospital,
Athens, Greece
Supported by the Special Research Fund, Account Code: 4280,
National and Kapodistrian University of Athens, Greece
Correspondence to: Constantin Fotiadis, Associate Professor
in Surgery, 3rd
Department of Surgery, Athens University Medical School, 12
Diligiani str, 14561, Athens, Greece.
costfot@yahoo.gr
Telephone: +30-210-6230600
Received: 2004-10-30
Accepted: 2004-12-08
Abstract
Aim: To develop an
experimental model of islet allotran-splantation in diabetic rats
and to determine the positive or adverse effects of MMF as a single
agent.
Methods:
Thirty-six male Wistar rats and 18 male Lewis rats were used as
recipients and donors respectively. Diabetes was induced by the use
of streptozotocin (60 mg/kg) intraperitoneally. Unpurified islets
were isolated using the collagenase digestion technique and
transplanted into the splenic parenchyma. The recipients were
randomly assigned to one of the following three groups: group A
(control group) had no immunosuppression; group B received
cyclosporine (CsA) (5 mg/kg); group C received mycophenolate mofetil
(MMF) (20 mg/kg). The animals were killed on the 12th
d. Blood and grafted tissues were obtained for laboratory and
histological assessment.
Results: Median
allograft survival was significantly higher in the two therapy
groups than that in the controls (10 and 12 d for CsA and MMF
respectively vs 0 d for the control group, P<0.01).
No difference in allograft survival between the CsA and MMF groups
was found. However, MMF had less renal and hepatic toxicity and
allowed weight gain.
Conclusion:
Monotherapy with MMF for immunosu-ppression was safe in an
experimental model of islet allotransplantation and was equally
effective with cyclosporine, with less toxicity.
Ó 2005
The WJG Press and Elsevier Inc. All rights reserved.
Key words:
Diabetes; Islet transplantation; Rats; Mycophenolate mofetil;
Cyclosporine
Fotiadis C, Xekouki P, Papalois AE, Antonakis PT, Sfiniadakis I,
Flogeras D, Karampela E, Zografos G. Effects of mycophenolate
mofetil vs cyclosporine administration on graft survival and
function after islet allotransplantation in diabetic rats. World
J Gastroenterol 2005;
11(18): 2733-2738
http://www.wjgnet.com/1007-9327/11/2733.asp
INTRODUCTION
Islet cell transplantation can provide a minimally invasive
method of restoring euglycemia and insulin independence early in the
course of diabetes mellitus[1].
This alternative treatment comprises a very promising therapeutic
approach since the early 1970s[2-4]
and recent reports in the literature support this hypothesis[5-9].
However, the results "fall
short" compared to the expectations mainly due to the loss of
thousands of islets during the three-stage islet isolation process,
the need for immunosuppressive agents having significant
diabetogenic side effects and the difficulty to detect graft
rejection early[10].
Thus, the reported 1-year insulin-independent survival after islet
transplantation in 1999 was only 14%[11].
A major issue in transplantation is graft
rejection. The administration of immunosuppressive drugs such as
cyclosporine (CsA), tacrolimus and corticosteroids is essential in
order to prevent this complication[12].
Nevertheless immunosuppressants are not devoid of serious side
effects such as the induction of diabetes, nephrotoxicity and
carcinogenesis[13-17].
In 1993 mycophenolate mofetil (MMF), the 2-4-morpholino ethyl ester
of mycophenolic acid, the biologically active component, was
introduced as a novel immunosu-ppressive agent[18].
MMF reversibly inhibits the enzyme inosine monophosphate
dehydrogenase (IMPDH), an important enzyme in de novo synthesis of
purine building blocks of DNA, namely guanine and adenine[19].
Lymphocytes, which play a significant role in graft rejection, have
no way of producing adequate amounts of purines if IMPDH is not
available[20].
Thus, MMF prevents proliferation of both T cells and B cells and
thereby inhibits antibody production. Moreover, through depletion of
intracellular GTP levels in lymphocytes, MMF suppresses
glycosylation and the expression of some adhesion molecules, thereby
reducing lymphocyte migration to the transplant[21].
However, its effect on T cell proliferation received more attention
because of the importance of T cells in the allogeneic response[22].
MMF is considered as a safe drug and the most
frequently reported side effects are mild and involve mainly the
gastrointestinal system (diarrhea, abdominal pain, nausea and
vomiting)[23-25].
