Immunosuppression affects circulating follicular regulatory T cells in kidney transplant recipients
Carla C. Baan1, Qian Niu2, Aleixandra Mendoza Rojas1, Marjolein Dieterich1, LanLan Wang2, Teun van Gelder1, Dennis A. Hesselink1, Nicole M. van Besouw1.
1Department of Internal Medicine, Erasmus MC, Rotterdam, Netherlands; 2West China Hospital, Sichuan University, Chengdu, People's Republic of China
Background: FoxP3+ follicular regulatory T cells (Tfr) have been identified as the cell population controlling T follicular helper (Tfh) cells and B cells that are involved in effector immune responses against transplanted tissue.
Materials: To understand the biology of Tfr cells in kidney transplant patients receiving tacrolimus based immunosuppression, we measured circulating (c)Tfh and cTfr cells in peripheral blood at 5-7 years after transplantation by flow cytometry. Of this cohort 26% (58/227) had been treated for rejection of which 16% was diagnosed as T cell mediated rejection (TCMR), 7% as chronic (c)ABMR and 3% as mixed rejection. Median time after anti-rejection therapy was 4.9 years (range 0.4–7 years). Age and gender matched heathy individuals served as controls.
Results: While the absolute numbers of cTfh cells were comparable between kidney recipients and healthy controls, the numbers for cTfr cells were 46% lower in immunosuppressed recipients (median 8.8×106/mL vs. 16.2×106/mL, p<0.001). More importantly, the ratio of Tfr/Tfh was decreased, indicating a disruption of the balance between cTfh and cTfr cells. This shifted balance was observed for both non-rejectors and rejectors. Next, the impact of a previous anti-rejection therapy history on cTfr cells. After pulse steroid anti-rejection therapy 29% (median) fewer cTfr cells were measured, after IvIG a 40% reduction was found and five years after alemtuzumab therapy hardly any cTfr cells were present (p<0.01 for all group vs non-rejectors). No association with tacrolimus trough levels was found. The Tfr/Tfh ratio correlated with kidney function (eGFR: rs=0.15, p=0.03).
Conclusions: Our work shows that anti-rejection therapy significantly affects the number of cTfr cells in kidney transplant recipients. The observed profound, long lasting effects by these agents might dysregulate cTfr functions.
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