Effect of everolimus initiation and early calcineurin inhibitor withdrawal on myocardial FOXP3+ regulatory T cells in heart transplantation

BACKGROUND: Through immunosuppression CD4+FoxP3+ regulatory T-cells (Tregs) play an indispensable role in allograft rejection. Post-HTx treatment with everolimus is associated with slower progression of cardiac allograft vasculopathy (CAV) - chronic rejection - than CNI based therapy. We hypothesized treatment with everolimus reduced the risk of CAV by modulating myocardial FoxP3 levels.

METHODS: 15 patients from the Schedule trial comparing everolimus, MMF, steroid and early CNI (Everolimus, n=8) withdrawal to conventional CNI based immunosuppression (Controls, n=7) after de novo HTx were included and FoxP3+ cells were quantified in 56 endomyocardial biopsies, and compared in the two patient groups. CAV was evaluated invasively using coronary intravascular ultrasound (IVUS).

RESULTS: Baseline FoxP3 biopsy levels were similar in the two groups. The Everolimus group showed a significant increase in Foxp3 densities from baseline to time of one-year follow-up (median (IQR)=4.8×10(-7)(20.4) Tregs/μm(2), P=0.046) while Controls showed no significant change (median (IQR)=3.1×10(-7)(6.5) Tregs/μm(2), P=0.116). At 1-month follow-up FoxP3 densities correlated with the observed change in TAV from baseline to time of 1-year follow-up (r=0.641, P=0.034). FoxP3 densities at 1-week predicted acute cellular rejection (ACR) levels at 1month (P=0.026). No other correlations with ACR were found.

CONCLUSION: Everolimus treatment combined with early CNI elimination is associated with increased densities of Tregs 12-months post-HTx compared to patients receiving CNI based regimen. Furthermore, the density of myocardial FoxP3+ cells early after transplantation appears to predict at least one measure of CAV burden after one year.