Its major advantages are the lack of nephrotoxicity and diabetogenic
effects, which makes MMF an important agent in renal and islet
transplantation. Although its use in renal transplantation has been
established[2628],
its use in clinical islet transplantation is still limited[29,30].
There are also a few reports regarding the use of MMF in combination
with other regimens in experimental models of islet xeno- and
allotransplantation[31-37]
but in very few cases as monotherapy.
The aim of this study was to evaluate the
efficacy of MMF as monotherapy on islet graft function and
development in a period as early as 12 d after allogeneic islet
transplantation in chemically induced diabetic rats, with a dose
lower than the usually administered and to compare it with the
efficacy of a widely used immunosuppressant such as cyclosporine A.
MATERIALS AND METHODS
Animals and experimental groups
Thirty-six male Wistar rats and 18 male Lewis rats weighing
220-300 g were used as recipients and donors respectively (animals
were obtained from Pasteur Institute, Athens, Greece and Democretos
Research Center, Athens, Greece). All the principles for laboratory
animal care were followed according to the European Union
Regulations and the Greek law for the use of laboratory animals (Act
160, Volume 64, No. A, May 1991, License Ref. 1267/2570). The
recipients were randomly allotted to three groups of 12 animals:
group A (control group) had no immunosuppression, group B received
CsA (Neoral - Novartis) at a dose of 5 mg/kg, and group C received a
low dose MMF (CellCept - Roche) (20 mg/kg), which is half the usual
dose.
Induction of diabetes
Diabetes was induced by single intraperitoneal injection of 60 mg/kg
streptozotocin (STZ - Sigma - S-0130) freshly resolved in a solution
of PBS (phosphate buffer solution Sigma 1000-3) at a concentration
of 10 mg/mL (pH 4.5 using citric acid) 7 d prior to transplantation.
It has been documented that doses bigger than 50 mg/kg cause
irreversible and complete destruction of beta cells in adult rats[38].
Isolation of unpurified islets
Islets were acquired with a modification to the technique previously
described by Papalois et al.[39].
Briefly, after the animals were anesthetized a midline abdominal
incision was performed and the common bile duct was recognized and
ligated in its middle. Then the duct was catheterized with a fine
catheter (polyethylene tubing, PE 10 - ID 0.28 mm and A 0.61
mm - Becton Dickinson) and 6 mL of collagenase (Sigma - Type XI - C
7657) solution (0.9 ng/mL) were infused slowly until the pancreas
was distended. Subsequently pancreatic resection was performed and
the donor was killed. The pancreatic specimen was incubated in water
bath (at 37 ℃)
for 20 min. After incubation the distended pancreas was washed twice
in cold Hanks solution in order to terminate collagenase activity
and to wash out collagenase and fat tissue. The product was then
filtered through a 400-mL
filter in order to retain duct remnants, sutures, lymph nodes and
pancreatic capsule remnants. The cell suspension was then considered
ready for transplantation. We omitted the separation of the
endocrine from the exocrine tissue in order to avoid the loss of
islet yield during the purification process. A 100-mL
sample was taken and islets were counted by dithizone staining. The
mean±SE
islet yield for transplantation was 1 81±2145.
Transplantation technique
Spleen was used as the site of transplantation[40-42].
The rats were anesthetized as previously described and 0.7 cc of the
isolated cell suspension was injected slowly using an insulin
syringe into the splenic parenchyma. Leakage was avoided with a 2-0
silk suture tied at the spleen's
pole.
Determination of biochemical indices
Blood glucose levels were measured in blood obtained from rat-tails
using a Glucometer Elite blood glucose-measuring instrument (Bayer
AB, Gothenburg, Sweden). Measurements were performed one week prior
to transplantation (d -7), right after transplantation (d 0) and at
the 3rd,
5th,
7th,
10th
and 12th
d post-transplantation. Diabetes was diagnosed when two consecutive
glucose readings were over 180 mg/dL. Grafts were considered as
functional when blood glucose levels were below 200 mg/dL after the
2nd
post-operative d for two consecutive measurements. The 2 d interval
was allowed for islets to become functional. Liver enzymes (SGOT,
SGPT, gGT) as well as creatinine values were determined from blood
samples obtained on d 12 from 11 animals of the two therapy groups
and from 5 animals of the control group that were still alive. The
normal range of each of the biochemical indices for the Wistar rats
used in our laboratory is as follows: SGOT: 116-278 IU/L, SGPT:
29-80 IU/L, gGT: 0.6-2.1 IU/L, creatinine: 0.4-0.8 mg/dL.
