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

• Published in: PloS one 2014-06, Vol.9 (6), p.e99926-e99926
• Main Authors: Wolfram, Dolores, Starzl, Ravi, Hackl, Hubert, Barclay, Derek, Hautz, Theresa, Zelger, Bettina, Brandacher, Gerald, Lee, W P Andrew, Eberhart, Nadine, Vodovotz, Yoram, Pratschke, Johann, Pierer, Gerhard, Schneeberger, Stefan
• Format: Article
• Language: English
• Subjects: Allografts; Alterations; Analysis; Animals; Arthritis; Biology and Life Sciences; Biomarkers; Biopsy; Bone grafts; Classification; Cluster analysis; Clustering; Computation; Computer applications; Computer Simulation; Cytokines; Diagnosis; Extremities - transplantation; Forests; Graft rejection; Graft Rejection - drug therapy; Graft Survival - drug effects; Graft Survival - immunology; Grafts; Immunology; Immunosuppression; Immunosuppressive Agents - therapeutic use; Immunotherapy; Inflammation; Interleukin 12; Interleukin 18; Interleukin 4; Interleukin-4 - metabolism; Laboratory animals; Male; Medicine and Health Sciences; Multiplexing; Muscles; Principal components analysis; Proteins; Rats; Regression analysis; Regression models; Rejection; Rodents; Skin; Skin - immunology; Skin care products; Syngeneic grafts; Tacrolimus; Tacrolimus - therapeutic use; Technology assessment; Thoracic surgery; Transplantation; Transplantation, Homologous; Transplants; Transplants & implants; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumor necrosis factor-α
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0099926

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.