Solhjou Z, Uehara M, Bahmani B, Maarouf O H, Ichimura T, Brooks C R, Xu W, Yilmaz M, Elkhal A, Tullius S G, Guleria I, McGrath M M, Abdi R
Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Am J Transplant. 2017 Sep;17(9):2326-2337. doi: 10.1111/ajt.14266. Epub 2017 Apr 18.
Ischemia-reperfusion injury (IRI) evokes intragraft inflammatory responses, which markedly augment alloimmune responses against the graft. Understanding the mechanisms underlying these responses is fundamental to develop therapeutic regimens to prevent/ameliorate organ IRI. Here, we demonstrate that IRI results in a marked increase in mitochondrial damage and autophagy in dendritic cells (DCs). While autophagy is a survival mechanism for ischemic DCs, it also augments their production of interleukin (IL)-6. Allograft-derived dendritic cells (ADDCs) lacking autophagy-related gene 5 (Atg5) showed higher death rates posttransplantation. Transplanted ischemic hearts from CD11cCre/Atg5 conditional knockout mice showed marked reduction in intragraft expression of IL-6 compared with controls. To antagonize the effect of IL-6 locally in the heart, we synthesized novel anti-IL-6 nanoparticles with capacity for controlled release of anti-IL-6 over time. Compared with systemic delivery of anti-IL-6, localized delivery of anti-IL-6 significantly reduced chronic rejection with a markedly lower amount administered. Despite improved allograft histology, there were no changes to splenic T cell populations, illustrating the importance of local IL-6 in driving chronic rejection after IRI. These data carry potential clinical significance by identifying an innovative, targeted strategy to manipulate organs before transplantation to diminish inflammation, leading to improved long-term outcomes.
缺血再灌注损伤（IRI）引发移植物内的炎症反应，这会显著增强针对移植物的同种免疫反应。了解这些反应背后的机制对于制定预防/改善器官IRI的治疗方案至关重要。在此，我们证明IRI导致树突状细胞（DCs）中线粒体损伤和自噬显著增加。虽然自噬是缺血性DCs的一种存活机制，但它也会增加其白细胞介素（IL）-6的产生。缺乏自噬相关基因5（Atg5）的同种异体移植物来源的树突状细胞（ADDCs）在移植后显示出更高的死亡率。与对照组相比，来自CD11cCre/Atg5条件性敲除小鼠的移植缺血心脏在移植物内IL-6的表达显著降低。为了在心脏局部拮抗IL-6的作用，我们合成了新型抗IL-6纳米颗粒，其具有随时间控制释放抗IL-6的能力。与全身给予抗IL-6相比，局部给予抗IL-6显著降低了慢性排斥反应，且给药量明显更低。尽管同种异体移植物组织学有所改善，但脾T细胞群体没有变化，这说明了局部IL-6在驱动IRI后慢性排斥反应中的重要性。这些数据通过确定一种创新的、有针对性的策略，即在移植前对器官进行处理以减轻炎症，从而改善长期预后，具有潜在的临床意义。