Animal sacrifice
The overall time of observation was 12 d. On the last day the
animals were killed and blood as well as grafted tissues were
obtained for laboratory assessments and histological examination.
Histological examination of the grafted tissues
Spleens carrying the transplanted islet grafts were removed and
fixed in formalin saline. Paraffin tissue sections (3-mm thick) were
stained with hematoxylin-eosin. Intracellular content of insulin was
demonstrated immunohistochemically using the peroxidase technique by
means of polyclonal anti-insulin antibodies (rabbit anti-insulin,
Monosan, Netherlands) and with an indirect biotin streptavidin
detection kit (iViewTM
DAB detection kit, Ventana Medical
Systems, SA, France), which detects mouse IgG, mouse IgM, and rabbit
polyclonal primary antibodies. Pancreas tissue was used as positive
control. We estimated the intensity of staining as weak and intense.
Evaluation was performed using light microscopy (HE 200). The
presence of insulin positive cells and intact islets was assessed
using a semi-quantitative scoring system: none (0-1), occasional
(1-8), many (9-18) and plentiful (>18) (numbers representing
count of islets per 10 big optic fields). The presence of
infiltrating inflammatory cells was also assessed using a
semi-quantitative method (0 = occasional infiltrating cells, + =
few, ++ = moderate, +++ = many, ++++ = massive infiltration)[35].
Eleven out of the twelve grafted sites were available for
histological examination from the CsA and MMF groups (one rat from
each group died during the transplantation procedure). All grafted
tissues from the control group were obtained for histological
assessment regardless of the animal's
day of death.
Statistical analysis
All values were presented as mean±SD.
Statistical analysis was performed using the Student's
t
test comparing group means. To evaluate the differences in graft
survival, the Kaplan-Meier survival analysis was performed and a log
rank test was used for the evaluation of differences. P values
less than 0.05 were considered significant. Comparisons among time
measurements of each variable during treatment period for each study
group were analyzed using one factor repeated measures ANOVA (pair
wise multiple comparisons were performed using Tukey critical
difference). Mann-Whitney U test (exact significance) was
used for the comparisons between groups.
RESULTS
The operation-related mortality in the three groups was as follows:
no rat died in the control group, 1 out of 12 rats died in group B
(8.3%) and 1 out of 12 died in group C (8.3%). All rats in CsA and
MMF groups that survived the operation were alive at the 12th
d (the day of killing). In the control group, however, mean survival
was 8.1 d and only five rats reached the day of killing (41.7%).
This difference was statistically significant (P<0.01,
Table 1).
Table 1 Islet
allograft survival and animal survival in recipients treated with
CsA and MMF
| Variable |
Group
A |
Group
B |
Group
C |
P
|
| Controls |
CsA |
MMF |
| n
= 12 |
n
= 11 |
n
= 11 |
x2 |
| 3rd-d
graft survival (%) |
3
(25) |
9
(82) |
9
(82) |
<0.01 |
| Graft
survival in days after |
0
(1.2) |
10
(4.9) |
12
(5.1) |
Kruskal
Wallis |
| Tx
(median SD) |
|
|
|
<0.01 |
| Animal
survival in days |
8.1
(3.7) |
12
(0.0) |
12
(0.0) |
Kruskal
Wallis |
| after
Tx (median SD) |
|
|
|
<0.01 |
Tx:
transplantation, CsA: cyclosporine A, MMF: mycophenolate mofetil.
The functional outcome of islet allografts was
evaluated after d 3 (Table 1). In the control group, 3-d allograft
survival was significantly less than both cyclosporine and MMF
groups (25% vs 82%, P<0.01, Table 1). Median
allograft survival was also significantly higher in the two therapy
groups than that in the controls (10 and 12 d for CsA and MMF
respectively vs 0 d for the control group, P<0.01,
Table 1). Actuarial allograft survival was calculated for all three
groups and the Kaplan-Meier curves were constructed (Figure 1). In
both therapy cases the differences in allograft survival in
comparison to the control group were statistically significant (log
rank test, P<0.01 for MMF vs control and P<0.01
for CsA vs control). In contrast, the difference in actuarial
allograft survival between the CsA and MMF groups was not
statistically significant (log rank test, P = 0.505).
