An immunosuppressive regimen using FTY720 combined with cyclosporin in canine kidney transplantation

FTY720 induces apoptosis, specifically in lymphocytes, and prolongs allograft survival in rats and dogs. The purpose of this study was to define an effective range of FTY720 doses that could be combined with a suboptimal dose (10 mg/kg) of cyclosporin for canine kidney allograft recipients. The combination significantly prolonged allograft survival in all groups receiving FTY720 at a dose of 0.1, 0.3, 1.0, or 3.0 mg/kg. None of the recipients died due to notable side effects of the drug. In peripheral blood, the number of lymphocytes was extremely low, whereas the percentage of granulocytes increased during FTY720 administration. No significant difference in cyclosporin trough levels was observed between the cyclosporin-alone group and the combination groups. We conclude from the present study that FTY720 has a potent effect at an extremely low dose and a wide therapeutic window when combined with cyclosporin in canine kidney transplants. Received: 16 May 1997 Received after revision: 6 October 1997 Accepted: 19 November 1997     

FTY720联合雷帕霉素抗胰腺癌细胞增殖作用的体外研究

目的 探讨FTY720和雷帕霉素联合用药体外抗胰腺癌细胞增殖的相互作用.方法 采用Panc-1和AsPc-1胰腺癌细胞株作为体外研究模型.以不含FTY720或雷帕霉素培养液处理的细胞株为对照组,FTY720单独用药的浓度范围为1～15 μmol/L;雷帕霉素单独用药的浓度范围为0.002～200 μmol/L,联合用药方案采用两组浓度的雷帕霉素联合7组不同浓度的FTY720;或者采用两组浓度的FTY720联合5组不同浓度的雷帕霉素.采用MTT法评估药物对细胞增殖的抑制率,采用双变量相关性分析法统计药物剂量与细胞增殖抑制率之间的相关性.结果 单独用药作用下,FTY720或雷帕霉素用药剂量与胰腺癌细胞增殖的抑制率呈现剂量依赖性（FTY720＋AsPc-1：r=0.887,P=0.000;雷帕霉素＋AsPc-1：r=0.822,P=0.000 ;FTY720＋Panc-1：r=0.796,P=0.000;雷帕霉素＋Panc-1：r=0.786,P=0.000）.当10μmol/L FTY720和0.002 μmol/L雷帕霉素联用时,对AsPc-1细胞增殖的抑制率达50%（P=0.000）,对Panc-1细胞增殖的抑制率达40%（P=0.000）,两药联用具有协同作用.结论 FTY720及雷帕霉素在体外均能呈剂量依赖性地抑制胰腺癌细胞增殖,联合用药后能协同抑制胰腺癌细胞的增殖.     

FTY720在异种胰岛移植排斥反应中的作用

目的　研究FTY72 0单独用药和联合应用FTY72 0及环孢素A (CsA)在抑制猪 大鼠异种胰岛移植排斥反应中的作用。方法　大鼠肾被膜下移植成年猪胰岛 (APIs) 2 μl,单独应用FTY72 0 ( 1.0mg/kg·d和 3 .0mg/kg·d)和联合应用FTY 72 0及CsA(FTY 72 0 1.0mg/kg·d +CsA15mg/d和FTY72 0 3 .0mg/kg·d +CsA15mg/kg·d)。移植后 12d应用免疫组织化学染色方法来观察移植物内细胞浸润情况。结果　单独应用FTY72 0不能抑制API异种移植排斥反应的发生 ;在FTY72 0 +CsA组 ,排斥反应过程被明显抑制。在移植后第 12天 ,可以见到大量完整的API ,仅偶尔有细胞浸润。内分泌组织完整。结论　在猪 大鼠异种胰岛细胞模型中 ,联合应用FTY72 0及CsA可有效抑制排斥反应直到移植后第 12天 ,且未出现任何明显毒性作用。     

FTY720诱导大鼠心脏移植物长期存活

目的 观察FTY720对大鼠同种异体心脏移植物存活时间的影响。方法 进行SD Wistar大鼠的腹部异位心脏移植，将受者随机分为对照组、甲泼尼龙(MP)组、环孢素A((SsA)组、FTY720组、FTY720与CsA二药联用组和FTY720、CsA及MP三药联用组，各组按分组要求分别于术前3d至术后14d通过灌胃给予FTY720和CsA，术前1d至术后2d腹腔注射给予MP，观察各组动物术后外周血淋巴细胞数量变化和移植物存活时间。结果 FTY720组、二药联用组和三药联用组的大鼠外周血淋巴细胞在给药后3h开始明显下降，停药后开始回升，至停药14d后恢复正常；移植心脏的存活时间，对照组平均为7．8d，CsA组为16．0d，MP组为27．6d，三药联用组为16．8d，而FTY720组和二药联用组分别超过了150d和124d。结论 FTY720可诱导同种异体大鼠心脏移植物长期存活。     

