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The induction of a donor-specific tolerance in islet xenotransplantation models by Bcl-2/Fas ligand transfection combined with immunosuppressive agents .

通过 Bcl-2/Fas 配体转染联合免疫抑制剂诱导胰岛异种移植模型中的供体特异性耐受。

基本信息

批准号：
11671161
负责人：
NAKATA Seizou
金额：
$ 2.5万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671161/
关键词：
islet CTLA4-Ig Fas Ligand Bcl-2 BB-rat IDDM NKT cells NKT細胞 Fas Ligand インスリン依存型糖尿病膵島移植

项目摘要

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease caused by the βcells destruction by autoreactive T cells. Islet transplantation is expected as an ideal therapy of the disease, but the outcome of isolated islet transplantation has been disappointing. Recently the gene therapy is applied to the transplantation models. Especially Bcl-2 which controls apoptosis, Fas Ligand which leads T cells to apoptosis, and CTLA4-Ig which inhibits T cell activation, are expected to restrain the rejection. In the present study, we investigated the effect of the transfection of these molecules to islets.It was revealed that the transfection of these molecules to islets by HVJ-liposome method is impossible. On the other hand , the transfection using adenovisrus vectors to islets worked efficiently.Islet survival transfected CTLA4-Ig gene did not prolonged despite the expression of the protein. Systemic administration of Ad.CTLA4-Ig could prolong the islet graft survival (10.0±2.4 days v.s. 5.7±0.5 days of no treatment group survival). Furthermore, the adenovirus-mediated CTLA4-Ig gene transfer combined with FK506 significantly prolonged islet graft survival more than 100 days.We have demonstrated that IDDM graft recurrence in the pancreas graft could be prevented with the administration of anti- ICAM-1/LEA-1 mAbs in a Wistar-Furth to a spontaneously diabetes prone-BB rat whole pancreatico- duodenal transplantation model. In this model, donor-derived chimeric RT6+ NKT cells which originated from the lymphoid tissues in the donor graft might be related to the inhibition of IDDM recurrenceShimizu et al. advanced the basic research of Bcl-2 families and demonstrated that the Bcl-2 family of proteins bind to the VDAC in order to regulate the mitochondrial membrane potential and the release of cytochrome c during apoptosis.

胰岛素依赖型糖尿病（Insulin-dependent diabetes mellitus，IDDM）是一种由自身反应性T细胞破坏β细胞引起的自身免疫性疾病。胰岛移植有望成为治疗该病的理想方法，但孤立性胰岛移植的效果一直令人失望。近年来，基因治疗被应用于移植模型。特别是控制细胞凋亡的Bcl-2、导致T细胞凋亡的Fas配体和抑制T细胞活化的CTLA 4-IG，被期望抑制排斥反应。本实验研究了这些分子对胰岛细胞的转染作用，发现HVJ-脂质体法不可能将这些分子转染到胰岛细胞。而腺病毒载体转染胰岛细胞效果良好，转染CTLA 4-IG基因的胰岛细胞存活时间并没有延长，尽管CTLA 4-Ig基因在胰岛细胞中表达。CTLA 4-IG可延长胰岛移植物的存活时间（10.0±2.4 d vs.无治疗组存活5.7±0.5天）。此外，腺病毒介导的CTLA 4-IG基因转移联合FK 506显著延长胰岛移植物存活超过100天。我们已经证明，在自发性糖尿病倾向BB大鼠全胰十二指肠移植模型中，在Wistar-Furth中给予抗ICAM-1/莱亚-1单克隆抗体可以预防胰岛移植物中的IDDM移植物复发。在该模型中，来源于供体移植物中淋巴组织的供体来源的嵌合RT 6 + NKT细胞可能与抑制IDDM复发有关。Shimizu等推进了Bcl-2家族的基础研究，并证明Bcl-2家族蛋白与VDAC结合以调节线粒体膜电位和细胞色素c在凋亡过程中的释放。