Figure 1
(PDF) Actuarial
allograft survival curves in the three study groups based on serum
glucose levels, showing significantly prolonged survival in the two
therapy arms in comparison to the controls.
Glucose changes from baseline were recorded
(Figure 2). Significant overall differences between the three groups
were observed at the 3rd,
5th,
7th,
10th
and 12th
post-transplantation day (ANOVA, Figure 2). These differences, at
all times but one, were attributed to higher glucose levels in the
control groups (Tukey). The difference between the CsA and the
control group was not significant only on the 3rd
post-transplantation day and consequently the overall difference was
attributed to lower glucose levels in the MMF group. The glucose
values over time tended to be at lower levels in the MMF group
compared to the CsA group although this observation was not
statistically significant (P = 0.747).
Figure
2
(PDF)
Effect of MMF and CsA on the blood
glucose levels of the recipients over time after transplantation.
Weight changes were also recorded for all
recipients (Figure 3). Statistically significant differences in the
proportion of weight change from baseline were found between the
three groups after the 7th
post-operative day. These changes were significant also in the 10th
and the 12th
d. The MMF group (Figure 3) was the only one in which weight gain
was recorded, although this observation was not statistically
significant.
Post-transplantation biochemical data (SGOT, SGPT,
gGT and creatinine) in the two therapy cases and in the control
group were also recorded. All the post-transplantation biochemical
parameters in the control group and in the MMF group were within
normal range. The same observation was made for the CsA group,
except for gGT values (Table 2). All biochemical data recorded,
except for SGOT values, were significantly lower in the MMF group in
comparison to corresponding values in the CsA group (Table 2).
Compared with the control group creatinine levels were significantly
lower in the MMF group (P<0.027) and gGT levels were
significantly elevated in the CsA group (P<0.01, Table 2).
Table 2 SGOT, SGPT, gGT
and creatinine measurements in the controls as well as in the two
therapy groups
| Variable |
Group
A Controls |
Group
B CsA |
Group
C MMF |
| SGOT
(mean, SD) |
144
(27.6) |
119
(47) |
131
(46) |
| SGPT
(mean, SD) |
48.4
(12.9) |
66
(27) |
33
(15)f |
| gGT
(mean, SD) |
1.14
(0.42) |
2.8
(0.5)b |
0.7
(0.5)f |
| Creatinine
(mean, SD) |
0.6
(0.16) |
0.6
(0.1) |
0.4
(0.1)d,f |
bP<0.01
vs controls, dP<0.027
vs controls, fP<0.01
vs CsA.
Figure
3
(PDF) Effect of MMF
and CsA on the percentage of weight change of the recipients.
Light microscopy histological assessment of the
grafts from the three different groups revealed the appearance of
exocrine tissue, islets clumped together or free-lying in the
surrounding exocrine tissue, peri-islet tissue inflammatory
infiltration and areas of necrosis (Table 3). In untreated rats a
massive infiltrate covered most of the allografts and completely
destroying most of them (Table 3). Twelve days after transplantation
various numbers of islets and various degrees of infiltration were
observed in allografts removed from animals treated with CsA or MMF
alone. Immunohistochemical staining for insulin in the control group
was relatively weak (Figure 4A), whereas in both treatment groups a
marked number of cells had more intense insulin staining (Figures 4B
and C). Bigger and better developed islets were found in the MMF-treated
group (Figure 4C).
Table 3 Histologic
evaluation after transplantation
| Group
Animal |
CsA
Inf/End |
MMF
Inf/End |
Controls
Inf/End |
| 1 |
0/Occasional |
0/Occasional |
0/Occasional |
| 2 |
0/Occasional |
+/Occasional |
+++/None |
| 3 |
0/Many |
+/Occasional |
++++/None |
| 4 |
++++/Occasional |
+/Plentiful |
++++/None |
| 5 |
++++/Occasional |
+++/Plentiful |
++++/None |
| 6 |
++++/Many |
++++/Occasional |
++/Occasional |
| 7 |
++++/Many |
++++/Occasional |
++/Occasional |
| 8 |
++++/Many |
++++/Occasional |
+++/Occasional |
| 9 |
Necrosis |
++++/Occasional |
++++/Occasional |
| 10 |
Necrosis |
++++/Occasional |
Necrosis |
| 11 |
Necrosis |
Necrosis |
Necrosis |
| 12 |
– |
– |
Necrosis |
Inf: infiltrating
cells, End: endocrine cells. Sections with abundant necrosis were
not evaluated.