FTY720对大鼠肾小球硬化的作用及机制探讨

目的观察FTY720对5／6肾切除大鼠肾小球硬化的作用并探讨其作用机制。方法选择SD雄性大鼠24只，将其分为假手术组、模型组和FTY720治疗组，每组8只。后两组制作5／6肾切除肾小球硬化模型。末次手术后治疗组给予FTY720灌胃。术前、术后第8、12周取大鼠尾静脉血，采用计数板计算外周血淋巴细胞总数；第12周末处死大鼠后做常规病理检查和免疫组化检测，观察FTY720对肾小球中增殖细胞核抗原（PNCA）、p27、CD3表达的影响。结果治疗组外周血淋巴细胞计数较肾硬化组明显减少。治疗组大鼠肾小球病理损害明显减轻。免疫组化显示，与肾硬化组相比，治疗组PCNA表达明显减弱，p27蛋白表达升高。结论FTY720能减少肾小球内淋巴细胞浸润、上调p27蛋白、下调PCNA的表达，减轻肾小球细胞增殖，延缓肾小球硬化的进展。     

Pharmacodynamics of Single Doses of the Novel Immunosuppressant FTY720 in Stable Renal Transplant Patients

FTY720, a new and potent immunosuppressant, causes in animal models a rapid, reversible reduction of all subsets of peripheral blood lymphocytes, inducing their migration to secondary lymphoid organs. In this human phase I trial, the pharmacodynamics of single oral doses of FTY720 were evaluated. A randomized, double-blind, placebo-controlled, time-lagged study of six different single ascending oral doses of FTY720 ranging from 0.25 to 3.5 mg was conducted in stable renal transplant patients receiving a cyclosporine-based regimen. Absolute and subset lymphocyte counts, as well as absolute differential leukocyte counts, were determined by differential blood counts and flow cytometry at screening and multiple intervals thereafter. A pharmacodynamic model was established. Twenty-four single doses of FTY720 that were administered caused a transient, reversible pan-lymphopenia within 4 h. Lymphocyte subgroup analysis revealed that almost all subsets declined, with CD4- and CD45RA-positive cells being affected the most. Natural killer cells, granulocytes and monocytes were not influenced by FTY720. The lymphocyte count returned to baseline within 72 h in all dosing cohorts except the highest. Pharmacokinetik/pharmacodynamic modelling revealed a nonlinear dose effect and resulted in a good fit with observed values. These data show that FTY720 is highly effective in humans, with single oral doses of FTY720 ranging from 0.25 to 3.5 mg causing a reversible selective panlymphopenia.     

FTY720 Pretreatment Reduces Warm Hepatic Ischemia Reperfusion Injury Through Inhibition of T-Lymphocyte Infiltration

Ischemia and reperfusion (IR) injury remains a significant problem in clinical liver transplantation. We investigated the effects of lymphocyte depletion with FTY720 in models of warm hepatic IR. Using 60-min partial warm hepatic IR, three groups of rats were studied: Sham--laparotomy alone; Control--water p.o. x 3 d before ischemia; Treatment--FTY720 p.o. x 3 d before ischemia. Animals were sacrificed for analysis at 6 h and 24 h post reperfusion. The effect of FTY720 pretreatment on survival was also studied using 150 min total hepatic IR with portojugular shunt. FTY720 treatment significantly reduced serum glutamic pyruvic transaminase and peripheral blood lymphocytes compared to controls at 6h and 24h (p < 0.0005). Histological grade was significantly improved in treated livers vs. controls (p < 0.05). CD3 immunocytochemical analysis revealed a significant reduction in T-cell infiltration in FTY720-treated livers (p < 0.0002). No difference in tissue myeloperoxidase levels was observed. Seven-day survival was significantly improved in treated rats vs. controls following total hepatic ischemia (p < 0.05). In conclusion, FTY720 ameliorates the biochemical and histological manifestations of hepatic IR by preventing T-lymphocyte infiltration and prolongs survival following a more severe ischemic insult. Myeloperoxidase data suggest this mechanism is independent of neutrophil activation. These results indicate that T lymphocytes are pivotal mediators in hepatic IR and may have important implications in liver transplantation.     

