Apoptotic death of infiltrating cells in human cardiac allografts is regulated by IL-2, FASL, and FLIP

Abstract

Introduction In vitro studies have shown that apoptotic cell death is triggered by a IL-2–dependent activation of the Fas–FasL pathway and that this pathway can be inhibited by FLIP. Methods To define whether FLIP regulates apoptotic death of graft infiltrating T-cells during IL-2–mediated rejection, we analyzed endomyocardial biopsies (EMB) from cardiac allograft recipients for CD3, DNA strand breaks (TUNEL assay), FLIP (mRNA and protein), and FasL mRNA expression. Results Apoptosis was present in CD3 + T-cell infiltrates. The number of TUNEL-stained mononuclear cells was inversely correlated with FLIP mRNA expression levels ( P = .09). FLIP protein was present in 5% to 10% of the infiltrating cells and was constitutively produced by cardiomyocytes irrespective of the rejection grade. Rejection biopsies had elevated IL-2 and FasL mRNA expression levels compared to the expression levels before and after acute rejection ( P = .03 and P = .11), while FLIP mRNA expression levels were significantly decreased during rejection ( P = .05). Conclusion Our results indicate that during the IL-2–induced rejection process, infiltrated T cells become more sensitive to apoptosis.