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.

Neurotoxin from Naja naja atra venom inhibits skin allograft rejection in rats

“…As a major outcome of immune rejection, allograft survival is always a focus of studies [38]. In our study, both NNAV and NTX significantly prolonged the survival time of allografts (Fig.…”

Immune activation- and regulation-related patterns in stable hand transplant recipients

“…There are no reports of peripheral blood Notch signaling in hand transplant recipients except for our present report. TNF‐alpha in kidney transplantation as well as in animal model of limb transplantation was one of the best predictors of rejection and also preceded histopathological alterations . CD8 identifies cytotoxic/suppressor T cells.…”

Acute rejection in vascularized composite allotransplantation

“…Furthermore, differential diagnosis from other causes of skin inflammation is challenging and in some cases not feasible. Recently, Wolfram et al [69] identified biomarkers for early and specific detection of acute rejection as well as differentiation from other inflammatory diseases. Computational modeling offered the potential of identifying tissue-specific mediators that could assist in diagnosis and identify new therapeutic targets [69].…”

“…Recently, Wolfram et al [69] identified biomarkers for early and specific detection of acute rejection as well as differentiation from other inflammatory diseases. Computational modeling offered the potential of identifying tissue-specific mediators that could assist in diagnosis and identify new therapeutic targets [69]. Although these studies are intriguing, there is no current and direct applicability to clinical care.…”