Everolimus-Induced Immune Effects after Heart Transplantation: A Possible Tool for Clinicians to Monitor Patients at Risk for Transplant Rejection

Abstract

Background: Patients treated with an inhibitor of the mechanistic target of rapamycin (mTORI) in a calcineurin inhibitor (CNI)-free immunosuppressive regimen after heart transplantation (HTx) show a higher risk for transplant rejection. We developed an immunological monitoring tool that may improve the identification of mTORI-treated patients at risk for rejection. Methods: Circulating dendritic cells (DCs) and regulatory T cells (Tregs) were analysed in 19 mTORI- and 20 CNI-treated HTx patients by flow cytometry. Principal component and cluster analysis were used to identify patients at risk for transplant rejection. Results: The percentages of total Tregs (p = 0.02) and CD39+ Tregs (p = 0.05) were higher in mTORI-treated patients than in CNI-treated patients. The principal component analysis revealed that BDCA1+, BDCA2+ and BDCA4+ DCs as well as total Tregs could distinguish between non-rejecting and rejecting mTORI-treated patients. Most mTORI-treated rejectors showed higher levels of BDCA2+ and BDCA4+ plasmacytoid DCs and lower levels of BDCA1+ myeloid DCs and Tregs than mTORI non-rejectors. Conclusion: An mTORI-based immunosuppressive regimen induced a sufficient, tolerance-promoting reaction in Tregs, but an insufficient, adverse effect in DCs. On the basis of patient-specific immunological profiles, we established a flow cytometry-based monitoring tool that may be helpful in identifying patients at risk for rejection.

Dendritic Cells: A Bridge between Tolerance Induction and Cancer Development in Transplantation Setting

“…Klaeske et al analyzed DCs derived from heart transplant recipients with mTORi- and CNI-based therapy to identify patients with an increased risk of rejection and observed higher levels of BDCA2 + and BDCA4 + pDCs and lower levels of BDCA1 + myeloid DCs in patients under an mTORi-based immunosuppressive regimen. They concluded that mTORi exerts an insufficient tolerance-promoting reaction in DCs, which could explain the increased risk of rejection in patients under mTORi-based therapy [ 107 ]. Mycophenolate mofetil (MMF) is a reversible inhibitor of inosine 5′-monophosphate dehydrogenase, which is a rate-limiting enzyme in the de novo synthesis of purines.…”