STRATEGIES FOR LARGE SCALE ISLET REPLACEMENT

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在本报告期间，由于对更理想的生物免疫抑制方案的渴望，没有进行进一步的胰岛肿块或解剖部位实验。为了寻找一种更具临床意义、毒性更低的治疗方案，灵长类动物在抗LFA-1单抗治疗的覆盖下进行了同种异体胰岛移植，结果非常有希望。在我们的临床前胰岛移植模型中，抗LFA-1已被证明是一种非常有效的免疫抑制剂，这为其在临床试验中的使用奠定了基础。然而，更有希望的是最近使用了一种纯粹的生物方案，抗LFA-1单抗和贝拉泰普单独使用，导致糖尿病立即逆转，胰岛存活367、223、373、73和269天。这种生物疗法有望成为一种临床相关的、可耐受的疗法，有可能转化为临床。 此外，我们还研究了3A8的使用，3A8是一种针对CD40的非耗竭鼠单抗。在3A8、巴利昔单抗和西罗莫司的覆盖下移植的同种异体胰岛动物的移植物存活时间分别为155、312、208、120和45天，证实了在移植中以非耗竭的方式阻断CD40途径的可能性。未来的计划包括在我们的胰岛模型和移植中测试重组抗CD40抗体以更好地表征CD40阻断，以及使用基于抗CD40的生物方案来建立临床前数据以便转化到临床。

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. In this report period, no further islet mass or anatomic site experiments have been done due to the desire for a more optimal biologic immunosuppressive regimen. In search of a more clinically relevant, less toxic regimen, primates were transplanted allogeneic islets under cover of anti-LFA-1 monoclonal antibody-based therapy with very promising results. Anti-LFA-1 has proven to be a very potent immunosuppressant in our preclinical islet transplant model, making the case for its use in clinical trials. More promising though has been the recent use of a purely biologic regimen, anti-LFA-1 mAb and belatacept alone, resulting in immediate reversal of diabetes and islet survival for 367, 223, 373, 73 and 269 days. This biologic regimen promises to be a clinically relevant, tolerable regimen with potential for translation into the clinic. Additionally, we have investigated the use of 3A8, a non-depleting mouse monoclonal antibody targeting CD40. Animals transplanted allogeneic islets under cover of 3A8, basiliximab and sirolimus had graft survivals of 155, 312, 208, 120, 45 days, establishing the potential of blocking the CD40 pathway in a non-depleting fashion in transplantation. Future plans include the testing of recombinant anti-CD40 antibodies for better characterization of CD40-blockade in our islet model and transplantation, and using anti-CD40-based biologic regimens to establish preclinical data for translation into the clinic.