Anti-CD25 therapy affects the death signals of activated T-cells after clinical heart transplantation

Abstract

IL-2 was initially defined as the T-cell growth factor mediating allograft rejection. However, recent experimental studies have shown that IL-2 also regulates the mechanism by which the immune system eliminates activated T-cells. IL-2 is required for the apoptosis of antigen specific T-cells by upregulating FAS receptors. To define whether inhibition of the IL-2 pathway by immunosuppressive agents prevents activation induced cell death (AICD) of activated T-cells, we measured intragraft mRNA expression of IL-2, IL-15, CD25, FAS, FASL, and characterized the phenotype of graft infiltrating T-cells (CD3, CD25) by real time RT-PCR and immunohistochemistry, respectively. Analysis was performed in EMB (n536) from cardiac allograft recipients who were treated with anti-CD25 mAb induction therapy (Daclizumab, n58) or with placebo (n56), in combination with CsA, steroids, and mycophenolate mofetil. Treatment with anti-CD25 mAb significantly affected the IL-2 pathway. In the presence of circulating anti-CD25 mAb, the first 4 months post-transplant, extremely low intragraft IL-2, and CD25 mRNA transcription levels and low numbers of activated CD25 positive T-cells were found compared to the levels measured in EMB from placebo treated patients (5-10 fold, p, 0.0001). The inhibition of the IL-2 pathway during anti-CD25 mAb therapy was associated with reduced FASL mRNA expression and low numbers of CD3 positive T-cells in the graft. Significantly lower FASL mRNA expression levels and CD3 positive T-cells were measured in EMB of anti-CD25 mAb treated patients than in EMB from patients who received placebo (p50.01 and p50.02, respectively). No effect of anti-CD25 therapy was found on intragraft IL-15 and FAS mRNA expression levels. In conclusion, our data suggest that immune activation in the absence of IL-2 is associated with impaired apoptosis of activated T-cells in the graft. Manipulation of the immune system by immunosuppressive agents such as anti-CD25 mAb might prevent the induction of activation induced cell death (AICD) of alloreactive T-cells by hindering the IL-2 dependent FASL expression.