Figure
4
A:
Three weak stained islets (long arrows) located into the exocrine
tissue 12 d after transplantation without immunosuppression. A
dilated pancreatic duct (short arrow) is also present (anti-insulin,
×200); B:
Intact islets into the exocrine tissue (long arrows) 12 d after
engraftment and immunosuppression with CsA. The insulin staining is
positive and intense (anti-insulin, ×200); C:
A well-developed and large islet (long arrow) into the exocrine
tissue 12 d after transplantation and immunosuppression with MMF.
Anti-insulin stain shows beta cell granulation within islets. At the
lower right corner of the figure splenic parenchyma is present
(short arrow) (anti-insulin, ×200).
DISCUSSION
In the present study we compared the efficacy of MMF and CsA in an
experimental model of islet allotransplantation. The present study
was based on a previous one[45]
in which the efficacy of two different doses of MMF (12 and 23
mg/kg) with CsA (5 mg/kg) was compared. In the previous study MMF in
the dose of 23 mg/kg was equally effective with CsA in maintaining
graft function. However, graft survival in the group of 12 mg/kg was
not satisfactory. Consequently it was decided to omit the MMF group
that was not effective, trying to have higher MMF levels and at the
same time to test a dose that is half of that presented in many
reports.
Immunosuppression with cyclosporine (5 mg/kg)
maintained graft function for a median of 10 d, while administration
of MMF at a dose of 20 mg/kg was equally effective prolonging graft
survival for a median of 12 d. The present results are in accordance
with those reported by other researchers demonstrating that
treatment with CsA and MMF alone or in combination with other
immunosuppressants reduces allograft and xenograft rejection.
However, in these studies higher doses were employed (10-30 mg/kg
for CsA and 40 mg/kg for MMF)[32-37].
Previously reported data have shown that CsA increases insulin
resistance and has nephrotoxic and hepatotoxic effects, especially
when combined with other agents such as glucocorticoids and
sirolimus[41-43].
In clinical studies MMF has been shown to be a safe drug and
furthermore there is evidence that it not only maintains the graft
but improves renal function as well[26-28].
The ability of MMF to preserve islet allo- and
xenograft function is not only due to the selective
antiproliferative effect on B and T cells, but also due to the
protection of the microvasculature from the immune response, even
from the 10th
d after transplantation. As a consequence the grafts nutritive
microcirculation[44]
is preserved. In the present study, despite the limited observation
period, the fact that larger and better-developed islets were found
in the MMF group in comparison to the cyclosporine group suggests an
immediate beneficial effect of MMF in the preservation of islet
architecture. Interestingly, in our previous report such beneficial
effect on islet architecture was observed even when approximately
half of the present dose of MMF was used[45].
It was observed that transplantation of
allogeneic islet tissue without immunosuppression resulted in 100%
rejection within few days. It has been well established that the
islet allografts survive about 5 d in diabetic rats without
immunosuppression[37].
The fact that very few of the grafts in the control group became
functional after the 3rd
d of transplantation is probably due to the presence of exocrine
tissue. Exocrine tissue contamination of freely transplanted
pancreatic islets deteriorates the process of graft
revascularization and induces additional injury by provoking a
deleterious inflammatory response and consequently leading to graft
destruction[46,47].
Taking into account the massive infiltration detected in the grafts
of untreated recipients in the present study, this might be the
reason for the low graft survival in this group.
In this experimental model of islet
transplantation creatinine, SGPT and gGT values were found to be
lower in the MMF group compared to those found in the CsA group and
with the exception of gGT values all other biochemical data in the
CsA group did not exceed the normal range. The significantly
increased gGT values found in the CsA case are indicative of a
cholostatic effect of the specific drug, a well-documented side
effect[48].
Interestingly, creatinine values were found to be lower in the MMF
group compared to controls. This finding is in accordance with the
published data that MMF may protect from and even reverse
nephrotoxicity caused by other immunosuppressant agents, such as CsA[26,49].
The fact that the MMF group was the only one in which weight gain
was recorded indicates that this agent is well tolerated without
serious side effects.
