用细胞间黏附分子-1反义寡脱氧核苷酸预防同种异体移植排斥反应。

Protection against allograft rejection with intercellular adhesion molecule-1 antisense oligodeoxynucleotides.

作者信息

Stepkowski S M, Wang M E, Condon T P, Cheng-Flournoy S, Stecker K, Graham M, Qu X, Tian L, Chen W, Kahan B D, Bennett C F

机构信息

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

出版信息

Transplantation. 1998 Sep 27;66(6):699-707. doi: 10.1097/00007890-199809270-00003.

DOI:10.1097/00007890-199809270-00003

PMID:9771832

Abstract

BACKGROUND

We designed an antisense phosphorothioate oligodeoxynucleotide (oligo) to specifically inhibit the expression of rat intercellular adhesion molecule-1 (ICAM-1) mRNA (IP-9125).

METHODS

IP-9125 oligo was delivered intravenously by osmotic pump alone or in combination with cyclosporine (CsA) to recipients in order to prevent the rejection of kidney or heart allografts. In additional experiments, kidney allografts were perfused with IP-9125 before grafting.

RESULTS

IP-9125 inhibited ICAM-1 mRNA and ICAM-1 protein expression in rat aortic endothelial cells; scrambled controls IP-12140 and IP-13944 were ineffective. Untreated ACI (RT1a) recipients rejected Lewis (RT1l) kidney allografts at a mean survival time of 8.5+/-1.1 days. A 14-day intravenous administration of 2.5 mg/kg/day IP-9125 prolonged the survival of kidney allografts to 39.2+/-16.4 days; 5.0 mg/kg/day, to 43.0+/-17.5 days; and 10.0 mg/kg/day, to 50.4+/-21.6 days. In contrast, a scrambled control IP-12140 was not effective. A combination of 10 mg/kg/day IP-9125 and 1.0 mg/kg/day CsA delivered for 14 days synergistically extended kidney allograft survival times 88.5+/-7.5 days. In contrast, the combination of 10.0 mg/kg/day control IP-12140 with CsA was ineffective (20.7+/-3.2 days) when compared with CsA alone (20.2+/-4.0 days). Similar results were obtained for heart transplants in recipients treated with IP-9125 alone or in combination with CsA. Furthermore, in situ immunostaining showed that IP-9125 significantly reduced the expression of ICAM-1 protein in kidney allografts. Finally, perfusion of kidney grafts alone with 20.0 mg per 2 ml of IP-9125 protected kidney allografts from rejection (37.5+/-7.5 days; P < 0.001), whereas perfusion with 20 mg per 2 ml of control IP-12140 was ineffective (12.6+/-5.0 days).

CONCLUSIONS

Rat ICAM-1 IP-9125 oligo inhibits ICAM-1 protein expression in vitro and in vivo as well as blocks allograft rejection when used for pretreatment of donors, graft perfusion, or postoperative treatment of recipients.

摘要

背景

我们设计了一种反义硫代磷酸寡脱氧核苷酸（oligo），以特异性抑制大鼠细胞间黏附分子-1（ICAM-1）mRNA（IP-9125）的表达。

方法

将IP-9125 oligo单独或与环孢素（CsA）联合通过渗透泵静脉注射给受体，以防止肾或心脏同种异体移植的排斥反应。在额外的实验中，肾移植在移植前用IP-9125灌注。

结果

IP-9125抑制大鼠主动脉内皮细胞中ICAM-1 mRNA和ICAM-1蛋白的表达；随机对照的IP-12140和IP-13944无效。未经治疗的ACI（RT1a）受体排斥Lewis（RT1l）肾移植，平均存活时间为8.5±1.1天。每天静脉注射2.5 mg/kg的IP-9125，持续14天，可将肾移植的存活时间延长至39.2±16.4天；每天5.0 mg/kg，延长至43.0±17.5天；每天10.0 mg/kg，延长至50.4±21.6天。相比之下，随机对照的IP-12140无效。每天10 mg/kg的IP-9125与每天1.0 mg/kg的CsA联合给药14天，可协同延长肾移植存活时间至88.5±7.5天。相比之下，每天10.0 mg/kg的对照IP-12140与CsA联合使用时无效（20.7±3.2天），而单独使用CsA时为（20.2±4.0天）。在单独使用IP-9125或与CsA联合治疗的受体的心脏移植中也获得了类似的结果。此外，原位免疫染色显示IP-9125显著降低了肾移植中ICAM-1蛋白的表达。最后，每2 ml含20.0 mg的IP-9125单独灌注肾移植可防止肾移植排斥（37.5±7.5天；P<0.001），而每2 ml含20 mg的对照IP-12140灌注则无效（12.6±5.0天）。