Yang Z, Rostami S, Koeberlein B, Barker C F, Naji A
Department of Surgery, University of Pennsylvania Medical Center, Philadelphia 19104-4283, USA.
Transplantation. 1999 Jun 27;67(12):1517-23. doi: 10.1097/00007890-199906270-00004.
Systemic administration of soluble recombinant fusion protein of cytotoxic T lymphocyte antigen 4 (CTLA4Ig) induces blockade of the CD28/B7 costimulatory pathway and promotes survival of allogeneic and xenogeneic grafts. We tested the efficacy of local expression of CTLA4Ig gene in the myocardium, induced by transduction with a recombinant adenovirus encoding the CTLA4Ig gene, on the survival of rat cardiac allografts.
The donor hearts were perfused ex vivo with recombinant adenovirus encoding CTLA4Ig cDNA (AdCTLA4Ig) via intra-aorta coronary artery before transplantation. The distribution and duration of CTLA4Ig transgene expression in the myocardium was assessed by reverse transcriptase polymerase chain reaction (RT-PCR) or in situ RT-PCR after transplantation.
In situ RT-PCR demonstrated abundant expression of CTLA4Ig transgene in the endo-myocardium of AdCTLA4Ig-perfused cardiac grafts. Lewis and Brown Norway cardiac allografts transduced with AdCTLA4Ig survived indefinitely in nonimmunosuppressed Wistar Furth recipients. However, donor-strain skin grafts were rejected by long-term recipients of cardiac allografts, which also triggered the rejection of the primary heart grafts.
A single ex vivo intra-aortic infusion of recombinant adenovirus encoding the CTLA4Ig gene induced efficient transduction of the endo-myocardium and promoted the permanent survival of cardiac allografts in nonimmunosuppressed hosts. Despite the beneficial effect of local immunosuppression on cardiac allograft survival, the strategy failed to promote a state of donor-specific peripheral tolerance.
细胞毒性T淋巴细胞抗原4（CTLA4Ig）可溶性重组融合蛋白的全身给药可诱导CD28/B7共刺激通路的阻断，并促进同种异体和异种移植物的存活。我们测试了用编码CTLA4Ig基因的重组腺病毒转导诱导的CTLA4Ig基因在心肌中的局部表达对大鼠心脏同种异体移植物存活的影响。
在移植前，通过主动脉冠状动脉对供体心脏进行体外灌注编码CTLA4Ig cDNA的重组腺病毒（AdCTLA4Ig）。移植后通过逆转录聚合酶链反应（RT-PCR）或原位RT-PCR评估CTLA4Ig转基因在心肌中的分布和持续时间。
原位RT-PCR显示，AdCTLA4Ig灌注的心脏移植物的内膜中CTLA4Ig转基因大量表达。用AdCTLA4Ig转导的Lewis和棕色挪威心脏同种异体移植物在未免疫抑制的Wistar Furth受体中无限期存活。然而，心脏同种异体移植的长期受体排斥供体菌株皮肤移植物，这也引发了原发性心脏移植物的排斥。
单次主动脉内输注编码CTLA4Ig基因的重组腺病毒可诱导内膜的有效转导，并促进未免疫抑制宿主中同种异体心脏移植物的永久存活。尽管局部免疫抑制对心脏同种异体移植存活有有益作用，但该策略未能促进供体特异性外周耐受状态。
