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

Autor:	Aral AM; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States., Zamora R; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States.; Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States., Barclay D; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States., Yin J; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States., El-Dehaibi F; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States., Erbas VE; Department of Plastic, Reconstructive and Aesthetic Surgery, Medicalpark Gaziantep Hospital, Gaziantep, Turkey., Dong L; Plastic and Aesthetic Surgery Department, XiJing Hospital, Xi'an, China., Zhang Z; Plastic and Aesthetic Surgery Department, XiJing Hospital, Xi'an, China., Sahin H; Private Cagsu Hospital, Duzce, Turkey., Gorantla VS; Department of Surgery, Wake Forest Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston Salem, NC, United States., Vodovotz Y; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, United States.; Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2021 May 04; Vol. 12, pp. 591154. Date of Electronic Publication: 2021 May 04 (Print Publication: 2021).
DOI:	10.3389/fimmu.2021.591154
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Aral, Zamora, Barclay, Yin, El-Dehaibi, Erbas, Dong, Zhang, Sahin, Gorantla and Vodovotz.)
Databáze:	MEDLINE
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