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

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 CDS, 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.