The Effects of Tacrolimus on Tissue-Specific, Protein-Level Inflammatory Networks in Vascularized Composite Allotransplantation.
The Effects of Tacrolimus on Tissue-Specific, Protein-Level Inflammatory Networks in Vascularized Composite Allotransplantation.
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他克莫司对血管化复合材料同种异体移植中组织特异性，蛋白质水平炎症网络的影响。
DOI：
10.3389/fimmu.2021.591154
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发表时间：
2021
影响因子：
7.3
通讯作者：
Vodovotz Y
中科院分区：
文献类型：
--
作者：
Aral AM;Zamora R;Barclay D;Yin J;El-Dehaibi F;Erbas VE;Dong L;Zhang Z;Sahin H;Gorantla VS;Vodovotz Y
血管化复合同种异体移植（VCA）后炎症事件的系统水平的见解是这些复杂程序的免疫调节策略的成功的关键。迄今为止，他克莫司（TAC）免疫抑制对VCA炎症网络的影响，如急性排斥反应（AR），尚未研究。我们使用系统生物学方法来阐明他克莫司在VCA后动态组织特异性免疫应答背景下对动态网络和全身性炎症的主要驱动因素的影响。刘易斯（LEW）大鼠受体接受来自完全主要组织相容性复合物不匹配的布朗挪威（BN）供体或匹配的LEW供体的原位后肢VCA。第1组（同基因对照组）接受LEW肢体无TAC，第2组（治疗组）接受BN肢体有TAC。使用主成分分析（PCA）、动态贝叶斯网络（DyBN）推断和动态网络分析（DyNA）分析皮肤、肌肉和外周血中27种炎症介质的时间依赖性变化，以定义全身性炎症的主要特征、中心节点和推定的反馈结构。对皮肤+肌肉数据重复分析以构建“虚拟VCA”，并对皮肤+肌肉+外周血数据重复分析以构建“虚拟动物”。来自个体组织的PCA、DyBN和DyNA结果表明，TAC处理后瘦素、VEGF、各种趋化因子、NLRP 3炎性体（IL-1β、IL-18）和IL-6发挥重要作用。趋化因子MCP-1、MIP-1α和IP-10与对照组AR相关。统计分析表明，24/27炎症介质之间的控制和TAC治疗的大鼠外周血，皮肤，和/或肌肉随时间的推移显着改变。“虚拟VCA”和“虚拟动物”分析表明皮肤是动态炎症网络的关键控制点，其连接性/复杂性随时间推移呈现U形轨迹，并反映在体循环中。我们的研究定义了TAC对VCA中动态炎症网络复杂时空演变的影响。我们还展示了计算分析的潜在效用，以阐明非线性，跨组织的相互作用。这些方法可能有助于定义精确医学方法，以更好地个性化VCA接受者的TAC免疫抑制。
Systems-level insights into inflammatory events after vascularized composite allotransplantation (VCA) are critical to the success of immunomodulatory strategies of these complex procedures. To date, the effects of tacrolimus (TAC) immunosuppression on inflammatory networks in VCA, such as in acute rejection (AR), have not been investigated. We used a systems biology approach to elucidate the effects of tacrolimus on dynamic networks and principal drivers of systemic inflammation in the context of dynamic tissue-specific immune responses following VCA. Lewis (LEW) rat recipients received orthotopic hind limb VCA from fully major histocompatibility complex-mismatched Brown Norway (BN) donors or matched LEW donors. Group 1 (syngeneic controls) received LEW limbs without TAC, and Group 2 (treatment group) received BN limbs with TAC. Time-dependent changes in 27 inflammatory mediators were analyzed in skin, muscle, and peripheral blood using Principal Component Analysis (PCA), Dynamic Bayesian Network (DyBN) inference, and Dynamic Network Analysis (DyNA) to define principal characteristics, central nodes, and putative feedback structures of systemic inflammation. Analyses were repeated on skin + muscle data to construct a “Virtual VCA”, and in skin + muscle + peripheral blood data to construct a “Virtual Animal.” PCA, DyBN, and DyNA results from individual tissues suggested important roles for leptin, VEGF, various chemokines, the NLRP3 inflammasome (IL-1β, IL-18), and IL-6 after TAC treatment. The chemokines MCP-1, MIP-1α; and IP-10 were associated with AR in controls. Statistical analysis suggested that 24/27 inflammatory mediators were altered significantly between control and TAC-treated rats in peripheral blood, skin, and/or muscle over time. “Virtual VCA” and “Virtual Animal” analyses implicated the skin as a key control point of dynamic inflammatory networks, whose connectivity/complexity over time exhibited a U-shaped trajectory and was mirrored in the systemic circulation. Our study defines the effects of TAC on complex spatiotemporal evolution of dynamic inflammation networks in VCA. We also demonstrate the potential utility of computational analyses to elucidate nonlinear, cross-tissue interactions. These approaches may help define precision medicine approaches to better personalize TAC immunosuppression in VCA recipients.
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影响因子：
17.1
作者：
Brown, David;Namas, Rami A.;Vodovotz, Yoram
通讯作者：
Vodovotz, Yoram
影响因子：
7.3
作者：
Day JD;Metes DM;Vodovotz Y
通讯作者：
Vodovotz Y
影响因子：
4.4
作者：
Fujita, Yoshimasa;Fujii, Takao;Umehara, Hisanori
通讯作者：
Umehara, Hisanori
DOI：
10.1084/jem.170.6.2081
发表时间：
1989-12-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fiorentino DF;Bond MW;Mosmann TR
通讯作者：
Mosmann TR
影响因子：
29.4
作者：
ELSON, CO;SARTOR, RB;RIDDELL, RH
通讯作者：
RIDDELL, RH