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FTY720是一种改变淋巴细胞迁移的免疫抑制剂,与环孢素A联合使用可消除慢性排斥反应。

FTY720, an immunosuppressant that alters lymphocyte trafficking, abrogates chronic rejection in combination with cyclosporine A.

作者信息

Koshiba Takaaki, Van Damme Boudewijn, Rutgeerts Omer, Waer Mark, Pirenne Jacques

机构信息

Abdominal Transplant Surgery Department, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium.

出版信息

Transplantation. 2003 Apr 15;75(7):945-52. doi: 10.1097/01.TP.0000058469.38572.10.

Abstract

BACKGROUND

Chronic rejection remains the leading cause of failure after transplantation (Tx). FTY720, a new immunosuppressant altering lymphocyte trafficking, is effective against acute rejection, but its activity against chronic rejection is not known.

METHODS

A valid model of chronic rejection was produced. Heart transplantation (HTx) was performed using fully mismatched RA (RT1p) and PVG (RT1c) rats. Administration of donor-specific blood transfusion 12 days before HTx prolongs graft survival, but features of chronic rejection including intimal hyperplasia and vascular obliteration (VO) develop with time only in allogeneic Tx. This is therefore a valid model of chronic rejection. VO was assessed on post-Tx day 90 in six groups differing according to the maintenance immunosuppressive regimen administered. group 1, donor-specific blood transfusion only and no other treatment; group 2, FTY720 (0.3 mg/kg/day orally) for 90 days; group 3, cyclosporine A (CsA) (1 mg/kg/day orally) for 90 days; group 4, combined administration of FTY720 and CsA for 90 days; group 5, transient administration of combined FTY720 and CsA for 7 days; and group 6, syngeneic HTx (RA to RA). Graft infiltrate, endothelial immunoglobulin (Ig) G deposition, and complement binding were also examined on post-Tx day 90.

RESULTS

In control group 1, severe VO was observed, compared with syngeneic HTx (group 6). Monotherapy with FTY720 (group 2) or with CsA (group 3) significantly but partially reduced VO. On the contrary, combined administration of FTY720 and CsA (group 4) abrogated VO. A 1-week treatment with combined FTY720 and CsA (group 5) reduced VO but only partially. In group 1, arteriosclerosis was accompanied by graft infiltrate, endothelial IgG deposition, and complement binding. In groups 2, 3, and 5, graft infiltrating scores were partially decreased compared with group 1 but remained higher than in syngeneic controls; endothelial IgG deposition and complement binding were still present. In group 4, continuous administration of combined FTY720 and CsA reduced graft infiltrate to the level of syngeneic control and abrogated both endothelial IgG deposition and complement binding.

CONCLUSIONS

Maintenance treatment with either FTY720 or CsA monotherapy partially prevents chronic rejection; short-term treatment with combined FTY720 and CsA reduces chronic rejection only partially; and continuous treatment with combined FTY720 and CsA abrogates chronic rejection, and this is accompanied by dramatic reduction of graft infiltrating cells, endothelial IgG deposition, and complement binding. Prevention of chronic rejection by maintenance treatment with FTY720 and CsA represents indirect evidence that normal lymphocyte trafficking and function are mandatory for development of chronic rejection.

摘要

背景

慢性排斥反应仍是移植术后失败的主要原因。FTY720是一种新型免疫抑制剂,可改变淋巴细胞的迁移,对急性排斥反应有效,但对慢性排斥反应的活性尚不清楚。

方法

建立了一个有效的慢性排斥反应模型。采用完全不匹配的大鼠品系,将大鼠主动脉(RT1p)和门静脉(RT1c)进行心脏移植。在心脏移植前12天给予供体特异性输血可延长移植物存活时间,但慢性排斥反应的特征,包括内膜增生和血管闭塞(VO),仅在同种异体移植中随时间发展。因此,这是一个有效的慢性排斥反应模型。在移植后第90天,对六组大鼠进行评估,这六组大鼠根据维持免疫抑制方案的不同而有所差异。第1组,仅进行供体特异性输血,无其他治疗;第2组,口服FTY720(0.3 mg/kg/天),持续90天;第3组,口服环孢素A(CsA)(1 mg/kg/天),持续90天;第4组,联合使用FTY720和CsA,持续90天;第5组,联合使用FTY720和CsA,短暂给药7天;第6组,同基因心脏移植(大鼠主动脉到大鼠主动脉)。在移植后第90天,还检测了移植物浸润、内皮免疫球蛋白(Ig)G沉积和补体结合情况。

结果

与同基因心脏移植组(第6组)相比,对照组第1组观察到严重的血管闭塞。单独使用FTY720(第2组)或CsA(第3组)进行单一疗法可显著但部分减少血管闭塞。相反,联合使用FTY720和CsA(第4组)可消除血管闭塞。联合使用FTY720和CsA进行1周治疗(第5组)可减少血管闭塞,但仅部分有效。在第1组中,动脉硬化伴有移植物浸润、内皮IgG沉积和补体结合。在第2、3和5组中,与第1组相比,移植物浸润评分部分降低,但仍高于同基因对照组;内皮IgG沉积和补体结合仍然存在。在第4组中,持续联合使用FTY720和CsA可将移植物浸润降低至同基因对照组水平,并消除内皮IgG沉积和补体结合。

结论

单独使用FTY720或CsA进行维持治疗可部分预防慢性排斥反应;联合使用FTY720和CsA进行短期治疗仅部分减少慢性排斥反应;持续联合使用FTY720和CsA可消除慢性排斥反应,同时移植物浸润细胞、内皮IgG沉积和补体结合显著减少。通过使用FTY720和CsA进行维持治疗预防慢性排斥反应,间接证明了正常的淋巴细胞迁移和功能是慢性排斥反应发生所必需的。

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