| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Research Laboratories, Yoshitomi Pharmaceutical Industries, Ltd., Iruma, Saitama, Japan
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
and that of
CD3 (
-chain), which reflects T cell infiltration, in allografts were
temporally analyzed using a semiquantitative PCR method. In WKAH skin
allografts, mRNA levels of IL-2, IFN-, and CD3 were increased as
compared with isograft controls, peaking on days 4 to 5. CsA (10 mg/kg)
significantly inhibited elevations of IL-2 and IFN- mRNA, while
slightly inhibiting that of CD3 mRNA in allografts. On the contrary,
FTY720 (0.1 mg/kg) markedly inhibited the elevation of CD3 mRNA, while
slightly inhibiting those of IL-2 and IFN- mRNA. FTY720 (0.1 mg/kg)
combined with CsA (10 mg/kg) almost completely suppressed the
intragraft expressions of mRNA for IL-2, IFN-, and CD3.
Immunohistochemical staining and flow cytometric analysis also
confirmed that FTY720 decreased T cell infiltration into allografts.
From these results, the synergistic effect of FTY720 combined with CsA
on prolongation of allograft survival is presumably based on the
respective inhibitions of T cell infiltration and cytokine production
in grafts. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
An allograft is thought to be rejected by intragraft immune
responses, including infiltration of T cells into the graft and the
activation of these T cells by Th1-associated cytokines (9, 10, 11, 12, 13, 14). The
aim of the current study was to determine the effects of FTY720 and CsA
on intragraft immune responses, and thereby to elucidate the mechanism
underlying the remarkable synergistic effect produced by the
combination of FTY720 and CsA. Using a semiquantitative PCR method, we
temporally analyzed mRNA levels of IL-2 and IFN- and that of CD3,
which reflects T cell mass, in WKAH skin allografts transplanted to
MHC-incompatible F344 rats treated with FTY720, CsA, and both. The
infiltration of CD3+ T cells into allografts was also
analyzed by flow cytometry and immunohistochemical staining with
anti-rat CD3 mAb.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Inbred strains of male F344 and WKAH rats were purchased from Charles River Japan (Atsugi, Kanagawa, Japan) and Japan SLC (Hamamatsu, Shizuoka, Japan), respectively. All rats were used at 4 to 6 wk of age.
Agents
FTY720 was synthesized according to previously described methods (1), dissolved in distilled water, and given orally. CsA (oral solution of Sandimmune, Sandoz, Basel, Switzerland) was dissolved in pure olive oil (Sigma Chemicals, St. Louis, MO) and administered orally. Control animals received the vehicle only.
Rat allogeneic MLC
Allogeneic MLC was performed using nylon nonadherent spleen cells from F344 rats as responder cells and mitomycin C (Kyowa Hakko, Tokyo, Japan)-pretreated spleen cells from WKAH rats as stimulator cells (5, 15). Responder cells at a concentration of 5 x 105 cells/well were cocultured with equal numbers of stimulator cells in RPMI 1640 medium containing 5 µm 2-ME and 10% FCS (Boehringer Mannheim, Mannheim, Germany). After a 48-h culture at 37°C in 5% CO2, the cells were recovered and used for RNA isolation.
Rat skin allograft
Full thickness skin grafts (square pieces 2.0 x 2.0 cm) were transplanted to the lateral thorax of recipient rats and covered with sterile bactericidal gauze. The entire chest was then wrapped with an elastic bandage. The dressings were removed on day 5 and the grafts were inspected daily until rejection, which was defined as more than 90% necrosis of the graft epithelium. The rat strain combination for MHC-incompatible transplantation was WKAH (RT1k) to F344 (RT1lv1) (3, 5). Either FTY720 or CsA was orally administered daily to the transplanted animals at the aforementioned doses.
