Hepatocyte growth factor gene therapy for pancreatic islets in diabetes:: Reducing the minimal islet transplant mass required in a glucocorticoid-free rat model of allogeneic portal vein islet transplantation
Hepatocyte growth factor gene therapy for pancreatic islets in diabetes:: Reducing the minimal islet transplant mass required in a glucocorticoid-free rat model of allogeneic portal vein islet transplantation
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DOI：
10.1210/en.2003-1070
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发表时间：
2004-02-01
期刊：
影响因子：
4.8
通讯作者：
Stewart, AF
中科院分区：
文献类型：
--
作者：
Lopez-Talavera, JC;Garcia-Ocaña, A;Stewart, AF
胰岛移植治疗糖尿病受到人类胰岛供者的限制。肝细胞生长因子(HGF)是一种有效的β细胞有丝分裂原和生存因子，并在小鼠模型中改善胰岛移植结果。然而，小鼠模型采用了肾被膜下移植和免疫缺陷小鼠，这一特点不能代表人类胰岛移植方案。因此，我们开发了一种更严格、边缘质量的大鼠胰岛移植模型，它更接近于人类胰岛移植方案：胰岛供体是同种异体Lewis胰岛；受体是正常的SpragueDawley大鼠；胰岛在门静脉内输送；免疫抑制是使用Edmonton小组使用的相同免疫抑制剂实现的。我们证明1)Edmonton免疫抑制方案令人惊讶地诱导大鼠胰岛素抵抗和β细胞毒性，2)腺病毒不会对胰岛移植结果产生不利影响，3)Edmonton免疫抑制剂可延缓或阻断腺病毒转导的胰岛的排斥反应，更重要的是，4)移植前使用HGF的腺病毒基因治疗显著改善胰岛移植结果，5)这种增强功能持续数月，6)HGF增强胰岛功能和存活，即使在免疫抑制剂诱导的胰岛素抵抗和β细胞毒性的情况下也是如此。这种方法可能会提高人类胰岛移植的结果。
Islet transplantation for diabetes is limited by the availability of human islet donors. Hepatocyte growth factor (HGF) is a potent beta-cell mitogen and survival factor and improves islet transplant outcomes in a murine model. However, the murine model employs renal subcapsular transplant and immunodeficient mice, features not representative of human islet transplantation protocols. Therefore, we have developed a more rigorous, marginal-mass rat islet transplant model that more closely resembles human islet transplantation protocols: islet donors are allogeneic Lewis islets; recipients are normal Sprague Dawley rats; islets are delivered intraportally; and immunosuppression is accomplished using the same immunosuppressants employed by the Edmonton group. We demonstrate that 1) surprisingly, the Edmonton immunosuppression regimen induces marked insulin resistance and beta-cell toxicity in rats, 2) adenovirus does not adversely affect islet transplant outcomes, 3) the Edmonton immunosuppressants may delay or block rejection of adenovirally transduced islets, and more importantly, 4) pretransplant islet adenoviral gene therapy with HGF markedly improves islet transplant outcomes, 5) this enhanced function persists for months, and 6) HGF enhances islet function and survival even in the setting of immunosuppressant-induced insulin resistance and beta-cell toxicity. This approach may enhance islet transplantation outcomes in humans.