In conclusion, low dose MMF provided effective
immunosuppression in an experimental allograft islet transplantation
model and compared favorably to CsA in terms of islet morphology and
side effects. Given the fact that complications of immunosuppressive
therapy continues to be one of the major hurdles to successful islet
transplantation, management of immunosuppression requires careful
risk vs benefit assessment. Favorable benefit/side effects
ratio for the biochemical and histological parameters with the low
dose monotherapy of MMF was observed in the present study, compared
to data presented in other reports. This drug might represent a
standard suitable immunosuppressive agent for improving the out come
of pancreatic islet allo-transplantation.
REFERENCES
1
Robertson RP. Islet Transplantation as a Treatment for
Diabetes-A Work in Progress. N Engl J Med 2004; 350:
694-705
2
Ballinger WF, Lacy PE. Transplantation of intact
pancreatic islets in rats. Surgery 1972; 72: 175-186
3
Reckard CR, Ziegler MM, Barker CF. Physiological and
immunological consequences of transplanting isolated
pancreatic islets. Surgery 1973;
74: 91-99
4
Thomas DR, Fox M, Grieve AA. Isolation of islets of
Langerhans for transplantation. Nature 1973; 242:
258-260
5
Alejandro R, Lehmann R, Riccordi C, Kenyon NS,
Angelico MC, Burke G, Esquenazi V, Nery J, Betancourt AE, Kong
SS, Miller J, Mintz DH. Long-term
function (6 years) of islet allografts in type 1 diabetes. Diabetes
1997; 46: 1983-1989
6
Oberholzer J, Triponez F, Mage R, Andereggen E, Buhler
L, Cretin N, Fournier B, Goumaz C, Lou J, Philippe J, Morel
P. Human islet transplantation:
Lessons from 13 autologous and 13 allogeneic transplantations. Transplantation
2000;
69: 1115-1123
7
Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E,
Warnock GL, Kneteman NM, Rajotte RV. Islet transplantation
in seven patients with type 1
diabetes mellitus using a glucocorticoid-free immunosuppressive
regimen. N Engl J
Med 2000; 343:
230-238
8
Ryan EA, Lakey JR, Rajotte RV, Korbutt GS, Kin T, Imes
S, Rabinovitch A, Elliott JF, Bigam D, Kneteman NM, Warnock
GL, Larsen I, Shapiro AM. Clinical
outcomes and insulin secretion after islet transplantation with the
Edmonton
Protocol. Diabetes 2001; 50:
710-719
9
Hirshberg B, Rother KI, Digon BJ 3rd, Lee J, Gaglia JL,
Hines K, Read EJ, Chang R, Wood BJ, Harlan DM. Benefits
and risks of solitary islet
transplantation for Type 1 diabetes using steroid-sparing
immunosuppression. Diabetes
Care 2003; 26:
3288-3295
10 Titus
TH, Badet L, Gray DWR. Islet cell transplantation for
insulin-dependant diabetes mellitus: perspectives from
the present and prospects for
the future. Available from: http://www-ermm.cbcu.cam.ac.ac.uk//00001861h.htm
11 International
islet transplant registry. Newsletter 9 2001; 8: 4-18
12
Braun F. Update of current immunosuppressive drugs in
clinical organ transplantation. Transpl Int 1998; 11:
77-81
13
Kahan BD, Koch SM. Current immunosuppressant regimens:
considerations for critical care. Curr Opin Crit Care
2001; 7: 242-250
14
Dunn CJ, Wagstaff AJ, Perry CM, Plosker GL, Goa KL.
Cyclosporine: an updated review of the
pharmacokinetic properties,
clinical efficacy and tolerability of a microemulsion-based
formulation (neoral)1 in
organ transplantation. Drugs
2001; 61: 1957-2016
15
Delaunay F, Khan A, Cintra A, Davani B, Ling ZC,
Andersson A, Ostenson CG, Gustafsson J, Efendic S, Okret
S. Pancreatic beta cells are
important targets for the diabetogenic effects of glucocorticoids. J
Clin Invest 1997;
100: 2094-2098
16
Yale JF, Roy RD, Grose M, Seemayer TA, Murphy GF,
Marliss EB. Effects of Cyclosporine on Glucose Tolerance in
the
rat. Diabetes 1985; 34:
1309-1313
17
Drachenberg CB, Klassen DK, Weir MR, Wiland A, Fink JC,
Bartlett ST, Cangro CB, Blahut S, Papadimitriou JC. Islet
cell damage associated with
tacrolimus and cyclosporine: Morphological features in pancreas
allograft biopsies
and clinical correlation. Transplantation
1999; 68: 396-402
18
Allison AC, Eugui EM. The design and development of an
immunosuppressive drug, mycophenolate mofetil.
