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P-2.15 Immunosuppression affects circulating follicular regulatory T cells in kidney transplant recipients

Carla C. Baan, Netherlands

Head of laboratory
Internal Medicine
Erasmus MC, University, Medical Center

Biography


Carla C. Baan, PhD, is Professor and head of the Nephrology & Transplantation Laboratory at Erasmus Medical Center, University Hospital Rotterdam, The Netherlands. Dr Baan obtained her doctorate from Erasmus University, The Netherlands.
Her position involves the supervision of doctorate research related to the role of cytokines, regulatory T cells, B cells, cell therapy and immunosuppressive drugs in clinical organ transplantation.At the laboratory immunological tests to monitor pathways of donor directed reactivity are developed and used including multi-parameter flow cytometry/Facs sort and Elispot for T and B cell profiling, phosphospecific flow cytometry for the analysis of intracellular signaling pathways, cell culture assays to measure antigen specific proliferation & cytotoxicity, GWAS and PCR for gene expression and epigenetics, and immunohistochemistry.The aim of this translational work is to titrate the immunosuppressive burden on our patients in such a way that side-effects (infections, malignancies, cardiovascular events) are kept at a minimum while at the same time rejection processes are prevented.
Dr Baan has been the President of the European Society for Organ Transplantation (2011-2013) and has been a member of the board of the International Society for Heart and Lung Transplantation (2015-2016). Currently, dr Baan is the Executive Editor_Basic Sciences of the Transplantation Journal.

Abstract

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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