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PLoS One. 2014 Jun 13;9(6):e99926. doi: 10.1371/journal.pone.0099926. eCollection 2014.

Insights from computational modeling in inflammation and acute rejection in limb transplantation.

Author information

1
Department of Plastic, Reconstructive and Aesthetic Surgery, Innsbruck Medical University, Innsbruck, Austria.
2
Language Technologies Institute, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.
3
Division of Bioinformatics, Biocenter, Innsbruck Medical University, Innsbruck, Austria.
4
Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
5
Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria.
6
Department of Pathology, Innsbruck Medical University, Innsbruck, Austria.
7
Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
8
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.

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.

PMID:
24926998
PMCID:
PMC4057425
DOI:
10.1371/journal.pone.0099926
[Indexed for MEDLINE]
Free PMC Article
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