Springer Semin
Immunopathol 1993; 14: 353-380
19
Allison AC, Eugui EM. Preferential suppression of
lymphocyte proliferation by mycophenolic acid and predicted
long-term effects of
mycophenolate mofetil in transplantation. Transplant Proc
1994; 26: 3205-3210
20
Allison AC, Hovi T, Watts RWE, Webster ADB. The role
of de novo purine synthesis in lymphocyte transformation.
Ciba Found Symp
1977; 48: 207-223
21
Allison AC, Eugui EM. Mycophenolate mofetil and its
mechanisms of action. Immunopharmacology 2000; 47:
85-118
22
Rosenberg AS, Singer A. Cellular basis of skin graft
rejection: an in vivo model of immune-mediated tissue
destruction. Annu Rev
Immunol 1992; 10: 333-358
23
Mathew TH. A blinded, long term, randomized,
multicenter study of mucophenolate mofetil in cadaveric
renal transplantation: results
at three years. Tricontinental Mycophenolate Mofetil Renal
Transplant Study
Group. Transplantation 1998;
65: 1450-1454
24
Mycophenolate Mofetil Acute Renal Rejection Study Group.
Mycophenolate mofetil for the treatment of a first acute
renal allograft rejection:
three-year follow-up. The Mycophenolate Mofetil Acute Renal
Rejection Study
Group. Transplantation
2001; 71: 1091-1097
25
Pescovitz MD, Conti D, Dunn J, Gonwa T, Halloran P,
Sollinger H, Tomlanovich S, Weinstein S, Inokuchi S, Kiberd
B, Kittur D, Merion RM, Norman
D, Shoker A, Wilburn R, Nicholls AJ, Arterburn S, Dumont E.
Intravenous
mycophenolate mofetil: safety,
tolerability and pharmacokinetics. Clin Transplant 2000; 14:
179-188
26
Vasquez EM, Sifontis NM, Pollak R, Benedetti E. Impact
of mycophenolete mofetil on recurrent rejection in
kidney transplant patients. Clin
Transplant 2001; 15: 253-257
27
Meier-Kriesche HU, Steffen BJ, Hochberg AM, Gordon RD,
Liebman MN, Morris JA, Kaplan B. Long-term use
of mycophenolate mofetil is
associated with a reduction in the incidence and risk of late
rejection. Am J Transplant
2003; 3: 68-73
28
Budde K, Curtis J, Knoll G, Chan L, Neumayer HH, Seifu
Y, Hall M. Enteric-coated Mycophenolate Sodium can be
safely administered in
maintenance renal transplant patients: results of a 1-year study. Am
J Transplant 2004;
4: 237-243
29
Pattou F, Vantyghem MC, Noel C, Kerr-Conte J, Gmyr V,
Martinache I, Vandewalle B, N'Cuyen
H, Lecomte-Houcke
M,
Lefebvre J, Proye C. Sequential intraportal islet allografts in
immunosuppressed type I diabetic patients:
Preliminary
results. Transplant Proc 2000; 32: 391-392
30
Oberholzer J, Toso C, Triponez F, Ris F, Bucher P,
Demirag A, Lou J, Majno P, Buehler L, Philippe J, Morel P.
Human
Islet allotransplantation with Basiliximab in type 1 diabetic
patients with end-stage renal failure. Transplant
Proc
2002; 34: 823-825
31
Hao L, Lafferty KJ, Allison AC, Eugui EM. RS-61443
allows islet allografting and specific tolerance induction in
adult
mice.
