STRATEGIES FOR LARGE SCALE ISLET REPLACEMENT

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 广泛应用β细胞替代疗法治疗1型糖尿病将需要容易获得的胰岛素产生细胞来源。猪供体的异种移植提供了一种有吸引力的替代方案。我们已经公开了移植到非免疫抑制灵长类动物中的新生猪胰岛经历快速排斥，而施用基于CD 28/CD 154共刺激阻断的方案导致：1）持续的胰岛素非依赖性，2）异种移植后葡萄糖耐量的逐渐改善和持续的猪C肽产生，以及3）异种移植后缺乏PERV的传播（Cardona等人，Nature Medicine; 2006年3月）。 用抗CD 40单克隆抗体替代上述研究方案中使用的抗CD 154单克隆抗体，重现了这些结果。尽管这两种类似的基于共刺激阻断的方案取得了成功，但与FDA已经批准用于银屑病（一种自身免疫性皮肤病）的其他更新颖的药物相比，由于相关的血栓栓塞并发症和其早期发展阶段，其临床应用的前景有限。 在本报告年度，使用抗LFA-1 mAb和基于alefacept的方案导致新生猪胰岛植入和存活（60天），在两只动物中的一只中，产生了有希望的初步数据，如果可重现，建立了一个有效的，临床相关的免疫抑制方案，可以作为将新生猪胰岛移植进入临床试验的平台。因此，代表了一个潜在的短期解决方案的关键供应问题，在临床胰岛移植的数百万患有1型糖尿病。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Widespread application of beta-cell replacement therapy for type 1 diabetes will require a readily accessible source of insulin-producing cells. Xenotransplantation from porcine donors presents an attractive alternative. We have published that neonatal porcine islets transplanted into non-immunosuppressed primates underwent rapid rejection, while administration of a CD28/CD154 costimulation blockade-based regimen resulted in: 1) sustained insulin independence, 2) progressive improvement in glucose tolerance and sustained porcine c-peptide production over time after xenotransplant, and 3) lack of transmission of PERV after xenotransplantation (Cardona et al., Nature Medicine; March 2006). These results were reproduced with the substitution of an anti-CD40 monoclonal antibody for the anti-CD154 monoclonal antibody that was used in the regimen in the studies described above. Despite success with these two similar costimulation blockade-based regimens, the prospect for their clinical use is limited due to associated thromboembolic complications and their early developmental stage in comparison to other more novel agents already FDA approved for psoriasis, an autoimmune skin disorder. In this report year, using an anti-LFA-1 mAb and alefacept-based regimen led to neonatal porcine islet engraftment and survival (60 days) in one of two animals, resulting in promising preliminary data that if reproducible, establishes a potent, clinically relevant immunosuppressive regimen that could serve as a platform for moving neonatal porcine islet transplantation into clinical trials. Thus, representing a potential near-term solution to the critical supply problem in clinical islet transplantation for the millions afflicted with type 1 diabetes.