mRNA analysis using RT-PCR
The skin grafts removed from the transplanted recipients or alloantigen-stimulated lymphocytes were homogenized with RNA isolation reagent (Nippon Gene, Tokyo, Japan). Total RNA was isolated according to the manufacturer’s protocol and then quantitated spectrophotometrically. Total RNA from the graft (1.2 µg) or from the lymphocytes (0.6 µg) was reverse transcribed in a 60-µl volume containing 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 5 mM MgCl2, 1 mM each dNTP (dATP, dGTP, dTTP, and dCTP), 60 U RNase inhibitor (Takara, Kyoto, Japan), 15 U avian myeloblastosis virus reverse transcriptase (Takara), and 150 pmol random 9 mer at 30°C for 10 min and 42°C for 30 min.
Five microliters of cDNA was amplified in a 25-µl volume containing
10 mM Tris-HCl (pH 8.3), 50 mM KCl, 2 mM MgCl2, 200 mM each
dNTP (dATP, dGTP, dTTP, and dCTP), 200 nM appropriate primer pair, and
0.625 U Taq DNA polymerase (Takara). Primer sequences for
IL-2, IFN-, CD3 (-chain), and HPRT genes were obtained from
previous reports (16, 17). The PCR products of IL-2, IFN-, CD3, and
HPRT are 351, 419, 253, and 608 bp, respectively. After an initial
denaturation step, the cDNA mixture was subjected to amplification
cycles, each cycle consisting of denaturation (94°C for 15 s),
annealing (65°C (IFN-, CD3, and HPRT) or 72°C (IL-2 for 15
s) and extension (72°C for 15 s) using a thermal cycler (Gene
Amp PCR System 9600, Perkin-Elmer Cetus, Foster, CA). The number of
amplification cycles was 30 (IL-2), 26 (IFN-), 28 (CD3), or 24
(HPRT). An aliquot (10 µl) of the PCR product was electrophoresed on
2% agarose gel, and amplified DNA fragments were stained with SYBR
Green I (Molecular Probes, Eugene, OR) (18, 19). Fluorescence intensity
of the specific band was visualized and measured using a fluorescence
image analyzer (Fluor Imager 575, Molecular Dynamics, Sunnyvale, CA).
The specificity of PCR products was verified by restriction analysis,
using two restriction enzymes indicative of the expected amplified
sequence in a previous report (16).
Measurement of numbers of CD3+ T cells in peripheral blood and skin allografts
Peripheral blood was periodically collected from a tail vein of allografted rats. The skin graft removed from transplanted recipients was chopped into small fragments, then incubated for 1 h at 37°C on a rocker in 4 ml of RPMI 1640 containing 10% FCS, 2 mg/ml collagenase (Calzyme, San Luis Obispo, CA), and 20 µg/ml DNase I (Boehringer Mannheim). The digested skin graft was passed through a stainless steel mesh, and skin parenchymal cells were sedimented over Ficoll buffer, density 1.090 g/cm3 (Immuno-Biologic Laboratories, Fujioka, Japan), at 1700 x g for 20 min. The cells were stained with FITC-conjugated anti-rat CD3 mAb (clone: 1F4, Caltag Laboratories, South San Francisco, CA) or biotin-conjugated anti-rat CD3 mAb (clone: G4.18, PharMingen, La Jolla, CA) and streptavidin-Cy-Chrome (PharMingen). Numbers of CD3+ T cells were determined by flow cytometry with EPICS XL-MCL (Coulter, Miami, FL).
Immunohistochemical staining of skin allograft sections
Skin allografts were removed, embedded in tissue compound, and frozen in liquid N2. Cryostat sections (6 µm thickness) were prepared, fixed with ice-cold acetone, and stained by immunoperoxidase methods. Briefly, sections were incubated with 5 mg/ml of biotinylated anti-rat CD3 mAb (clone: G4.18) for 1 h, and then with an avidin-biotinylated peroxidase complex (ABC kit, Vectastain, Vector, Burlingame, CA) for 1 h. Ab binding was visualized using a peroxidase substrate containing 0.05% 3,3'-diaminobenzidine and 0.01% hydrogen peroxide in 0.1 M Tris-HCl buffer (pH 7.3).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
,
and CD3 mRNA levels in allografts by the PCR method
For semiquantitative assessment of the measurement of IL-2,
IFN-, and CD3 mRNA levels in allografts by the PCR method in our
present study, a twofold dilution of cDNA solution prepared from
allografts separated 5 days after transplantation (day 5) was amplified
with IL-2-, IFN--, CD3-, or HPRT-specific primers. The fluorescence
intensity of the PCR product diminished as the cDNA level in the
reaction mixture decreased (Fig. 1
).
