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.