DataSheet_2_Peripheral nerve repair is associated with augmented cross-tissue inflammation following vascularized composite allotransplantation.pdf

IntroductionVascularized composite allotransplantation (VCA), with nerve repair/coaptation (NR) and tacrolimus (TAC) immunosuppressive therapy, is used to repair devastating traumatic injuries but is often complicated by inflammation spanning multiple tissues. We identified the parallel upregulation of transcriptional pathways involving chemokine signaling, T-cell receptor signaling, Th17, Th1, and Th2 pathways in skin and nerve tissue in complete VCA rejection compared to baseline in 7 human hand transplants and defined increasing complexity of protein-level dynamic networks involving chemokine, Th1, and Th17 pathways as a function of rejection severity in 5 of these patients. We next hypothesized that neural mechanisms may regulate the complex spatiotemporal evolution of rejection-associated inflammation post-VCA.
MethodsFor mechanistic and ethical reasons, protein-level inflammatory mediators in tissues from Lewis rats (8 per group) receiving either syngeneic (Lewis) or allogeneic (Brown-Norway) orthotopic hind limb transplants in combination with TAC, with and without sciatic NR, were compared to human hand transplant samples using computational methods.
ResultsIn cross-correlation analyses of these mediators, VCA tissues from human hand transplants (which included NR) were most similar to those from rats undergoing VCA + NR. Based on dynamic hypergraph analyses, NR following either syngeneic or allogeneic transplantation in rats was associated with greater trans-compartmental localization of early inflammatory mediators vs. no-NR, and impaired downregulation of mediators including IL-17A at later times.
DiscussionThus, NR, while considered necessary for restoring graft function, may also result in dysregulated and mis-compartmentalized inflammation post-VCA and therefore necessitate mitigation strategies. Our novel computational pipeline may also yield translational, spatiotemporal insights in other contexts.

【引言】血管化复合组织异体移植（Vascularized composite allotransplantation, VCA）联合神经修复/吻合术（nerve repair/coaptation, NR）与他克莫司（tacrolimus, TAC）免疫抑制疗法，可用于修复毁灭性创伤，但常并发跨多组织的炎症反应。本研究在7例手部异体移植患者中发现，相较于基线状态，完全VCA排斥反应时皮肤与神经组织内趋化因子信号、T细胞受体信号、Th17、Th1及Th2通路等转录通路均同步上调；并在其中5例患者中明确，随着排斥反应严重程度升高，涉及趋化因子、Th1及Th17通路的蛋白质层面动态网络复杂度逐步增加。随后本研究提出假说：神经机制可能调控VCA术后排斥相关炎症的复杂时空演化过程。
【方法】出于机制研究与伦理考量，本研究采用计算分析方法，将两组Lewis大鼠（每组8只）的组织样本与手部异体移植患者样本进行对比；其中大鼠接受同源（Lewis系）或异体（Brown-Norway系）原位后肢移植，联合他克莫司给药，分别设置坐骨神经NR处理组与未处理组，检测其组织内蛋白质层面的炎症介质水平。
【结果】对上述炎症介质的交叉相关分析显示，包含NR处理的人类手部异体移植VCA组织，与接受VCA+NR处理的大鼠组织相似度最高。基于动态超图分析结果，相较于未进行NR处理的大鼠，同源或异体移植后实施NR的大鼠，其早期炎症介质的跨室区定位更为显著，且在后期阶段包括IL-17A在内的介质下调过程受损。
【讨论】综上，尽管神经修复/吻合术被认为是恢复移植物功能的必要手段，但也可能导致VCA术后炎症反应失调与室区定位异常，因此需要制定相应的干预策略。本研究开发的新型计算分析流程，亦可在其他研究场景中提供具有转化价值的时空维度研究视角。