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The Effects of Tacrolimus on Tissue-Specific, Protein-Level Inflammatory Networks in Vascularized Composite Allotransplantation

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...

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Autores principales: Aral, Ali Mubin, Zamora, Ruben, Barclay, Derek, Yin, Jinling, El-Dehaibi, Fayten, Erbas, Vasil E., Dong, Liwei, Zhang, Zhaoxiang, Sahin, Huseyin, Gorantla, Vijay S., Vodovotz, Yoram
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129572/
https://www.ncbi.nlm.nih.gov/pubmed/34017323
http://dx.doi.org/10.3389/fimmu.2021.591154
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author Aral, Ali Mubin
Zamora, Ruben
Barclay, Derek
Yin, Jinling
El-Dehaibi, Fayten
Erbas, Vasil E.
Dong, Liwei
Zhang, Zhaoxiang
Sahin, Huseyin
Gorantla, Vijay S.
Vodovotz, Yoram
author_facet Aral, Ali Mubin
Zamora, Ruben
Barclay, Derek
Yin, Jinling
El-Dehaibi, Fayten
Erbas, Vasil E.
Dong, Liwei
Zhang, Zhaoxiang
Sahin, Huseyin
Gorantla, Vijay S.
Vodovotz, Yoram
author_sort Aral, Ali Mubin
collection PubMed
description 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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spelling pubmed-81295722021-05-19 The Effects of Tacrolimus on Tissue-Specific, Protein-Level Inflammatory Networks in Vascularized Composite Allotransplantation Aral, Ali Mubin Zamora, Ruben Barclay, Derek Yin, Jinling El-Dehaibi, Fayten Erbas, Vasil E. Dong, Liwei Zhang, Zhaoxiang Sahin, Huseyin Gorantla, Vijay S. Vodovotz, Yoram Front Immunol Immunology 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. Frontiers Media S.A. 2021-05-04 /pmc/articles/PMC8129572/ /pubmed/34017323 http://dx.doi.org/10.3389/fimmu.2021.591154 Text en Copyright © 2021 Aral, Zamora, Barclay, Yin, El-Dehaibi, Erbas, Dong, Zhang, Sahin, Gorantla and Vodovotz https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Aral, Ali Mubin
Zamora, Ruben
Barclay, Derek
Yin, Jinling
El-Dehaibi, Fayten
Erbas, Vasil E.
Dong, Liwei
Zhang, Zhaoxiang
Sahin, Huseyin
Gorantla, Vijay S.
Vodovotz, Yoram
The Effects of Tacrolimus on Tissue-Specific, Protein-Level Inflammatory Networks in Vascularized Composite Allotransplantation
title The Effects of Tacrolimus on Tissue-Specific, Protein-Level Inflammatory Networks in Vascularized Composite Allotransplantation
title_full The Effects of Tacrolimus on Tissue-Specific, Protein-Level Inflammatory Networks in Vascularized Composite Allotransplantation
title_fullStr The Effects of Tacrolimus on Tissue-Specific, Protein-Level Inflammatory Networks in Vascularized Composite Allotransplantation
title_full_unstemmed The Effects of Tacrolimus on Tissue-Specific, Protein-Level Inflammatory Networks in Vascularized Composite Allotransplantation
title_short The Effects of Tacrolimus on Tissue-Specific, Protein-Level Inflammatory Networks in Vascularized Composite Allotransplantation
title_sort effects of tacrolimus on tissue-specific, protein-level inflammatory networks in vascularized composite allotransplantation
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129572/
https://www.ncbi.nlm.nih.gov/pubmed/34017323
http://dx.doi.org/10.3389/fimmu.2021.591154
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