Novel Application of Localized Nanodelivery of Anti-Interleukin-6 Protects Organ Transplant From Ischemia-Reperfusion Injuries.
Novel Application of Localized Nanodelivery of Anti-Interleukin-6 Protects Organ Transplant From Ischemia-Reperfusion Injuries.
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抗Interleukin-6的局部纳米传递的新颖应用可保护器官移植免受缺血 - 再灌注损伤。
DOI：
10.1111/ajt.14266
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发表时间：
2017-09
期刊：
影响因子：
--
通讯作者：
Abdi R
中科院分区：
文献类型：
--
作者：
Solhjou Z;Uehara M;Bahmani B;Maarouf OH;Ichimura T;Brooks CR;Xu W;Yilmaz M;Elkhal A;Tullius SG;Guleria I;McGrath MM;Abdi R
缺血再灌注损伤(IRI)可引起移植物内炎症反应，显著增强对移植物的同种异体免疫反应。了解这些反应的潜在机制是开发预防/改善器官IRI的治疗方案的基础。在这里，我们证明了IRI导致树突状细胞(DC)线粒体损伤和自噬显著增加。虽然自噬是缺血树突状细胞的一种生存机制，但它也增加了它们产生IL-6。缺乏自噬相关基因5(ATG5)的同种异体树突状细胞(ADDC)移植后死亡率较高。CD11cCre/ATG5条件性基因敲除小鼠移植的缺血心脏与对照组相比，移植物内IL6的表达显著减少。为了对抗IL-6在心脏局部的作用，我们合成了新型的抗IL-6纳米粒，该纳米粒能够随着时间的推移控制释放抗IL-6。与全身注射抗IL6相比，局部注射抗IL6显著减少慢性排斥反应，且给药量明显减少。尽管同种异体移植的组织学有所改善，但脾T细胞群没有变化，说明局部IL6在推动IRI后慢性排斥反应中的重要性。这些数据具有潜在的临床意义，可以确定一种创新的、有针对性的策略，在移植前操纵器官以减少炎症，从而改善长期结果。
Ischemia reperfusion injury (IRI) evokes intra-graft 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 (DC). While autophagy is a survival mechanism for ischemic DC, it also augments their production of IL6. Allograft derived dendritic cells (ADDC) lacking autophagy related gene 5 (Atg5) showed higher death rates post-transplantation. Transplanted ischemic hearts from CD11cCre/Atg5 conditional knockout mice showed marked reduction in intra-graft expression of IL6 as compared to controls. To antagonize the effect of IL6 locally in the heart, we synthesized novel anti-IL6 nanoparticles with capacity for controlled release of anti-IL6 over time. As compared to systemic delivery of anti-IL6, localized delivery of anti-IL6 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 IL6 in driving chronic rejection after IRI. These data carry potential clinical significance, by identifying an innovative, targeted strategy to manipulate organs prior to transplantation to diminish inflammation, leading to improved long term outcomes.
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DOI：
10.1016/j.clim.2015.04.013
发表时间：
2015-09
期刊：
Clinical immunology (Orlando, Fla.)
影响因子：
--
作者：
Fisher JD;Acharya AP;Little SR
通讯作者：
Little SR
DOI：
10.4049/jimmunol.1100766
发表时间：
2011-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Booth AJ;Grabauskiene S;Wood SC;Lu G;Burrell BE;Bishop DK
通讯作者：
Bishop DK
DOI：
10.1084/jem.20110640
发表时间：
2011-12-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ireland JM;Unanue ER
通讯作者：
Unanue ER
影响因子：
5.4
作者：
Baratin, M;Bonin, K;Daniel, C
通讯作者：
Daniel, C
影响因子：
7.7
作者：
Fiorina, Paolo;Jurewicz, Mollie;Abdi, Reza
通讯作者：
Abdi, Reza