TOLERANCE INDUCTION TO PRIMATE ISLET ALLOGRAFTS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。该项目的目标是开发新的，临床相关的策略，以允许胰岛异体移植接受。这将使用毒性较低的药物来解决，目的是在没有长期免疫抑制（移植耐受）的情况下实现持久的同种异体移植物接受。我们已经成功地评估了LEA29Y，一种新的免疫调节试剂，在临床前灵长类动物模型中取代他克莫司和保护异体胰岛。结果表明，LEA29Y是一种有效的免疫抑制剂，可以有效地预防无类固醇免疫抑制方案中的排斥反应，从而在我们的临床前模型中显着延长异体胰岛移植存活。我们评估了一种嵌合抗人CD40单克隆抗体Chi 220单独和与LEA29Y的有效性。LEA29Y和Chi220联合使用可显著促进同种异体胰岛移植物的长期存活。这是令人鼓舞的，因为LEA29Y能够与西罗莫司和Chi220两种药物中的任何一种协同作用。其他正在进行的药物方案优化实验将解决用另一种药物霉酚酸酯（MMF）替代西罗莫司的结果。在Aim 2下，我们在开发一种临床可接受的方案方面取得了进展，该方案用于产生长期稳定的造血嵌合，作为实现对移植胰岛耐受的手段。我们已经成功地在非人类灵长类动物中优化了一种基于白细胞的方案，该方案可导致持久的造血嵌合（100天）。由于我们的实验室工作涉及小鼠嵌合和MHC相容性，我们相信使用MHC定义的动物结合这种改进的方案来实现稳定的嵌合将是在临床前模型中实现真正的长期胰岛同种异体移植功能所必需的关键因素。目前，对恒河猴MHC知之甚少，需要开发测试来定义和筛选我们可用的非人类灵长类动物种群。一旦研究进展到临床研究水平，MHC可以很容易地在人类供体-受体受试者中进行测试，结果与匹配程度相关

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. This project's goal is to develop novel, clinically relevant strategies to permit islet allograft acceptance. This will be addressed using agents with reduced toxicities, with the objective of achieving durable allograft acceptance without long-term immunosuppression (transplantation tolerance). We have successfully evaluated LEA29Y, a novel immunomodulatory reagent, to replace tacrolimus and protect allogeneic islets in a pre-clinical primate model. Results suggest that LEA29Y is a potent immunosuppressant that can effectively prevent rejection in a steroid-free immunosuppressive protocol, leading to marked prolongation of islet allograft survival in our pre-clinical model. We evaluated the effectiveness of a chimeric anti-human CD40 monoclonal antibody, Chi 220, alone and with LEA29Y. The combination of LEA29Y and Chi220 dramatically facilitated long-term survival of islet allografts. This is encouraging, as LEA29Y is able to act in synergy with either of two agents, sirolimus and Chi220. Additional ongoing drug regimen optimization experiments will address the outcome of replacement of sirolimus with yet another drug, mycophenolate mofetil (MMF). Under Aim 2, we have made progress toward developing a clinically acceptable regimen for the production of long-term stable hematopoietic chimerism as a means of achieving tolerance to transplanted islets. We have successfully optimized a leukopheresis-based protocol in non-human primates that leads to durable hematopoietic chimerism (100 days). Due to our laboratory work involving chimerism and MHC compatibility in mice, we believe use of MHC-defined animals combined with this improved regimen for achieving stable chimerism will be the critical elements necessary to achieve true long-term islet allograft function in this preclinical model. Presently, little is known about Rhesus MHC and tests need to be developed to define and screen our available non-human primate population for these. Once research advances to the level of clinical studies, MHC can be readily tested in human donor-recipient subjects, and outcomes correlated with the degree of matching