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



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).



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.



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.
Department of Pathology, Rigshospitalet, Copenhagen, Denmark. Electronic address: RNZ440@alumni.ku.dk.
Kiran
K
Mirza
Department of Cardiology, Rigshospitalet, Copenhagen, Denmark.
Finn
F
Gustafsson
Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo.
Lars
L
Gullestad
Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, Faculty of Medicine, University of Oslo.
Satish
S
Arora
Department of Pathology, Rigshospitalet, Copenhagen, Denmark.
Claus
C
Andersen
D000328:Adult; D065095:Calcineurin Inhibitors / Q000627:therapeutic use*; D002908:Chronic Disease; D000068338:Everolimus / Q000627:therapeutic use*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006084:Graft Rejection / Q000276:immunology* / Q000469:parasitology; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000473:pathology*; D011446:Prospective Studies; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014184:Transplantation, Homologous; D018084:Ultrasonography, Interventional; D028761:Withholding Treatment
D065095:Calcineurin Inhibitors; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D000068338:Everolimus
Acute Cellular Rejection; Chronic Allograft Vasculopathy; Everolimus; FOXP3