Research for immuno-logical tolerance induction in islet xeno-transplantation -Therapeutic effect of a adenovirus or retrovirus mediated CTLA4Ig gene transfer combined with immunosuppressive regents-

[背景与目的]腺病毒介导的CTLA 4 Ig基因转移在几种啮齿动物移植模型中已被报道能提高移植物存活率。在这项研究中，我们研究了腺病毒载体在胰岛同种异体移植中离体和全身转移CTLA 4 Ig基因的功效。[方法]将BN大鼠胰岛移植到化学诱导的糖尿病LEW大鼠体内。首先，在移植之前进行离体CTLA 4 Ig基因转移到分离的胰岛中。其次，在移植程序后立即通过静脉内施用完成全身基因转移。[结果]肾包膜下移植物存活时间稍有延长（8.6±1.3天）与未转导移植物的存活相比（6.7±1.2天）;当联合短期FK 506治疗时，移植物存活时间进一步延长（32.6±10.7天vs.单独使用FK 506时为13.7±1.0天）。在全身转导动物中，肾被膜下移植胰岛存活时间（15.2±3.3）d，对照组（6.7±1.2）d。最后，在第100天，用来自相同供体品系（BN）的胰岛移植物再次移植具有长期存活的胰岛的LEW受体。然而，第二次胰岛移植在受体中始终失败。【结论】在该移植模型中，CTLA 4 Ig基因转移和FK 506治疗可协同提高胰岛移植物存活率，全身性转移CTLA 4 Ig基因比体外转移更有效，且胰岛移植不能实现供者特异性耐受。

【 Background & Aims 】 Adenovirus-mediated CTLA4Ig gene transfer has been reported to enhance graft survival in several rodent vansplantation models. In this study, we investigated the efficacy of ex vivo and systemic transfer of the CTLA4Ig gene by adenoviral vectors in pancreatic islet allo-transplantation.【Methods】 Islet grafts from BN rats were transplanted to chemically induced diabetic LEW rats. First, ex vivo CTLA4Ig gene transfer into isolated islets was performed prior to transplantation. Secondly, systemic gene transfer was accomplished by intravenous administration immediately after the transplantation procedure.【 Results 】 Survival of transduced grafts under the kidney capsule was slightly prolonged (8.6±1.3 days) compared with survival of untransduced grafts (6.7±1.2 days); when combined with a short course of FK506, graft survival was further extended (32.6±10.7 days vs. 13.7±1.0 days with FK506 alone).In systemically transduced animals, islet grafts under the kidney capsule survived longer (15.2±3.3 days) than in controls (6.7±1.2 days) , and when FK506 was administered perioperatively, all the islet grafts survived for more than 100 days. Finally, the LEW recipients with long-surviving islet were re-transplanted with islet grafts from the same donor strain (BN) on day 100. However, the second islet grafts consistently failed in the recipients.【Conclusions】 We conclude that in this transplant model, CTLA4Ig gene transfer and FK506 treatment synergistically improved islet graft survival, systemic transfer of the gene was more effective than ex vivo transfer to the islets, and donor-specific tolerance could not be achieved for islet transplantation.