Metallothionein: Localization in human transplant endomyocardium, relation to cytokines and allograft function

Background: The aim of this study was to investigate the role of metallothionein in cardiac transplants in relation to cytokines and allograft function. Recent studies have revealed an association of allograft dysfunction with elevated proinflammatory cytokines independent of cellular rejection. In animal experiments, cytokines induced overexpression of metallothionein, a low-molecular-weight protein implicated in cellular stress response. Methods: In 105 consecutive biopsies from 15 patients during the first 3 months after heart transplantation, metallothionein expression was investigated immunohistochemically. Its relation to serum interleukin-6, tumor necrosis factor-alpha, interleukin-2 (IL-2), soluble interleukin-2 receptor rejection, and echocardiographic parameters was determined. Forty-three biopsies of 12 patients with idiopathic ventricular tachycardia served as controls. Results: Metallothionein expression was demonstrated in small vessels, cardiomyocytes, fibrocytes, and interstitial round cells. A positive relation between interleukin-6 levels and the number of metallothionein-positive small vessels (p < 0.028) was observed. Patients with lower serum IL-2 levels showed significantly higher numbers of metallothionein-positive small vessels (p < 0.043). Grafts with prolonged ischemic time (>150 minutes) showed a significantly higher myocardial metallothionein score (p < 0.021). Metallothionein expression was associated with lower fractional shortening, larger left ventricular end-systolic diameter, and lower mean arterial pressure but not with acute cellular rejection. Conclusions: Metallothionein expression is associated with elevated interleukin-6 and decreased interleukin-2 serum levels and left ventricular allograft dysfunction in the absence of rejection.