De novo expression of fetal ED-A+ fibronectin and B+ tenascin-C splicing variants in human cardiac allografts: potential impact for targeted therapy of rejection

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Abstract
Management of acute and especially chronic rejection after human cardiac transplantation is still challenging. Chronic rejection, represented by allograft vasculopathy (CAV) and cardiac interstitial fibrosis (CIF) is known to cause severe long-term complications. Rejection associated tissue-remodelling entails the reoccurrence of fetal variants of Fibronectin (Fn) and Tenascin-C (Tn-C), which are virtually absent in adult human organs. In a rat model, an extensive re-expression could be demonstrated for ED-A+ Fn with spatial association to CAV and CIF. Thus, it is of great interest to investigate the cardiac tissue expression and distribution in human samples. From 48 heart transplanted patients, 64 tissue specimens derived from right ventricular biopsies were available. Histopathological analysis was performed according to the International Society for Heart and Lung Transplantation (ISHLT) guidelines for the detection of acute rejection. By immunohistochemistry, protein expression of ED-A+ Fn, B+ Tn-C, alpha-smooth muscle actin, CD31 and CD45 was assessed and analysed semiquantitatively. Co-localisation studies were performed by means of immunofluorescence double labelling. Histopathological analysis of the 64 samples revealed different ISHLT grades (0R in 36 cases, 1R in 20 cases and 2R in 8 cases). There was a distinct and quantitatively relevant re-occurrence of ED-A+ Fn and B+ Tn-C in most samples. Semi-quantitative evaluation did not show any correlation to the acute rejection grade for all markers. Interestingly, significant correlations to the extent of inflammation could be shown for ED-A+ Fn (r = 0.442, p = 0.000) and B+ Tn-C (r = 0.408, p = 0.001) as well as between both proteins (r = 0.663, p = 0.000). A spatial association of ED-A+ Fn and B+ Tn-C to CAV and CIF could be demonstrated. A relevant re-occurrence of ED-A+ Fn and B+ Tn-C following human heart transplantation could be demonstrated with spatial association to signs of rejection and a significant correlation to tissue inflammation. These data might contribute to the identification of novel biomarkers reflecting the rejection process and to the development of promising strategies to image, prevent or treat cardiac rejection.

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