Molecular Correlates of Endothelial mTOR Activation in Heart Transplants Recipients

M. Racape, A. Loupy, J. Reeve, J. Venner, R. Guillemain, L. Hidalgo, C. Lefaucheur, X. Jouven, P. Bruneval, P. Halloran, J. Duong.

Paris Transplant Group & ATAGC, Paris - Edmonton, France.

Meeting: 2015 American Transplant Congress

Abstract number: 168

Keywords: Heart transplant patients

Session Information

Session Name: Concurrent Session: Heart De-"Mystification": Rejection and Antibodies of All Types

Session Type: Concurrent Session

Date: Monday, May 4, 2015

Session Time: 2:15pm-3:45pm

Presentation Time: 3:03pm-3:15pm

Location: Room 118-C

Background

The detection of phosphorylated effectors of the mTOR pathway in endothelial cells has been associated with in allograft rejection in animal models. The aim of this study was to evaluate in heart transplant recipients the molecular phenotype related to the endothelial detection of pS6RP and p70SK phosphorylated effectors of the mTOR pathway.

Methods

This case control study included in four refferal centers, heart transplant patients with biopsy proven heart antibody-mediated rejection (ABMR) based on the updated ISHLT classification), having adequate endomyocardial (EMB) material for microarray analysis (n=59) and a matched control group of 28 patients without rejection (0R, pAMR0). We studied in all biopsies the endothelial expression of pS6RP and p70SK by IHC. In addition to this, we determined the allograft gene expression profile using the ABMR molecular Score in addition to pathogenesis-based transcripts reflecting endothelial activation (DSAST), macrophage burden (QCMAT), gamma-interferon response (GRIT) and T-cell burden (TCB) (http://atagc.med.ualberta.ca).

Results

Among the 87 cases included in main analyses, 59 were ABMRs (67.8%) and 28 (32.2%) were normal EMB. Endothelial expression of pS6RP and/or p70SK was observed in 42/59 (71%) of ABMR biopsies and 12 out of 28 normal biopsies (43%, p=0.02 as compared with ABMR). As compared with biopsies without endothelial p70S6K labelling, biopsies with positive endothelial p70S6K staining showed increased expression of DSAST (p=0.0079), GRIT (p=0.0157), TCB (p=0.0052) and increased ABMR molecular score reflecting interferon-effects, microcirculation stress and NK burden (p=0.0079). Biopsies with positive endothelial pS6RP staining showed with increased expression of DSAST transcripts (p=0.0001), GRIT (p=0.0003), TCB (p<0.0001), QCMAT (p=0.0023) and ABMR score (p<0.0001) as compared to biopsies without endothelial pS6RP labelling.

Conclusion

Endothelial activation of mTOR pathway is associated with antibody-mediated allograft rejection and increased expression of transcripts reflecting endothelial activation, gamma interferon response, microcirculation injury and NK burden. Our results suggest the importance of mTOR pathway activation in antibody-mediated heart allograft injury.

To cite this abstract in AMA style:

Racape M, Loupy A, Reeve J, Venner J, Guillemain R, Hidalgo L, Lefaucheur C, Jouven X, Bruneval P, Halloran P, Duong J. Molecular Correlates of Endothelial mTOR Activation in Heart Transplants Recipients [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/molecular-correlates-of-endothelial-mtor-activation-in-heart-transplants-recipients/. Accessed November 21, 2024.

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