Introduction: The mammalian target of rapamycin (mTOR) is a central regulator of the immune system and therefore one target of immunosuppressive drug therapy. Tolerance-inducing properties have been attributed to inhibitors of mTOR (mTORIs). The present study investigated the differences in regulatory T cell (Treg) and dendritic cell (DC) subsets as well as on the immune balance in comparison to CNI-based immunotherapy following heart transplantation (HTx).

Methods: HTx patients, whose HTx was between 12 months and 5 years ago, with either mTORI- (n=14) or CNI-based immunotherapy (n=20) were included. Flow cytometric analyses for the DC subsets expressing BDCA-1, -2, -3, -4 and for the Treg subsets expressing CD39, CD62L, CD120b and CD147 were performed. The immune balance (IL-2, IL-4, IL-10, IFN-g and IL-17A) and IL-34 levels were detected by multiplexing using the Luminex 200™.

Results: Age at HTx (mTORI: 56.2±7.7yrs, CNI: 52.7±10.2yrs) and at study begin (mTORI: 61.6±7.1yrs, CNI: 56.6±10.6yrs) as well as gender (mTORI: 69% male, CNI: 71% male) were comparable in both groups. While the myeloid DC subsets which are positive for BDCA-1 or BDCA-3 were suppressed by mTORI (BDCA-1 p=0.05, BDCA-3 p=0.04), BDCA-2+ plasmacytoid DCs were increased by trend (mTORI: 60.0%±12.0%, CNI: 53.1%±10.8%, p=0.09). The total percentage of Tregs as well as the percentage of the CD39+ Treg subset was increased in HTx patients with mTORI-based immunosuppression compared to CNI-based immunosuppression (mTORI: 37.2%±17.2%, CNI: 26.7%±10.6%, p=0.03). Furthermore, serum levels of the pro- and anti-inflammatory cytokines IL-2, IL-4, IL-10 and IFN-g were higher in patients treated with CNI-based immunosuppression suggesting that these patients suffer from an immune imbalance. Additionally, CNI-treated patients had significantly more rejections of grade IB or higher (p=0.05) than mTORI-treated patients.

Conclusion: Inhibition of mTOR following HTx promotes changes of distinct tolerance-inducing cell subsets of Tregs and DCs, an immune imbalance determined by increased cytokine levels and a lower rate of rejections compared to CNI-treated patients.

CITATION INFORMATION: Dieterlen M.-T, Klaeske K, Fischer J, Hahn J, Jawad K, Garbade J, Mohr F, Lehmann S. Impact of mTOR-Inhibition on Tolerance-Induction Following Heart Transplantation. Am J Transplant. 2017;17 (suppl 3).

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