Effect of peritransplant FTY720 alone or in combination with post-transplant tacrolimus in a rat model of cardiac allotransplantation

FTY720 is a recently discovered compound that is derived from the fungus Isaria sinclairii. Using a DA donor-to-LEW recipient rat combination, we assessed the efficacy of peritransplant FTY720 alone or in combination with post-transplant tacrolimus on the survival of cardiac allografts. Peritransplant FTY720 given orally at a dose of 5 mg/kg on days –1 and 0 prolonged graft survival from 5 to 13 days (P < 0.05). Combining peritransplant FTY720 with post-transplant tacrolimus resulted in a further prolongation of allograft survival. The lymphocyte count in transplanted rats decreased within 24 h to 46.6 %. Analysis of lymphocyte subsets by FACS revealed that FTY720 affected the total population of CD3-bearing T cells while the ratio of CD4 to CD8 cells remained unchanged. Kidney and liver biochemistry remained elevated for 2 weeks. In conclusion, FTY720 is a powerful immunosuppressive agent when used as induction therapy and may have an additive effect – perhaps a synergistic one – with post-transplant tacrolimus. Received: 27 October 1997 Received after revision: 23 March 1998 Accepted: 15 April 1998     

FTY720对大鼠急性脊髓损伤后RhoA表达的影响

目的观察大鼠急性脊髓损伤(spinal cord injury,SCI)后芬戈莫德(fingolimod,FTY720)对RhoA表达的影响,进一步探讨FTY720治疗SCI的可能机制。方法采用改良Allen’s法建立大鼠急性SCI模型。雌性SD大鼠75只,随机分为假手术组(n=15)、损伤组(n=30)和FTY720组(n=30)。FTY720组伤后30min一次性腹腔注射FTY7200.5mg/kg,假手术组和损伤组以相同方法给予浓度为0.9%的生理盐水。分别于伤后1天、3天、7天、14天及21天,应用RT-PCR和Western印迹法分别检测RhoA mRNA和RhoA蛋白的表达。结果损伤组RhoA mRNA和蛋白的表达于伤后3天开始明显增加,7天达到高峰,21天仍维持高水平表达;在同一时间点,与FTY720组和假手术组比较,差异有统计学意义(P0.05)。FTY720组伤后1天、3天和7天的RhoA表达高于假手术组(P0.05)。假手术组各时间点RhoA表达维持在较恒定水平。结论大鼠急性SCI后RhoA表达增加,FTY720可能通过抑制SCI后RhoA的表达,以达到减轻继发性SCI、促进脊髓神经功能恢复的目的。     

Effect of FTY720 on immunoregulation in concordant xenotransplantation

Abstract The present study was designed to analyze the immunosuppressive activity of FTY720 in concordant xenotransplantation. When T and B lymphocytes of human peripheral blood were incubated with FTY720, the number of viable cells decreased in a dose-dependent manner at doses higher than 4×10^-5 M. DNA fragmentation was observed at doses higher than 4×10 ^-5 M in B cell-rich fractions. These data demonstrate that FTY720 is cytotoxic to B lymphocytes as well as T lymphocytes and apoptosis may play an important role in this cytotoxicity. Golden Syrian hamsters were the donors and Lewis rats the recipients of skin grafts. The recipients were divided into the following four groups; (1) untreated recipients, (2) FTY720 (5mg/kg per day) was administered orally for 8 days (days -1–6), (3) FK 506 (1 mg/kg per day) was injected i. m. for 7 days (days 0–6), and (4) FK506 (1 mg/kg per day) was injected i.m. for 7 days (days 0–6) and FTY720 (5 mg/kg per day) was administered orally for 8 days (days-1–6). The mean graft survival times in groups 1–4 were.7 ± 0.52 days ( n = 6), 12.0 ± 0.71 days ( n = 6), 13.2 ± 1.6 days ( n = 6), and 37.7 ± 4.3 days ( n = 6), respectively. There was a significant difference in the mean survival time between groups one and four. Combined therapy with FTY720 and FK506 is a useful tool for immunoregulation in xenotransplantation.     

