FTY720单独或与环孢素和/或西罗莫司联合使用的免疫抑制作用。

Immunosuppressive effects of FTY720 alone or in combination with cyclosporine and/or sirolimus.

作者信息

Wang M E, Tejpal N, Qu X, Yu J, Okamoto M, Stepkowski S M, Kahan B D

机构信息

Department of Surgery, University of Texas Medical School, Houston 77030, USA.

出版信息

Transplantation. 1998 Apr 15;65(7):899-905. doi: 10.1097/00007890-199804150-00007.

DOI:10.1097/00007890-199804150-00007

PMID:9565092

Abstract

BACKGROUND

We examined the ability of FTY720, a novel immunosuppressant that prolongs the survival of allografts in experimental animal models, to potentiate the immunosuppressive effects of cyclosporine (CsA) and/or sirolimus (SRL) in vitro and in vivo.

METHODS

FTY720 alone (10-5000 ng/ml) or in combination with other drugs was added to human peripheral blood lymphocytes (PBLs) undergoing stimulation in vitro with phytohemagglutinin (PHA) or OKT3 monoclonal antibody. The combination index (CI) values were calculated to evaluate the nature of the interactions between FTY720 and CsA and/or SRL: CI values <1 reflect synergistic, CI=1, additive, and CI>1, antagonistic interactions. In addition, Wistar Furth (RT1u) rat recipients of Buffalo (RT1b) heart allografts were treated with FTY720 alone or in combination with other agents. FTY720 alone was also tested to block small bowel or liver allograft rejection in rats.

RESULTS

FTY720 alone produced only modest inhibition of the proliferation of human PBL stimulated with PHA or OKT3 monoclonal antibody. In combination with CsA or SRL, however, FTY720 produced synergistic effects, namely, CI values of 0.58 and 0.36, respectively. A 14-day course of FTY720 (0.05-8.0 mg/kg/day) by oral gavage prolonged heart allograft survival in dose-dependent fashion. Although a 14-day oral course of CsA (1.0 mg/kg/day) alone was ineffective (mean survival time=7.0+/-0.7 vs. 6.4+/-0.6 days in treated vs. untreated hosts), treatment with a combination of 1.0 mg/kg/day CsA and 0.1 mg/kg/day FTY720 extended allograft survival to 62.4+/-15.6 days (P<0.001; CI=0.15). Similarly, a 14-day oral course of 0.08 mg(kg/day SRL alone was ineffective (6.8+/-0.6 days; NS), but the combination of SRL with 0.5 mg/kg/day FTY720 extended the mean survival time to 34.4+/-8.8 days (CI=0.28). The CsA/SRL (0.5/0.08 mg/kg/day) combination acted synergistically with FTY720 (0.1 mg/kg/day) to prolong heart survivals to >60 days (CI=0.18).

CONCLUSIONS

FTY720 potentiates the immunosuppressive effects of CsA and/or SRL both in vitro (by inhibiting of T-cell proliferative response) and in vivo (by inhibiting allograft rejection).

摘要

背景

我们研究了新型免疫抑制剂FTY720在体外和体内增强环孢素（CsA）和/或西罗莫司（SRL）免疫抑制作用的能力，FTY720在实验动物模型中可延长同种异体移植物的存活时间。

方法

将单独的FTY720（10 - 5000 ng/ml）或与其他药物联合使用，添加到用植物血凝素（PHA）或OKT3单克隆抗体体外刺激的人外周血淋巴细胞（PBLs）中。计算联合指数（CI）值以评估FTY720与CsA和/或SRL之间相互作用的性质：CI值<1表示协同作用，CI = 1为相加作用，CI>1为拮抗作用。此外，用FTY720单独或与其他药物联合治疗接受布法罗（RT1b）心脏同种异体移植的Wistar Furth（RT1u）大鼠受体。还测试了单独使用FTY720阻断大鼠小肠或肝脏同种异体移植排斥反应。

结果

单独使用FTY720仅对PHA或OKT3单克隆抗体刺激的人PBL增殖产生适度抑制。然而，与CsA或SRL联合使用时，FTY720产生协同作用，联合指数分别为0.58和0.36。通过口服灌胃给予14天疗程的FTY720（0.05 - 8.0 mg/kg/天）以剂量依赖方式延长心脏同种异体移植的存活时间。虽然单独给予14天口服疗程的CsA（1.0 mg/kg/天）无效（治疗组与未治疗组的平均存活时间分别为7.0±0.7天和6.4±0.6天），但联合使用1.0 mg/kg/天的CsA和0.1 mg/kg/天的FTY720可将同种异体移植存活时间延长至62.4±15.6天（P<0.001；CI = 0.15）。同样，单独给予14天口服疗程的0.08 mg/（kg/天）SRL无效（6.8±0.6天；无显著性差异），但SRL与0.5 mg/kg/天的FTY720联合使用可将平均存活时间延长至34.4±8.8天（CI = 0.28）。CsA/SRL（0.5/0.08 mg/kg/天）组合与FTY720（0.1 mg/kg/天）协同作用可将心脏存活时间延长至>60天（CI = 0.18）。