Mesenchymal stem cell enhancement of islet engraftment and long term survival

项目总结（见说明）; 我们已经观察到肝内胰岛/MSC联合移植的食蟹猴受体的胰岛植入显著增强，胰岛同种异体移植物存活延长和排斥逆转。我们的目标是确定一个安全和最佳有效的移植协议，可以在临床环境中进行测试，以改善 胰岛移植物的长期存活和功能。MSC在实验和临床上被用于在各种环境中介导炎症和免疫;然而，MSC MHC与受体和细胞或实体器官供体对移植结果的影响尚未确定。在胰岛同种异体移植的情况下，当供体与供体配对时，MHC匹配不被考虑。 收件人。由于MSC扩增和建库可能需要长达6周，因此在临床环境中利用来自胰岛供体的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候名单上时进行骨髓抽吸和MSC扩展/储存，或者来自第三人的MSC 党将在目的1中研究MHC对胰岛/MSC移植结果的影响：利用食蟹猴肝内胰岛/MSC共移植模型来鉴定MSC产物的最佳来源，即，受体或第三方，通过确定MSC来源如何影响胰岛移植物的结果。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，并最终增强移植物功能。这将在目标2中进行评估：确定静脉内给予最佳MSC产品是否可以可重复地逆转胰岛同种异体移植物排斥反应，并随后维持或改善胰岛功能。基于已发表的有关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MSC移植到具有胰岛的肝脏中，以及移植后IV MSC的输注将导致T调节细胞的诱导，调节性单核细胞/巨噬细胞和内皮前体向炎症部位的募集（即，移植部位）和MSC迁移到引流移植部位的淋巴结。我们会进行研究， 目的3：确定MSC在肾和胰岛同种异体移植反应中有效性和无效性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：采用最佳MSC来源、剂量和给药时间进行移植，并对潜在生物标志物进行前瞻性监测，以便能够进行胰岛/MSC共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.