Thus, the analysis by the PCR method was semiquantitative in this
study.
|
, and CD3 mRNA levels in rat skin
allografts
Levels of IL-2, IFN-, and CD3 mRNA in allografts on days 2, 3,
4, 5, and 6 were analyzed by the PCR method (Fig. 2). Isografts were analyzed in parallel
to control for the nonspecific inflammatory response associated with
the transplantation procedure. Control skin tissue (before transplant)
contained detectable levels of IL-2, IFN-, and CD3 mRNA. The mRNA
background levels of the isografts were only slightly enhanced. In
contrast, IL-2, IFN-, and CD3 mRNA levels of allografts were
markedly enhanced, peaking on day 4 (IL-2 and IFN-) and day 5
(CD3).
|
Figure 3 shows the effects of
FTY720, CsA, and both on survival of rat skin allografts (WKAH)
transplanted to MHC-incompatible rats (F344). In this allograft model,
the median allograft survival was 7 days in vehicle-treated recipients
(control group). The respective median graft survivals for
FTY720-treated recipients at doses of 0.1 mg/kg and 1 mg/kg were 10.5
and 21 days, respectively, while those of CsA-treated recipients at
doses of 10 mg/kg and 30 mg/kg were 11 and 21 days, respectively. Thus,
0.1 mg/kg and 10 mg/kg were regarded as subtherapeutic doses for FTY720
and CsA, respectively. Combination treatment with FTY720 (0.1 mg/kg)
and CsA (10 mg/kg) resulted in a remarkable prolongation, with median
survival exceeding 70 days.
|
shows the time course change in
the number of CD3+ T cells in the peripheral blood of
allograft F344 rats. FTY720 (0.1 mg/kg) alone or combined with CsA (10
mg/kg) markedly decreased numbers of peripheral blood T cells during
the administration period when compared with vehicle (control) or CsA
(10 mg/kg) alone.
|
, and CD3 mRNA
levels in rat skin allografts
Figure 5 shows IL-2, IFN-, and
CD3 mRNA levels in allografts of the recipients treated with FTY720
(0.1 mg/kg), CsA (10 mg/kg), and both agents on days 4, 5, 6, and 7.
The mRNA levels in allografts of vehicle-treated recipients (control)
on day 7 were not determined, as preparing the total RNA from rejected
allografts was impossible. In the recipients treated with FTY720 (0.1
mg/kg), IL-2 and IFN- mRNA levels were enhanced in allografts and
peaked on day 5, although the peak level was lower than that of
vehicle-treated recipients. FTY720 (0.1 mg/kg) markedly suppressed the
elevation of CD3 mRNA in the allograft until day 6, but failed to
maintain this suppressive effect on day 7. On the contrary, CsA (10
mg/kg) markedly inhibited the elevations of IL-2 and IFN- mRNA in
allografts, while having little effect on the CD3 mRNA level. In
recipients treated with both FTY720 (0.1 mg/kg) and CsA (10 mg/kg), the
elevations of IL-2, IFN-, and CD3 mRNA in allografts were markedly
suppressed, and the levels were similar to those in isografts. This
suppressive effect was maintained at least until day 14 (data not
shown).