The effect of FTY 720 on engraftment in a model of spontaneous allograft acceptance

Further development in organ transplantation requires the utilization of new immunosuppressive drugs that-in addition to being effective against rejection-do not block tolerance. We previously reported that FTY 720, a drug that alters lymphocyte trafficking, has marked anti-rejection properties. We now investigate how FTY 720 influences tolerance in a model of graft acceptance by donor-specific blood transfusion (DSBT). Two different transplant models--heart transplantation (Htx) and intestinal transplantation (Itx)--were studied. We performed orthotopic Itx and heterotopic Htx using fully mismatched inbred male RA (RT1(p)) and PVG (RT1(c)) rats as donors and recipients. Tolerance was induced by DSBT on pre-transplant day -12. To test the effect of FTY 720 on DSBT-induced tolerance, we administered FTY 720 orally prior to DSBT. Itx: control rats succumbed to rejection at 18+/-4 days. DSBT alone prolonged survival to 101.9+/-18 days (P<0.05 vs untreated). Long-term survivors were tolerant (acceptance of secondary donor-specific Htx). Adjunction of FTY 720 prior to DSBT reduced survival to 55.9+/-44.7 days (P<0.05). However, long-term survivors still accepted secondary donor-specific Htx. Htx: control rats survived 9+/-0.6 days. DSBT alone prolonged survival indefinitely (>120 days) and induced tolerance (acceptance of secondary donor-specific Htx). Unlike in Itx, adjunction of FTY 720 prior to DSBT did not reduce Htx survival. Acceptance of secondary donor-specific Htx was not influenced by FTY 720. In Itx, FTY 720 counteracts the beneficial effect of pre-transplant DSBT and triggers acute rejection of primary, but not secondary grafts. In Htx, however, FTY 720 allows full development of tolerance. The mechanisms by which FTY 720 causes rejection in primary intestinal but not in heart grafts need to be elucidated.     

FTY720对大鼠急性脊髓损伤后神经功能恢复的影响及相关机制

目的:观察FTY720对大鼠急性脊髓损伤(ASCI)后神经功能的影响,并探讨其相关机制。方法:168只雌性SD大鼠,随机分成A、B、C三组,每组56只,A组(假手术组)大鼠麻醉后仅切除T9椎板,不打击脊髓,缝合后立即以0.3ml生理盐水灌胃。B、C组采用Allen′s法制作T9脊髓损伤模型,B组(对照组)以0.3ml生理盐水灌胃,C组(治疗组)以FTY720按3mg/kg生理盐水稀释至0.3ml灌胃。每组取8只大鼠分别于术后1d、3d、7d、14d、21d行斜板试验及BBB评分。分别于术后6h、12h、24h、48h、72h、7d、21d处死大鼠,每个时间点每组8只,取损伤段(A组取相应部位)脊髓行超薄切片,HE染色观察各组脊髓坏死情况、炎细胞浸润情况、胶质瘢痕形成情况及脊髓空洞大小,并计数各组术后12h淋巴细胞数、术后12h与72h炎性细胞、术后7d胶质瘢痕区细胞,计算伤后21d脊髓空洞面积与脊髓面积比值;取术后6h、12h、24h、72h的切片行SP免疫组化染色观察caspase-3表达及Tunel染色观察细胞凋亡情况,计算相应时间点免疫组化染色阳性细胞比值和凋亡指数。所有数据以SPSS 13.0进行统计学分析。结果:B、C两组各时间点斜板实验及BBB评分均较A组同时间点差(P<0.05),在术后1d时B、C组之间无显著性差异(P>0.05),术后3d、7d、14d、21d时C组优于B组(P<0.05)。HE染色结果显示A组各时间点脊髓形态正常;B、C组脊髓术后6h可见脊髓内出血、血肿形成,术后12h~48h脊髓进行性水肿、损伤中心区出现液化坏死,伴有炎细胞浸润,以中性粒细胞、淋巴细胞、单核细胞为主,至术后72h,损伤中心区形成无组织结构空洞,空洞周围有大量炎细胞浸润,以小胶质细胞/单核细胞为主;术后12h及72h,B组炎细胞浸润程度明显重于C组(P<0.05),术后12h C组淋巴细胞浸润程度相对B组明显减少(P<0.05),术后7d,脊髓水肿减轻,空洞周围形成胶质瘢痕,胶质瘢痕细胞计数B组明显大于C组(P<0.05),术后21d脊髓空洞形成,脊髓空洞比值B组明显大于C组(P<0.05)。SP免疫组化染色和Tunel染色结果显示A组各时间点几乎见不到caspase-3和细胞凋亡表达阳性细胞,B、C组脊髓损术后6h即可见凋亡细胞,到术后24h达高峰,而后随术后时间延长而逐渐减弱,但是仍然保持在较高水平;caspase-3表达与细胞凋亡同步,各时间点C组caspase-3表达阳性细胞比值和细胞凋亡指数均显著低于B组(P<0.05)。结论:FTY720可以显著改善大鼠ASCI后神经功能,其可能是通过抑制脊髓损伤后的炎症反应,减少caspase-3的表达及神经细胞凋亡,从而减轻脊髓继发性损伤。     