Transplant Proc 1990; 22: 876-879
32
Hao L, Wang Y, Chan SM, Lafferty KJ. Effect of
Mycophenolate Mofetil on islet allografting to chemically
induced
or
spontaneously diabetic animals. Transplant Proc 1992; 24:
2843-2844
33
Koulmanda M, Kovarik J, Mandel TE. Effect of
Mycophenolate Mofetil with and without anti-CD4 (GK 1.5) on
fetal
islet
iso-, allo-, and xenografts in NOD/Lt female mice. Transplant
Proc 1997; 29: 2161-2162
34
Wennberg L, Groth CG, Tibell A, Zhu S, Liu J, Rafael
E, Soderlund J, Biberfeld P, Morris RE, Karlsson-Parra A,
Korsgren
O. Triple drug treatment with Cyclosporine, Leflunomide and
Mycophenolate Mofetil prevents rejection of
pig
islets transplanted into rats and primates. Transplant Proc
1997; 29: 2498
35
Wennberg L, Karlsson-Parra A, Sundberg B, Rafael E,
Liu J, Zhu S, Groth CG, Korsgren O. Efficacy
of
immunosuppressive drugs in islet xenotransplantation. Transplantation
1997; 63: 1234-1242
36
Wijkstrom M, Song Z, Zhang J, Bari S, Sundberg B,
Groth CG, Korsgren O, Wennberg L. Efficacy of
Malononitriloamide
279 and 715 in islet xenotransplantation: A study in the pig-to-rat
model. Transplant Proc 2000;
32:
1024
37
Wennberg L, Song Z, Bennet W, Zhang J, Nava S,
Sundberg B, Bari S, Groth CG, Korsgren O. Diabetic
rats
transplanted with adult porcine islets and immunosuppressed with
Cyclosporine A, Mycophenolate Mofetil,
and
Leflunomide remain normoglycemic for up to 100 d. Transplantation
2001; 71: 1024-1033
38
Hamamoto Y, Tsuura Y, Fujimoto S, Nagata M, Takeda T,
Mukai E, Fujita J, Yamada Y, Seino Y. Recovery of
function
and mass of endogenous b-cells in streptozotocin-induced diabetic
rats treated with islet
transplantation.
Biochem Biophys Res Commun 2001; 287: 104-109
39
Papalois A, Papalois B, Tzardis P, Bonatsos G,
Nikolaou A, Katsorchis T, Pataryas T, Golematis B.
Allotransplantation
of
pancreatic islets in rats using multiple donors. Transplant Proc
1994; 26: 3474-3476
40 Fotiadis
C, Papalois A. The spleen as a site of transplantation and
implantation of hepatocytes and islets of
Langerhans.
Arch Hell Med 2000; 17: 528-530
41
Yale JF, Chamelian M, Courchesne S, Vigeant C.
Peripheral insulin resistance and decreased insulin secretion
after
Cyclosporine A treatment. Transplant Proc 1988; 20(3
Suppl 3): 985-988
42
Saudek F, Kazdova L, Nozickova M, Vrana A, Cihalova E,
Ruzbarsky V. The effect of combination therapy
with
cyclosporine A and hydrocortisone on glucose metabolism in diabetic
rats following pancreatic islet
transplantation.
Physiol Res 1995; 44: 79-86
43
Bramow S, Ott P, Thomsen Nielsen F, Bangert K,
Tygstrup N, Dalhoff K. Cholestasis and regulation of genes
related
to
drug metabolism and biliary transport in rat liver following
treatment with cyclosporine A and sirolimus
(Rapamycin).
Pharmacol Toxicol 2001; 89: 133-139
44
Beger C, Menger MD. RS-61443 prevents microvascular
rejection of pancreatic islet xenografts. Transplantation
1997;
63: 577-582
45
Xekouki P, Papalois A, Fotiadis C, Sfiniadakis J,
Karampela E, Papadopoulou A, Grigoriou T, Sechas MN. In vivo test
of
two low doses of Mycophenolate Mofetil in an experimental model of
islet allotransplantation. Transplant Proc
2002;
34: 1446-1448
46
Heuser M , Wolf B, Vollmar B, Menger M. Exocrine
contamination of isolated islets of Langerhans deteriorates
the
process of revascularization after free transplantation. Transplantation
2000; 69: 756-761
47
Furuya H, Kimura T, Murakami M, Katayama K, Hirose K,
Yamaguchi A. Revascularization and function of pancreatic
islet
isografts in diabetic rats following transplantation. Cell
Transplant 2003; 12: 537-544
48
Chan FK, Shaffer EA. Cholestatic effects of
cyclosporine in the rat. Transplantation 1997; 63:
1574-1578
49
Tedoriya T, Keogh AM, Kusano K, Savdie E, Hayward C,
Spratt PM, Wilson M, Macdonald PS. Reversal of
chronic
cyclosporine nephrotoxicity after heart transplantation-potential
role of mycophenolate mofetil. J Heart
Lung
Transplant 2002; 21: 976-982
Science
Editor Guo SY Language
Editor Elsevier HK
| |
PubMed
