ISHLT 2016 ANNUAL MEETING & SCIENTIFIC SESSIONS
April 27-30, 2016
Pushing New Scientific Frontiers: It’s In Our Heritage
Saturday April 30, 2016
10:55 : Precision Medicine in Organ Transplantation: Moving from Off the Rack to Bespoke, Alexandre Loupy, MD, PhD, Necker Hospital, Paris, France
Molecular Correlates of Endothelial mTOR Activation in Heart Transplant Recipients
Thursday April 28, 2016, CS-04 - Concurrent Session 04: Keep It Down: New Insights on Immunosuppression
11:45 - 12:00 PM:
M. Racapé1, A. Loupy1, J. Reeve2, J. Venner2, R. Guillemain3, L. Hidalgo2, C. Lefaucheur1, X. Jouven1, P. Bruneval3, J. Duong Van Huyen1, P. Halloran2. 1PARCC INSERM U970, Paris, France, 2ATAGC, University of Alberta, Edmonton, AB, Canada, 3Hôpital Européen Georges Pompidou, Paris, France,
Purpose: The detection of phosphorylated effectors of the mTOR pathway in endothelial cells by immunohistochemistry (IHC) has been associated with allograft rejection. The aim of this study was to evaluate in heart transplant recipients the molecular phenotype related to the endothelial detection of the phosphorylated effectors of the mTOR pathway, pS6RP.
Methods: This case-control study included 41 heart transplant patients from four French referral centers with biopsy proven antibody-mediated rejection (pAMR+) and a matched control group of 32 patients without rejection (pAMR0) based on the updated ISHLT classification. From these patients, 93 endomyocardial biopsies (EMB) had adequate material for microarray analysis and IHC. We studied in all EMB the endothelial expression of pS6RP by IHC. We also determined the allograft gene expression profile using the ABMR molecular score in addition to pathogenesis-based transcripts reflecting endothelial activation (DSAST and ENDAT), macrophage burden (QCMAT), gamma-interferon response (GRIT) and NK-cell burden (NKB) (http://atagc.med.ualberta.ca).
Results: Among the 93 EMBs included in main analyses, 49 were pAMR+ (52.7%) and 44 (47.3%) were pAMR0 normal EMBs. Endothelial expression of pS6RP was observed in 27/49 (55.1%) of pAMR+ biopsies and 12 out of 44 normal biopsies (27.3%, Fischer's exact: p=0.011). As compared with biopsies without endothelial pS6RP labeling, biopsies with positive endothelial pS6RP staining showed increased expression in DSAST (Mann-Whitney: p<0.0001), ENDAT (p=0.0008), QCMAT (p=0.0052), NKB (p=0.0001) and increased ABMR molecular score reflecting interferon-effects, microcirculation stress and NK burden (p=0.0001).
Conclusion: Endothelial activation of mTOR pathway is associated with antibody-mediated allograft rejection and increased expression in transcripts reflecting endothelial activation, macrophage burden, microcirculation and NK burden. Our results suggest the importance of the mTOR pathway activation in antibody-mediated heart allograft injury and the potential interest of using mTOR inhibitors in this setting.