FTY720 (fingolimod) in renal transplantation

Abstract:  FTY720 (Fingolimod) is a novel immunomodulator with a mode of action that is completely different from classical immunosuppressants. FTY is a structural and functional analogue of the natural serum lipid, sphingosine, and is the first in a new class of drugs called sphingosine 1-phosphate receptor (S1P-R) modulators. This review discusses the recent findings on the mechanism of action, preclinical models and outlines the results of the ongoing clinical development program. FTY is highly effective in prolonging allograft survival in preclinical models of transplantation and in experimental models of autoimmune diseases. In clinical trials, this novel compound was investigated in de novo renal transplantation and in multiple sclerosis. Pharmacokinetics are characterized by a prolonged absorption phase, a large volume of distribution, and a long elimination half-life. FTY induces a rapid and transient decrease in lymphocyte counts, which supports the modulatory effects of the drug on lymphocyte sequestration. The most common adverse event was asymptomatic transient bradycardia, a pharmacodynamic effect modulated by atrial S1 P-R. FTY failed to show an improvement in efficacy for the prevention of renal allograft rejection in two large phase III studies. FTY treatment regimens were associated with impaired renal function and the development of macula edema. Consequently, the further development in renal transplantation was stopped. Because initial clinical studies strongly suggest that FTY is highly effective in multiple sclerosis FTY is now being explored in phase III studies for the treatment of demyelinating diseases, Ongoing studies in multiple sclerosis are eagerly awaited because they may provide novel therapeutic options for patients with autominnue diseases.     

FTY720 Attenuates Hepatic Ischemia-Reperfusion Injury in Normal and Cirrhotic Livers

Hepatic ischemia-reperfusion injury is an inevitable consequence during liver surgery. The outcome is particularly poor in cirrhotic livers, which are more prone to hepatic ischemia-reperfusion injury. We aim to study whether FTY720 could attenuate hepatic ischemia-reperfusion injury both in normal and in cirrhotic livers. We applied a 70% liver-ischemia (60 min) model in rats with normal or cirrhotic livers. FTY720 was given 20 min before ischemia and 10 min before reperfusion (1 mg/kg, i.v.). Liver tissues and blood were sampled at 20 min, 60 min, 90 min, 6 h and 24 h after reperfusion for detection of MAPK-Egr-1, Akt pathways and caspase cascade. Hepatic ultrastructure and apoptosis were also compared. FTY720 significantly improved liver function in the rats with normal and cirrhotic livers. Akt pathway was activated at 6 and 24 h after reperfusion. FTY720 significantly down-regulated Egr-1, ET-1, iNOS and MIP-2 accompanied with up-regulation of A20, IL-10, HO-1 and Hsp70. MAPK (Raf-MEK-Erk) pathway was down-regulated. Hepatic ultrastructure was well maintained and fewer apoptotic liver cells were found in the FTY720 groups. In conclusion, FTY720 attenuates ischemia-reperfusion injury in both normal and cirrhotic livers by activation of cell survival Akt signaling and down-regulation of Egr-1 via Raf-MEK-Erk pathway.     

FTY720对小鼠外周血淋巴细胞及T细胞亚群的影响

目的　观察FTY72 0对近交系小鼠淋巴细胞及T细胞亚群变化的影响以指导临床用药。　方法　选用雄性C5 7/bl近交系小鼠。FTY72 0 3mg·kg-1·d-1,连续口服 14d。在各所选时间点计算淋巴细胞百分比 ,流式细胞术分析T细胞亚群变化。　结果　服用FTY72 0后 ,小鼠外周血淋巴细胞迅速下降 ,并于 4h降至最低值 ,之后保持稳定。停用FTY72 0后小鼠外周血淋巴细胞仍在低水平徘徊 2周 ,第 3周开始出现明显回升 ,停药后第 6周恢复至服药前水平。T细胞在服用FTY72 0后的变化与淋巴细胞相似。CD-8T细胞对FTY72 0相对较敏感。　结论　FTY72 0对外周血淋巴细胞的作用起效迅速 ,安全稳定 ,特异性强 ,可逆。对T细胞及其亚群的作用基本符合以上特点 ,CD-8T细胞对FTY72 0相对较敏感。     

