title: Insights from computational modeling in inflammation and acute rejection in limb transplantation.
abstract: Acute skin rejection in vascularized composite allotransplantation (VCA) is the major obstacle for wider adoption in clinical practice. This study utilized computational modeling to identify biomarkers for diagnosis and targets for treatment of skin rejection. Protein levels of 14 inflammatory mediators in skin and muscle biopsies from syngeneic grafts [n = 10], allogeneic transplants without immunosuppression [n = 10] and allografts treated with tacrolimus [n = 10] were assessed by multiplexed analysis technology. Hierarchical Clustering Analysis, Principal Component Analysis, Random Forest Classification and Multinomial Logistic Regression models were used to segregate experimental groups. Based on Random Forest Classification, Multinomial Logistic Regression and Hierarchical Clustering Analysis models, IL-4, TNF-α and IL-12p70 were the best predictors of skin rejection and identified rejection well in advance of histopathological alterations. TNF-α and IL-12p70 were the best predictors of muscle rejection and also preceded histopathological alterations. Principal Component Analysis identified IL-1α, IL-18, IL-1β, and IL-4 as principal drivers of transplant rejection. Thus, inflammatory patterns associated with rejection are specific for the individual tissue and may be superior for early detection and targeted treatment of rejection.
authors.affiliation: Department of Plastic, Reconstructive and Aesthetic Surgery, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Dolores
authors.initials: D
authors.lastname: Wolfram
authors.affiliation: Language Technologies Institute, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Ravi
authors.initials: R
authors.lastname: Starzl
authors.affiliation: Division of Bioinformatics, Biocenter, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Hubert
authors.initials: H
authors.lastname: Hackl
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Derek
authors.initials: D
authors.lastname: Barclay
authors.affiliation: Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Theresa
authors.initials: T
authors.lastname: Hautz
authors.affiliation: Department of Pathology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Bettina
authors.initials: B
authors.lastname: Zelger
authors.affiliation: Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Gerald
authors.initials: G
authors.lastname: Brandacher
authors.affiliation: Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: W P Andrew
authors.initials: WP
authors.lastname: Lee
authors.affiliation: Department of Plastic, Reconstructive and Aesthetic Surgery, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Nadine
authors.initials: N
authors.lastname: Eberhart
authors.affiliation: Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Vodovotz
authors.affiliation: Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Johann
authors.initials: J
authors.lastname: Pratschke
authors.affiliation: Department of Plastic, Reconstructive and Aesthetic Surgery, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Pierer
authors.affiliation: Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria; Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schneeberger
mesh_terms: D000818:Animals; D003198:Computer Simulation; D005121:Extremities / Q000637:transplantation*; D006084:Graft Rejection / Q000188:drug therapy*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D015847:Interleukin-4 / Q000378:metabolism; D008297:Male; D051381:Rats; D012867:Skin / Q000276:immunology; D016559:Tacrolimus / Q000627:therapeutic use; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D016559:Tacrolimus