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

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.

Identification of the immunological profile in rejection-free heart transplantation.

BACKGROUND: Tolerance induction following organ transplantation can be achieved by adoptive cell transfer of regulatory T-cells (Tregs) or dendritic cells (DCs). However, the target immunological profile is unknown. The present study aimed to identify an immunological profile connected to tolerance induction following heart transplantation (HTx). METHODS: Blood samples of long-term rejection-free HTx patients (LT-HTx, n = 20) and patients on the HTx waiting list (pre-HTx, n = 20) were compared. Flow cytometric and multiplex analyses of DCs, Tregs, subsets of both cell types and serum cytokines were performed. Furthermore, principle component and cluster analysis was used to identify a target immunological profile using a multiparametric dataset. RESULTS: Plasmacytoid DCs expressing blood DC antigen (BDCA) 2 and BDCA4 were significantly increased in LT-HTx patients (BDCA2+: 29.4 ±â€¯10.1%, p = .022; BDCA4+: 26.4 ±â€¯9.3%, p = .008) compared to pre-HTx patients (BDCA2+: 22.8 ±â€¯7.2%; BDCA4+: 18.9 ±â€¯7.4%). The percentage of total Tregs and of their CD62L+ subset was reduced in LT-HTx patients (%Tregs: 9.1 ±â€¯3.7%, p = .026; %CD62L+: 85.1 ±â€¯11.9%, p = .009) compared to pre-HTx patients (%Tregs: 11.8 ±â€¯3.6%; %CD62L+: 93.3 ±â€¯4.5%). LT-HTx patients showed different cytokine levels than pre-HTx patients. Principle component and cluster analysis revealed that the total DCs, BDCA2+ and BDCA4+ DCs and CD147+ Tregs had the strongest influence to distinguish among long-term rejection-free and pre-HTx patients. CONCLUSION: In conclusion, we defined the immune status of pre-HTx patients and the target immunological profile of LT-HTx patients. These data may help to establish a monitoring tool that is based on a multiparametric dataset.