|
and
7 show the effects of subtherapeutic and
therapeutic doses of FTY720 or CsA on IL-2, IFN-, and CD3 mRNA
levels in skin allografts 5 days after transplantation. A therapeutic
dose of FTY720 (1 mg/kg) markedly suppressed the elevation of CD3 mRNA,
while having little effect on the elevations of IL-2 and IFN- mRNA
levels in the allograft. A subtherapeutic dose of FTY720 (0.1 mg/kg)
had a similar effect. A subtherapeutic dose of CsA (10 mg/kg) did not,
whereas a therapeutic dose of CsA (30 mg/kg) did, markedly inhibit the
elevation of CD3 mRNA in allografts. Both doses of CsA markedly
inhibited the elevation of IL-2 and IFN- mRNA.
|
in rat
allogeneic MLR
CsA was reported to inhibit mRNA expression of Th1-associated
cytokines, including IL-2 and IFN-, by Ag- or mitogen-stimulated Th
cells (20, 21). The effects of FTY720 on alloantigen-induced mRNA
expressions of IL-2 and IFN- were examined in comparison with those
of CsA in allogeneic MLC using splenic T cells of F344 rats as
responder cells and mitomycin C-pretreated WKAH rat spleen cells as
stimulator cells (Fig. 8). CsA at 100 nM
completely inhibited IL-2 and IFN- mRNA expressions in
alloantigen-stimulated T cells. Unlike CsA, FTY720 up to 1000 nM
affected neither IL-2 nor IFN- mRNA expression.
|
Rat skin allografts were digested by collagenase on day 5, and
then the number of CD3+ T cells in allograft were analyzed
by flow cytometry with anti-rat CD3 mAb. As shown in Figure 9, FTY720 (0.1 mg/kg) markedly decreased
CD3+ T cells in allografts. FTY720 (0.1 mg/kg) combined
with CsA (10 mg/kg) had essentially the same effect. In addition, T
cell infiltration into allografts on day 5 was assessed by
immunohistochemical staining with anti-rat CD3 mAb. As shown,
A (x200) and B (x400) of Figure 10, CD3+ T cell
infiltration was seen in the dermis of allografted skin in the control
recipient. In contrast, CD3+ T cell infiltration was hardly
seen in the dermis of allografted skin in FTY720-treated recipients
(Fig. 10C, x200).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
) but not Th2-associated cytokines (IL-4 and IL-10), and
that Th2-associated cytokines were essential for xenograft rejection.
In addition to the elevation of cytokine expressions, T cell
infiltration into the graft is thought to be an important component of
graft rejection. Increased T cell infiltration of grafts has, in fact,
been described in various graft models (10, 23). The expression of
adhesion molecules related to T cell trafficking is enhanced in grafts,
and mAbs of these molecules inhibit graft rejection (11, 24, 25). In
our present MHC-incompatible allograft model, mRNA expressions of
Th1-associated cytokines (IL-2 and IFN-) in the allografts were
markedly enhanced (Fig. 2
), whereas that of a Th2-associated cytokine
(IL-4) was undetectable (data not shown). In parallel, CD3 mRNA levels
as a marker of T cell infiltration in the allografts were markedly
enhanced (Fig. 2). T cell infiltration was also confirmed by
immunohistochemical staining and flow cytometry with anti-CD3 mAb
(Figs. 9 and 10). Therefore, infiltration of T cells into allografts
and the activation of these T cells by Th1-associated cytokines
presumably contributed to the allograft rejection observed in our
present model.
E. C. Butcher and L. J. Picker suggested, in their review,
that integration and control of systemic immune responses depended on
regulated lymphocyte homing (8). As described in the preceding
companion paper, FTY720 accelerated lymphocyte-homing, leading to the
subsequent disappearance of T cells from peripheral blood and thoracic
duct lymph in rats (5). The current study assessed the effects of
FTY720, which modulates lymphocyte homing, on intragraft immune
responses. FTY720 significantly reduced the number of peripheral blood
T cells in skin-allografted rats (Fig. 4). On the other hand, FTY720
markedly decreased T cell infiltration into allografts while, in
contrast to CsA, having little effect on IL-2 and IFN- mRNA
expressions in allografts (Figs. 5 to 10). In addition, FTY720 had no
effect on IL-2 and IFN- mRNA expressions by alloantigen-stimulated
rat T cells in vitro (Fig. 8). These findings suggest that FTY720
prolongs allograft survival by decreasing the T cell infiltration into
grafts but not cytokine productions. It is probable that the decreasing
effect of FTY720 on T cell infiltration is due to reduction in the
number of circulating T cells by acceleration of lymphocyte homing to
lymph nodes and Peyer’s patches (5).