Prevention of graft rejection and graft-versus-host reaction by a novel immunosuppressant, FTY 720, in rat small bowel transplantation

In the present study, we examined the immunosuppressive effect of a new drug, FTY 720, on small bowel transplantation (SBT) in rats. Grafts from (LEW × BN) F 1-to-LEW rats treated with FTY 720 at 0.5 mg/kg from day 0 to 14 post-SBT survived significantly longer than untreated grafts. In addition, the administration of FTY 720 combined with cyclosporin (CyA; 5 mg/kg per day) had a synergistic effect on allograft survival. The graft-versus-host reaction (GVHR) that occurred in the LEW-to-F 1 rats was markedly reduced after the administration of FTY 720. FTY 720 combined with a low dose of CyA completely abrogated GVHR without any adverse reaction. FTY 720 treatment resulted in a significant decrease in the number of lymphocytes in the peripheral blood and the spleen, but the number of peripheral neutrophils was unchanged. Thus, FTY 720 would appear to be an ideal drug to combine with CyA in order to control the immune reaction after SBT. Received: 19 February 1997 Received after revision: 23 May 1997 Accepted: 9 June 1997     

The Effect of a Novel Immunosuppressant, FTY720, in Mice Without Secondary Lymphoid Organs

Purpose FTY720 is a novel immunosuppressive agent that is thought to reduce the number of peripheral blood lymphocytes (PBL) by directing them toward secondary lymphoid organs such as the lymph nodes and Peyer’s patches. We studied the effects of FTY720 on aly/aly mice that do not have either lymph nodes or Peyer’s patches, as well as on splenectomized aly/aly mice.Methods FTY720 was orally administered by gavage (1 mg/kg) to aly/aly mice as well as to aly/+ mice with and without a splenectomy on 14 consecutive days. The number of lymphocytes was then counted using True Cell beads and flow cytometry. The number of B220-, CD3-, and CD4-positive cells was also determined. In addition, skin grafts from C3H donor mice were performed on these mice.Results FTY720 was effective in significantly reducing the total lymphocyte count as well as the B220-, CD3-, and CD4-positive subtypes in the peripheral blood of aly/+ mice as well as in aly/aly mice with and without a splenectomy. While we did observe allograft skin graft rejection in both the aly/+ mice as well as the aly/aly mice recipients and splenectomized aly/aly mice, the graft survival was prolonged in all groups. The skin allografts treated by FTY720 thus demonstrated fewer lymphocytic cells and less infiltration of CD4-positive cells.Conclusions The administration of FTY720 to mice without lymph nodes, Peyer’s patches, or spleens still results in peripheral lymphopenia. In all groups, FTY720 was found to prevent the infiltration of CD4-positive cells in skin allografts while also prolonging skin allograft survival. The fate of these lymphocytes, however, is unclear.     

The impact of FTY720 (fingolimod) on vasodilatory function and arterial elasticity in renal transplant patients.

BACKGROUND: FTY720 has recently demonstrated a similar efficacy in prevention of acute graft rejection compared with mycophenolate mofetil (MMF) in a large phase III trial of de novo renal transplant recipients. Creatinine clearance, however, was significantly lower in FTY720-treated patients. In the present study, we examined the impact of FTY720 on vascular function in a subgroup of patients of this trial. METHODS: Eighteen patients (12 FTY720, 6 MMF) agreed to be enrolled for an analysis of vascular function. Vascular measurements were performed 1.5 years post-transplant and were repeated 3 months after conversion of the patients from FTY720 to MMF. Arterial stiffness was assessed as augmentation index (AI(75)); endothelium-dependent and -independent vasodilation were measured sonographically as flow-mediated dilation (FMD) and as vasodilation after application of glyceroltrinitrate (GTN). RESULTS: Conversion from 2.5 mg FTY720 to MMF led to a significant improvement of FMD (5.40 +/- 1.84 vs 7.77 +/- 3.36%, P 0.02). AI(75) and GTN tended to be higher after conversion without reaching significance (83 +/- 20.43 vs 78.69 +/- 15.39%, P 0.06; 13.76 +/- 4.52 vs 17.39 +/- 3.76%, P 0.07). In the MMF group, AI(75), FMD and GTN did not significantly change during the observation period. CONCLUSION: The present study constitutes the first analysis of the impact of FTY720 on vascular function in humans and reveals an improvement of arterial vasodilatory function after discontinuation of FTY720 in de novo renal transplant recipients on cyclosporine.