Polyethylene glycol-fusion repair of sciatic allografts in female rats achieves immunotolerance via attenuated innate and adaptive responses.
Polyethylene glycol-fusion repair of sciatic allografts in female rats achieves immunotolerance via attenuated innate and adaptive responses.
复制标题
雌性大鼠坐骨同种异体移植物的聚乙二醇融合修复通过减弱的先天和适应性反应实现免疫耐受。
DOI：
10.1002/jnr.24720
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发表时间：
2020
影响因子：
4.2
通讯作者：
Bittner,GeorgeD
中科院分区：
文献类型：
--
作者：
Smith,TylerA;Ghergherehchi,CameronL;Mikesh,Michelle;Shores,JaimieT;Tucker,HaleyO;Bittner,GeorgeD
消融/节段性丧失周围神经损伤（PNI）由于再生轴突生长缓慢且不准确而表现出不良的功能恢复。作为生长导向导管的有活力的外周神经同种异体移植物（PNA）会受到免疫排斥，所有无核供体/宿主轴突节段都会发生沃勒变性。相比之下，我们报告说，通过活坐骨神经乳头的神经缝合术和使用聚乙二醇（PEG）的聚乙二醇（PEG）融合方案修复的消融型坐骨神经乳头，立即恢复了许多轴突的轴突连续性，重新神经支配/维持了它们的神经肌肉接头，并防止了许多沃勒变性。PEG融合的PNA在2-6周内永久恢复了许多坐骨神经介导的行为。在远交雌性Sprague道利大鼠中，即使宿主/供体既没有免疫抑制也没有组织匹配，PEG融合的PNA也没有被排斥。使用电子显微镜、免疫组织化学和定量逆转录聚合酶链反应分析PEG融合坐骨神经PNA的先天性和适应性免疫应答，以了解形态学特征、T细胞和巨噬细胞浸润、主要组织相容性复合物（MHC）表达、细胞凋亡、细胞因子、趋化因子和细胞毒性效应物的表达。PEG融合的PNA在术后14-21天表现出减弱的先天性和适应性免疫应答，如（a）许多轴突和细胞保持活力，（B）细胞毒性和总T细胞和巨噬细胞的浸润显著减少，（c）炎性细胞因子、趋化因子和MHC蛋白的表达显著减少，（d）一致的低凋亡应答所证明的。在形态学和/或生物化学上，PEG融合的坐骨PNA通常类似于坐骨自体移植物或完整的坐骨神经。简而言之，PEG融合的PNAs是一个未经研究的，也许是唯一的，在非免疫豁免环境中活的同种异体移植组织免疫耐受的例子，相对于当前的方案，可以大大改善PNAs的临床结局。
Ablation/segmental loss peripheral nerve injuries (PNIs) exhibit poor functional recovery due to slow and inaccurate outgrowth of regenerating axons. Viable peripheral nerve allografts (PNAs) as growth‐guide conduits are immunologically rejected and all anucleated donor/host axonal segments undergo Wallerian degeneration. In contrast, we report that ablation‐type sciatic PNIs repaired by neurorrhaphy of viable sciatic PNAs and a polyethylene glycol (PEG)‐fusion protocol using PEG immediately restored axonal continuity for many axons, reinnervated/maintained their neuromuscular junctions, and prevented much Wallerian degeneration. PEG‐fused PNAs permanently restored many sciatic‐mediated behaviors within 2–6 weeks. PEG‐fused PNAs were not rejected even though host/donors were neither immunosuppressed nor tissue‐matched in outbred female Sprague Dawley rats. Innate and adaptive immune responses to PEG‐fused sciatic PNAs were analyzed using electron microscopy, immunohistochemistry, and quantitative reverse transcription polymerase chain reaction for morphological features, T cell and macrophage infiltration, major histocompatibility complex (MHC) expression, apoptosis, expression of cytokines, chemokines, and cytotoxic effectors. PEG‐fused PNAs exhibited attenuated innate and adaptive immune responses by 14–21 days postoperatively, as evidenced by (a) many axons and cells remaining viable, (b) significantly reduced infiltration of cytotoxic and total T cells and macrophages, (c) significantly reduced expression of inflammatory cytokines, chemokines, and MHC proteins, (d) consistently low apoptotic response. Morphologically and/or biochemically, PEG‐fused sciatic PNAs often resembled sciaticautograftsor intact sciatic nerves. In brief, PEG‐fused PNAs are an unstudied, perhaps unique, example of immune tolerance of viable allograft tissue in a nonimmune‐privileged environment and could greatly improve the clinical outcomes for PNIs relative to current protocols.