NYU Langone Health, Hansjörg Wyss Department of Plastic Surgery, New York, NY, USA.
Am J Transplant. 2018 Jul;18(7):1657-1667. doi: 10.1111/ajt.14668. Epub 2018 Feb 19.
Current pharmacologic regimens in transplantation prevent allograft rejection through systemic recipient immunosuppression but are associated with severe morbidity and mortality. The ultimate goal of transplantation is the prevention of allograft rejection while maintaining recipient immunocompetence. We hypothesized that allografts could be engineered ex vivo (after allotransplant procurement but before transplantation) by using mesenchymal stem cell-based therapy to generate localized immunomodulation without affecting systemic recipient immunocompetence. To this end, we evaluated the therapeutic efficacy of bone marrow-derived mesenchymal stem cells in vitro and activated them toward an immunomodulatory fate by priming in inflammatory or hypoxic microenvironments. Using an established rat hindlimb model for allotransplantation, we were able to significantly prolong rejection-free allograft survival with a single perioperative ex vivo infusion of bone marrow-derived mesenchymal stem cells through the allograft vasculature, in the absence of long-term pharmacologic immunosuppression. Critically, transplanted rats rejected a second, nonengineered skin graft from the same donor species to the contralateral limb at a later date, demonstrating that recipient systemic immunocompetence remained intact. This study represents a novel approach in transplant immunology and highlights the significant therapeutic opportunity of the ex vivo period in transplant engineering.
目前，移植中的药物治疗方案通过全身受者免疫抑制来预防同种异体移植物排斥反应，但与严重的发病率和死亡率相关。移植的最终目标是在维持受者免疫能力的同时预防同种异体移植物排斥反应。我们假设同种异体移植物可以通过间充质干细胞为基础的治疗在体外进行工程化（在同种异体移植采集后但在移植前），从而产生局部免疫调节，而不影响全身受者免疫能力。为此，我们评估了骨髓来源的间充质干细胞在体外的治疗效果，并通过在炎症或低氧微环境中预先刺激它们向免疫调节方向分化来激活它们。使用已建立的大鼠后肢同种异体移植模型，我们能够通过在同种异体血管中单次围手术期体外输注骨髓来源的间充质干细胞，显著延长排斥反应-free 同种异体移植物的存活时间，而无需长期药物免疫抑制。关键的是，移植后的大鼠在后期从同一供体物种的对侧肢体上排斥了第二个未经工程化的皮肤移植物，这表明受者的全身免疫能力仍然完好。这项研究代表了移植免疫学中的一种新方法，突出了移植工程中体外期的重要治疗机会。
