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.
Highlights
Rejection in Vascular Composite Allotransplantation (VCA) is characterized by an inflammatory cell-mediated cytotoxic process, which progressively harms the epidermis and the junction between dermis and epidermis, unless reversed or prevented by immunosuppression
On postoperative day 7, rejection Grade II was present in 7 animals (70%) and rejection Grade III in 3 animals (30%)
On postoperative days (POD) 5, biopsies from allogeneic transplants displayed group showed a mild rejection (Grade I) rejection in three animals, as well as a moderate to severe perivascular inflammation with or without mild epidermal and/or adnexal epidermal dyskeratosis or apoptosis (Grade II) in three animals
Summary
Rejection in Vascular Composite Allotransplantation (VCA) is characterized by an inflammatory cell-mediated cytotoxic process, which progressively harms the epidermis and the junction between dermis and epidermis, unless reversed or prevented by immunosuppression. Understanding the immune signaling patterns of skin rejection would enable the development of targeted and local therapy with fewer side effects. The current gold standard for the diagnosis of rejection is histological evaluation of tissue biopsies according to the BANFF 2007 working classification [1]. Assessing rejection by histology suffers from latency between initiation of tissue damage and diagnosis. Histological signs of skin rejection have been found in protocol biopsies despite absence of clinical signs of rejection. As stated previously by our group and others, the histopathological alterations associated with rejection are not specific, but rather similar to several common inflammatory dermatoses [2,3] or the result of an inflammatory trigger [4]. The differential diagnosis between skin rejection, infection and unspecific inflammation can be challenging in hand- and especially face transplantation. The conditions are similar in their appearance and may interfere with or trigger each other [5]
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