Mesenchymal stem cell enhancement of islet engraftment and long term survival

项目总结(见说明)； 在食蟹猴肝内胰岛/间充质干细胞联合移植中，我们观察到显著增强胰岛植入、延长同种异体胰岛移植物存活和逆转排斥反应。我们的目标是确定一种安全和最有效的移植方案，可以在临床环境中进行测试，以改善 同种异体胰岛移植的长期存活和功能。MSC在实验和临床上被用来在各种环境中调节炎症和免疫；然而，MSC MHC与受体和细胞或固体器官供体之间的关系尚未确定对移植结果的影响。在同种异体胰岛移植的设置中，当供体与供体配对时，不考虑MHC匹配 收件人。由于MSC扩增和储存可能需要长达6周的时间，因此在临床环境中使用来自胰岛供者的MSC是不切实际的。替代方案是接受者MSC，这需要在接受者在等待名单上时进行骨髓抽吸和MSC扩增/存库，或者来自第三方的MSC 聚会。MHC对胰岛/MSC移植结果的影响将在目标1中进行研究：利用食蟹猴肝内胰岛/MSC联合移植模型，通过确定MSC来源如何影响同种异体胰岛移植结果，确定MSC产品的最佳来源，即受体或第三方。我们的初步数据表明，在胰岛移植物失稳时静脉注射额外的MSC可以逆转排斥反应，并最终增强移植物的功能。这将在目标2中进行评估：确定静脉注射最佳的MSC产品是否可以重复地导致胰岛移植排斥反应的逆转和随后胰岛功能的维持或改善。基于已发表的关于MSC免疫调节作用机制的数据，以及 根据我们自己的初步数据(项目1和2)，我们假设将MSC移植到带胰岛的肝脏以及移植后输注IV MSC将导致T调节细胞的诱导，调节性单核/巨噬细胞和内皮前体细胞向炎症部位(即移植物部位)的募集，以及MSC向引流移植物部位的淋巴结的迁移。我们会进行研究，以 在目标3中解决这一问题：定义肾和胰岛移植反应中MSC有效和无效的预测性生物标志物。最后，来自项目1和2以及核心B和C的数据将被纳入目标4：以最佳的MSC来源、剂量和给药时间进行移植，并对潜在的生物标志物进行前瞻性监测，以便能够进行胰岛/MSC联合移植的试点临床试验。

PROJECT SUMMARY (See instructions); We have observed significant enhancement of islet engraftment, prolongation of islet allograft survival and reversal of rejection in cynomolgus monkey recipients of intrahepatic islet/MSC cotransplants. Our goal is to identify a safe and optimally effective transplant protocol that can be tested in the clinical setting to improve long-term islet allograft survival and function. MSC are being utilized experimentally and clinically to mediate inflammation and immunity in a variety of settings; however, the impact of MSC MHC in relation to the recipient and to the cellular or solid organ donor on transplant outcomes has not been defined. In the setting of islet allotransplantation, MHC matching is not taken into consideration when pairing a donor with a recipient. As MSC expansion and banking can take up to 6 weeks, it would be impractical in the clinical setting to utilize MSC from the islet donor. The alternatives are recipient MSC, which would require bone marrow aspiration and MSC expansion/banking while the recipient is on the waiting list, or MSC from a third party. The effect of MHC on islet/MSC transplant outcomes will be studied in Aim 1: To utilize a cynomolgus monkey, intrahepatic islet/MSC co-transplant model to identify the optimal source of the MSC product, i.e., recipient or 3rd party, by determining how MSC origin impacts islet allograft outcome. Our preliminary data suggests that IV administration of additional MSC at the time of islet allograft destabilization allows for reversal of rejection and, ultimately, enhancement of graft function. This will be assessed in Aim 2: To determine if intravenous administration of the optimal MSC product can reproducibly lead to reversal of islet allograft rejection and subsequent maintenance of or improvement in islet function. Based on published data regarding the mechanisms responsible for the immunomodulatory effect of MSC, as well as on our own preliminary data (Projects 1 and 2), we hypothesize that transplantation of MSC into the liver with islets, as well as infusion of IV MSC post-transplant will result in the induction of T regulatory cells, recruitment of regulatory monocytes/macrophages and endothelial precursors to sites of inflammation (i.e., the graft site) and migration of MSC to lymph nodes draining the graft site. We will undertake studies to address this in Aim 3: To define predictive biomarkers of MSC efficacy and non-efficacy in renal and islet allograft responses. Finally, the data from Projects 1 and 2 and Cores B and C will be incorporated in Aim 4: To undertake transplants with the optimal MSC source, dose and timing of administration, coupled with prospective monitoring of potential biomarkers, in order to enable a pilot clinical trial of islet/MSC cotransplantation.