mTOR Inhibitors Reduce the Endothelial Transmigration of Leukocytes After Ischemia
Department of Thoracic and Cardiovascular Surgery, University Hospital Frankfurt, Frankfurt am Main, Germany.
Meeting: 2015 American Transplant Congress
Abstract number: C23
Keywords: Endothelial activation, Endothelial cells, Immunosuppression, Rejection
Session Information
Session Name: Poster Session C: Antigen Presenting Cells in Alloimmune Responses/B Cells and Antibody in Alloimmune Responses
Session Type: Poster Session
Date: Monday, May 4, 2015
Session Time: 5:30pm-6:30pm
Presentation Time: 5:30pm-6:30pm
Location: Exhibit Hall E
Objective
mTOR inhibitors Everolimus and Sirolimus are currently used as maintenance immunosuppressive agents to prevent rejection of solid transplanted organs. Episodes of transplant rejection and graft infiltration are associated to initial ischemia/reperfusion injury and endothelial damage. Early use of mTOR inhibitors has been recently advocated. Therefore, we investigated the protective role of Everolimus and Sirolimus in reducing the transendothelial migration of leukocytes and the endothelial dysfunction.
Methods
An ischemia/reperfusion injury model with human microvascular endothelial cells (EC) was designed to evaluate transendothelial migration of human circulating immune cells trough EC monolayers and endothelial nitric oxide synthase (eNOS) expression of EC. For the analysis, ECs were either in naïve condition or activated with IFN-γ /TNF-α for 24h. After cell activation EC were placed under hypoxic conditions (<2% O2) for 2h and were further treated before re-oxygenation with Everolimus (10ng/ml Certican® Novartis, Basel, Switzerland) or Sirolimus (10ng/ml Rapamune, Pfizer, NY, USA) for 2 and 24h. Untreated cells served as control and hypoxic cells served as positive control.
Results
Everolimus endothelial treatment significantly influenced the transmigration of immune cells after hypoxia. Irrespectively of the activation/inflammatory status of the EC, Everolimus treatment for 24h resulted in a significant reduction of cell migration compared to 2h treatment and to control (activated-EC: 2h 0.98±0.00tmx vs 24h 0.95±0.00tmx p=0.03, naïve-EC: 2h 0.99±0.00tmx vs. 24h 0.97±0.00tmx p=0.006). However, Sirolimus only caused a significant drop of migrated immune cells in case of naïve EC (naïve-EC: 2h 1.00±0.04tmx vs. 24h 0.98±0.00tmx p=0.01), but not in activated ECs. Additionally, the expression levels of eNOS in EC were preserved after treatment with mTOR inhibitors.
Conclusion
Sirolimus and Everolimus prevent the migration of immune cells through ECs after ischemia. This fact could explain a reduction of graft infiltration after immunosuppressive treatment. Furthermore, mTOR inhibitors are able to preserve endothelial function. The time dependent observed effects suggest that continued application of mTOR inhibitors after ischemia could have a protective effect.
To cite this abstract in AMA style:
Werner I, Hernandez-Sierra A, Guo F, Moritz A, Beiras-Fernandez A. mTOR Inhibitors Reduce the Endothelial Transmigration of Leukocytes After Ischemia [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/mtor-inhibitors-reduce-the-endothelial-transmigration-of-leukocytes-after-ischemia/. Accessed May 16, 2025.« Back to 2015 American Transplant Congress