|
and 5). Levels of IL-2 and IFN- mRNA peaked on day 4 and
decreased on days 5 to 6, while that of CD3 mRNA peaked on day 5 and
decreased on day 6 in control allografts (Fig. 2). In FTY720-treated
recipients, fewer T cells infiltrated into allografts, and were
presumably activated by alloantigen. Levels of IL-2 and IFN- mRNA
peaked on day 5 and decreased on days 6 to 7, while that of CD3 mRNA
was increased on day 7 in the allografts (Fig. 5). It is possible that
this discrepancy between cytokine mRNA level and T cell mass in
allografts is due to the change of ability for cytokine transcription
by infiltrated T cells. This ability in control and FTY720-treated
recipients presumably peaked on days 4 and 5, respectively. On the
other hand, FTY720 markedly decreased T cells infiltration into
allografts, while having much less effect on the levels of IL-2 and
IFN- mRNA on day 5 (Fig. 7). The ability for cytokine transcriptions
by infiltrated T cells in FTY720-treated recipients may be higher than
that in control recipients on day 5.
In the current study, we determined the effects of FTY720 and CsA at
high and low doses, to characterize these agents in detail (Figs. 6 and 7). The low dose of CsA (10 mg/kg) markedly inhibited the elevations of
IL-2 and IFN- mRNA in allografts, while having little effect on that
of CD3 mRNA (Figs. 5, 6, and 7). The effect of subtherapeutic CsA (10
mg/kg) on prolongation of the allograft survival is presumably due to
insufficient decrease in T cell infiltration into the allografts (Figs. 5, 6, and 7). In contrast, the high dose of CsA (30 mg/kg) successfully
inhibited T cell infiltration into the allografts (Figs. 6 and 7).
Although the data are not shown, the high dose of CsA (30 mg/kg), in
contrast to the low dose (10 mg/kg), markedly reduced peripheral blood
T cells in skin-allografted rats. CsA (30 mg/kg) appears to reduce
circulating T cells by inhibiting intrathymic differentiation (26, 27, 28),
and thereby this drug may decrease T cell infiltration into allografts.
In contrast, FTY720 appears to reduce circulating T cells by
acceleration of lymphocyte homing (5). Thus, mechanism of the effect of
CsA on the inhibiting T cell infiltration into allografts is thought to
be different from that of FTY720. Both high and low doses of FTY720
equivalently inhibited T cell infiltration (Figs. 6 and 7). However,
the high dose is much more effective in prolonging allografts (Fig. 3).
These findings indicate that additional factors besides decrease in T
cell infiltration contribute to immunosuppression at the high dose of
FTY720. We have recently confirmed that repeated oral administration of
FTY720 decreased the alloreactivity of lymph node T cells in
skin-allografted rats dose dependently (our unpublished observations).
Further analyses are currently being performed to clarify the detailed
mechanism of this effect.
In our present allograft model, the immunosuppressive efficacy of
FTY720 (0.1 mg/kg) was essentially the same as that of CsA (10 mg/kg),
while the effects of FTY720 (0.1 mg/kg) on sequential expressions of
IL-2, IFN-, and CD3 mRNA in allografts were entirely different from
those of CsA (10 mg/kg). FTY720 more effectively inhibited T cell
infiltration of allografts, while CsA was more effective in reducing
IL-2 and IFN- expressions (Figs. 5, 6, and 7). Although FTY720
markedly decreased T cell infiltration into allografts, a small number
of T cells were infiltrated. FTY720 is presumably unable to inhibit
cytokine production by these infiltrated T cells. It is likely that
this cytokine production is successfully inhibited in the case of
combination treatment with FTY720 and CsA. From these observations, the
synergistic effect of FTY720 combined with CsA on prolongation of
allograft survival is presumed to be based on the respective
inhibitions of T cell infiltration and cytokine production in
grafts.
