Rehman Khaja K, Bertera Suzanne, Trucco Massimo, Gambotto Andrea, Robbins Paul D
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine Pittsburgh, PA 15261, USA.
Transplantation. 2007 Aug 15;84(3):301-7. doi: 10.1097/01.tp.0000275183.50435.b6.
The success of pancreatic islet transplantation is limited because of immune rejection of allogeneic transplanted tissue and potential adverse side effects of nonspecific immunosuppression. Local expression of an immunosuppressive agent at the site of islet transplant could promote long-term engraftment without associated systemic side effects.
We have examined the ability of adenoviral vector mediated local production of sCD40-immunoglobulin (Ig), blocking the CD40-CD40 ligand (CD40L) costimulatory pathway, from genetically modified allogeneic islets to facilitate long-term engraftment in fully allogeneic mouse model.
Transplantation of islets infected with an adenoviral vector expressing sCD40-Ig resulted in allograft survival longer than 120 days in five of the nine recipient mice (56%). However, mice that received mock infected (n=5) or control adenoviral vector (Ad.eGFP; n=6) rejected the allograft with a median survival of 15 and 16 days, respectively. Histopathology demonstrated that the grafts of the long-term surviving animals preserved islets with minimal mononuclear cell infiltration.
These results demonstrate that local inhibition of the CD40-CD40L pathway by adenoviral gene transfer of sCD40-Ig to the islets prior to transplant significantly prolonged islet allograft acceptance. This approach could be used clinically to facilitate islet transplantation.
由于同种异体移植组织的免疫排斥反应以及非特异性免疫抑制的潜在不良副作用，胰岛移植的成功率受到限制。在胰岛移植部位局部表达免疫抑制剂可促进长期植入，且无相关的全身副作用。
我们研究了腺病毒载体介导的基因修饰同种异体胰岛局部产生可溶性CD40免疫球蛋白（Ig）（阻断CD40 - CD40配体（CD40L）共刺激途径）在完全同种异体小鼠模型中促进长期植入的能力。
用表达sCD40 - Ig的腺病毒载体感染的胰岛进行移植，9只受体小鼠中有5只（56%）的同种异体移植物存活超过120天。然而，接受 mock 感染（n = 5）或对照腺病毒载体（Ad.eGFP；n = 6）的小鼠分别在第15天和第16天排斥同种异体移植物，中位生存期分别为15天和16天。组织病理学显示，长期存活动物的移植物中胰岛得以保留，单核细胞浸润极少。
这些结果表明，在移植前通过腺病毒基因转移将sCD40 - Ig导入胰岛对CD40 - CD40L途径进行局部抑制，可显著延长胰岛同种异体移植物的存活时间。这种方法可用于临床以促进胰岛移植。