In this study, we initially characterized intragraft immune responses during FTY720 and CsA treatment, and proposed a mechanism underlying the remarkable synergistic effect produced by simultaneous treatment with both agents. Finally, we believe that FTY720, which has a unique mechanism of action, is useful as an immunosuppressive drug for organ transplantation and as a tool for investigating immune responses.
|
Footnotes |
|---|
2 Abbreviations used in this paper: FTY720, 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride; CsA, cyclosporin A; FK506, tacrolimus; HPRT, hypoxanthine-guanine phosphoribosyltransferase.
Received for publication October 17, 1997. Accepted for publication January 30, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
in long-surviving mouse heart allografts after brief CD4-monoclonal antibody therapy. Transplantation 59:559.[Medline]
This article has been cited by other articles:
|
|
 |
|
  B. J. E. Raveney, D. A. Copland, L. B. Nicholson, and A. D. Dick Fingolimod (FTY720) as an Acute Rescue Therapy for Intraocular Inflammatory Disease Arch Ophthalmol, October 1, 2008; 126(10): 1390 - 1395. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. L. Wissinger, W. W. Stevens, S. M. Varga, and T. J. Braciale Proliferative Expansion and Acquisition of Effector Activity by Memory CD4+ T Cells in the Lungs following Pulmonary Virus Infection J. Immunol., March 1, 2008; 180(5): 2957 - 2966. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kurashima, J. Kunisawa, M. Higuchi, M. Gohda, I. Ishikawa, N. Takayama, M. Shimizu, and H. Kiyono Sphingosine 1-Phosphate-Mediated Trafficking of Pathogenic Th2 and Mast Cells for the Control of Food Allergy J. Immunol., August 1, 2007; 179(3): 1577 - 1585. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Maeda, H. Matsuyuki, K. Shimano, H. Kataoka, K. Sugahara, and K. Chiba Migration of CD4 T Cells and Dendritic Cells toward Sphingosine 1-Phosphate (S1P) Is Mediated by Different Receptor Subtypes: S1P Regulates the Functions of Murine Mature Dendritic Cells via S1P Receptor Type 3 J. Immunol., March 15, 2007; 178(6): 3437 - 3446. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Keul, M. Tolle, S. Lucke, K. von Wnuck Lipinski, G. Heusch, M. Schuchardt, M. van der Giet, and B. Levkau The Sphingosine-1-Phosphate Analogue FTY720 Reduces Atherosclerosis in Apolipoprotein E-Deficient Mice Arterioscler Thromb Vasc Biol, March 1, 2007; 27(3): 607 - 613. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Daniel, N. Sartory, N. Zahn, G. Geisslinger, H. H. Radeke, and J. M. Stein FTY720 Ameliorates Th1-Mediated Colitis in Mice by Directly Affecting the Functional Activity of CD4+CD25+ Regulatory T Cells J. Immunol., February 15, 2007; 178(4): 2458 - 2468. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. L. Meno-Tetang, H. Li, S. Mis, N. Pyszczynski, P. Heining, P. Lowe, and W. J. Jusko Physiologically Based Pharmacokinetic Modeling of FTY720 (2-Amino-2[2-(-4-octylphenyl)ethyl]propane-1,3-diol hydrochloride) in Rats After Oral and Intravenous Doses Drug Metab. Dispos., September 1, 2006; 34(9): 1480 - 1487. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Fujii, T. Kanai, Y. Nemoto, S. Makita, S. Oshima, R. Okamoto, K. Tsuchiya, T. Totsuka, and M. Watanabe FTY720 suppresses CD4+CD44highCD62L- effector memory T cell-mediated colitis Am J Physiol Gastrointest Liver Physiol, August 1, 2006; 291(2): G267 - G274. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. Awad, H. Ye, L. Huang, L. Li, F. W. Foss Jr., T. L. Macdonald, K. R. Lynch, and M. D. Okusa Selective sphingosine 1-phosphate 1 receptor activation reduces ischemia-reperfusion injury in mouse kidney Am J Physiol Renal Physiol, June 1, 2006; 290(6): F1516 - F1524. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Zhang, Y. Chen, R. L. Fairchild, P. S. Heeger, and A. Valujskikh Lymphoid Sequestration of Alloreactive Memory CD4 T Cells Promotes Cardiac Allograft Survival J. Immunol., January 15, 2006; 176(2): 770 - 777. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Sawicka, G. Dubois, G. Jarai, M. Edwards, M. Thomas, A. Nicholls, R. Albert, C. Newson, V. Brinkmann, and C. Walker The Sphingosine 1-Phosphate Receptor Agonist FTY720 Differentially Affects the Sequestration of CD4+/CD25+ T-Regulatory Cells and Enhances Their Functional Activity J. Immunol., December 15, 2005; 175(12): 7973 - 7980. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Kharel, S. Lee, A. H. Snyder, S. L. Sheasley-O'Neill, M. A. Morris, Y. Setiady, R. Zhu, M. A. Zigler, T. L. Burcin, K. Ley, et al. Sphingosine Kinase 2 Is Required for Modulation of Lymphocyte Traffic by FTY720 J. Biol. Chem., November 4, 2005; 280(44): 36865 - 36872. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Halin, M. L. Scimone, R. Bonasio, J.-M. Gauguet, T. R. Mempel, E. Quackenbush, R. L. Proia, S. Mandala, and U. H. von Andrian The S1P-analog FTY720 differentially modulates T-cell homing via HEV: T-cell-expressed S1P1 amplifies integrin activation in peripheral lymph nodes but not in Peyer patches Blood, August 15, 2005; 106(4): 1314 - 1322. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Shimizu, M. Takahashi, T. Kaneko, T. Murakami, Y. Hakamata, S. Kudou, T. Kishi, K. Fukuchi, S. Iwanami, K. Kuriyama, et al. KRP-203, a Novel Synthetic Immunosuppressant, Prolongs Graft Survival and Attenuates Chronic Rejection in Rat Skin and Heart Allografts Circulation, January 18, 2005; 111(2): 222 - 229. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Han, X. Zhang, G. Wang, H. Guan, G. Garcia, P. Li, L. Feng, and B. Zheng FTY720 suppresses humoral immunity by inhibiting germinal center reaction Blood, December 15, 2004; 104(13): 4129 - 4133. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K Mayer, F Birnbaum, T Reinhard, A Reis, S Braunstein, F Claas, and R Sundmacher FTY720 prolongs clear corneal allograft survival with a differential effect on different lymphocyte populations Br J Ophthalmol, July 1, 2004; 88(7): 915 - 919. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Bohler, J. Waiser, M. Schuetz, H. H. Neumayer, and K. Budde FTY720 exerts differential effects on CD4+ and CD8+ T-lymphocyte subpopulations expressing chemokine and adhesion receptors Nephrol. Dial. Transplant., March 1, 2004; 19(3): 702 - 713. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Sawicka, C. Zuany-Amorim, C. Manlius, A. Trifilieff, V. Brinkmann, D. M. Kemeny, and C. Walker Inhibition of Th1- and Th2-Mediated Airway Inflammation by the Sphingosine 1-Phosphate Receptor Agonist FTY720 J. Immunol., December 1, 2003; 171(11): 6206 - 6214. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Sanchez, T. Estrada-Hernandez, J.-H. Paik, M.-T. Wu, K. Venkataraman, V. Brinkmann, K. Claffey, and T. Hla Phosphorylation and Action of the Immunomodulator FTY720 Inhibits Vascular Endothelial Cell Growth Factor-induced Vascular Permeability J. Biol. Chem., November 21, 2003; 278(47): 47281 - 47290. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Welsch, S. Hagiwara, J. F. Goetschy, and N. R. Movva Ubiquitin Pathway Proteins Influence the Mechanism of Action of the Novel Immunosuppressive Drug FTY720 in Saccharomyces cerevisiae J. Biol. Chem., July 11, 2003; 278(29): 26976 - 26982. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Yopp, G. J. Randolph, and J. S. Bromberg Leukotrienes, Sphingolipids, and Leukocyte Trafficking J. Immunol., July 1, 2003; 171(1): 5 - 10. [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Woltman and C. van Kooten Functional modulation of dendritic cells to suppress adaptive immune responses J. Leukoc. Biol., April 1, 2003; 73(4): 428 - 441. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Fujino, N. Funeshima, Y. Kitazawa, H. Kimura, H. Amemiya, S. Suzuki, and X.-K. Li Amelioration of Experimental Autoimmune Encephalomyelitis in Lewis Rats by FTY720 Treatment J. Pharmacol. Exp. Ther., April 1, 2003; 305(1): 70 - 77. [Abstract] [Full Text]
|
|
|
|
|
|
J. H. Xie, N. Nomura, S. L. Koprak, E. J. Quackenbush, M. J. Forrest, and H. Rosen Sphingosine-1-Phosphate Receptor Agonism Impairs the Efficiency of the Local Immune Response by Altering Trafficking of Naive and Antigen-Activated CD4+ T Cells J. Immunol., April 1, 2003; 170(7): 3662 - 3670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Brinkmann, M. D. Davis, C. E. Heise, R. Albert, S. Cottens, R. Hof, C. Bruns, E. Prieschl, T. Baumruker, P. Hiestand, et al. The Immune Modulator FTY720 Targets Sphingosine 1-Phosphate Receptors J. Biol. Chem., June 7, 2002; 277(24): 21453 - 21457. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Li, G. M. L. Meno-Tetang, K. Chiba, N. Arima, P. Heining, and W. J. Jusko Pharmacokinetics and Cell Trafficking Dynamics of 2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol Hydrochloride (FTY720) in Cynomolgus Monkeys after Single Oral and Intravenous Doses J. Pharmacol. Exp. Ther., May 1, 2002; 301(2): 519 - 526. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Budde, R. L. Schmouder, R. Brunkhorst, B. Nashan, P. W. Lucker, T. Mayer, S. Choudhury, A. Skerjanec, G. Kraus, and H. H. Neumayer First Human Trial of FTY720, a Novel Immunomodulator, in Stable Renal Transplant Patients J. Am. Soc. Nephrol., April 1, 2002; 13(4): 1073 - 1083. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Miyamoto, A. Matsumori, M.-W. Hwang, R. Nishio, H. Ito, and S. Sasayama Therapeutic effects of FTY720, a new immunosuppressive agent, in a murine model of acute viral myocarditis J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1713 - 1718. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. D. Pinschewer, A. F. Ochsenbein, B. Odermatt, V. Brinkmann, H. Hengartner, and R. M. Zinkernagel FTY720 Immunosuppression Impairs Effector T Cell Peripheral Homing Without Affecting Induction, Expansion, and Memory J. Immunol., June 1, 2000; 164(11): 5761 - 5770. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-W. Hwang, A. Matsumori, Y. Furukawa, K. Ono, M. Okada, A. Iwasaki, M. Hara, and S. Sasayama FTY720, a New Immunosuppressant, Promotes Long-Term Graft Survival and Inhibits the Progression of Graft Coronary Artery Disease in a Murine Model of Cardiac Transplantation Circulation, September 21, 1999; 100(12): 1322 - 1329. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
