Immunosuppression Has Long-Lasting Effects on Circulating Follicular Regulatory T Cells in Kidney Transplant Recipients
Background: FoxP3+ follicular regulatory T cells (Tfr) have been identified as the cell population controlling T follicular helper (Tfh) cells and B cells which, are both involved in effector immune responses against transplanted tissue.Methods: To understand the biology of Tfr cells in kidney trans...
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Frontiers Media S.A.
2020-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.01972/full |
| _version_ | 1818341365850832896 |
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| author | Qian Niu Qian Niu Aleixandra Mendoza Rojas Aleixandra Mendoza Rojas Aleixandra Mendoza Rojas Marjolein Dieterich Marjolein Dieterich Dave L. Roelen Marian C. Clahsen-van Groningen Marian C. Clahsen-van Groningen Marian C. Clahsen-van Groningen Lanlan Wang Teun van Gelder Teun van Gelder Teun van Gelder Dennis A. Hesselink Dennis A. Hesselink Nicole M. van Besouw Nicole M. van Besouw Carla C. Baan Carla C. Baan |
| author_facet | Qian Niu Qian Niu Aleixandra Mendoza Rojas Aleixandra Mendoza Rojas Aleixandra Mendoza Rojas Marjolein Dieterich Marjolein Dieterich Dave L. Roelen Marian C. Clahsen-van Groningen Marian C. Clahsen-van Groningen Marian C. Clahsen-van Groningen Lanlan Wang Teun van Gelder Teun van Gelder Teun van Gelder Dennis A. Hesselink Dennis A. Hesselink Nicole M. van Besouw Nicole M. van Besouw Carla C. Baan Carla C. Baan |
| author_sort | Qian Niu |
| collection | DOAJ |
| description | Background: FoxP3+ follicular regulatory T cells (Tfr) have been identified as the cell population controlling T follicular helper (Tfh) cells and B cells which, are both involved in effector immune responses against transplanted tissue.Methods: To understand the biology of Tfr cells in kidney transplant patients treated with tacrolimus and mycophenolate mofetil (MMF) combination immunosuppression, we measured circulating (c)Tfh and cTfr cells in peripheral blood by flow cytometry in n = 211 kidney transplant recipients. At the time of measurement patients were 5–7 years after transplantation. Of this cohort of patients, 23.2% (49/211) had been previously treated for rejection. Median time after anti-rejection therapy was 4.9 years (range 0.4–7 years). Age and gender matched healthy individuals served as controls.Results: While the absolute numbers of cTfh cells were comparable between kidney transplant recipients and healthy controls, the numbers of cTfr cells were 46% lower in immunosuppressed recipients (p < 0.001). More importantly, in transplanted patients, the ratio of cTfr to cTfh was decreased (median; 0.10 vs. 0.06), indicating a disruption of the balance between cTfr and cTfh cells. This shifted balance was observed for both non-rejectors and rejectors. Previous pulse methylprednisolone or combined pulse methylprednisolone + intravenous immunoglobulin anti-rejection therapy led to a non-significant 30.6% (median) and 51.2% (median) drop in cTfr cells, respectively when compared to cTfr cell numbers in transplant patients who did not receive anti-rejection therapy. A history of alemtuzumab therapy did lead to a significant decrease in cTfr cells of 85.8% (median) compared with patients not treated with anti-rejection therapy (p < 0.0001). No association with tacrolimus or MMF pre-dose concentrations was found.Conclusion: This cross-sectional study reveals that anti-rejection therapy with alemtuzumab significantly lowers the number of cTfr cells in kidney transplant recipients. The observed profound effects by these agents might dysregulate cTfr functions. |
| first_indexed | 2024-12-13T15:57:39Z |
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| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-13T15:57:39Z |
| publishDate | 2020-08-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-497e142c88d241c6844ffd0e11838d1c2022-12-21T23:39:16ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-08-011110.3389/fimmu.2020.01972559167Immunosuppression Has Long-Lasting Effects on Circulating Follicular Regulatory T Cells in Kidney Transplant RecipientsQian Niu0Qian Niu1Aleixandra Mendoza Rojas2Aleixandra Mendoza Rojas3Aleixandra Mendoza Rojas4Marjolein Dieterich5Marjolein Dieterich6Dave L. Roelen7Marian C. Clahsen-van Groningen8Marian C. Clahsen-van Groningen9Marian C. Clahsen-van Groningen10Lanlan Wang11Teun van Gelder12Teun van Gelder13Teun van Gelder14Dennis A. Hesselink15Dennis A. Hesselink16Nicole M. van Besouw17Nicole M. van Besouw18Carla C. Baan19Carla C. Baan20Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, ChinaThe Rotterdam Transplant Group, Department of Internal Medicine–Nephrology & Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, NetherlandsThe Rotterdam Transplant Group, Department of Internal Medicine–Nephrology & Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, NetherlandsRotterdam Transplant Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, NetherlandsThe Rotterdam Transplant Group, Department of Clinical Pharmacology, University Medical Center Rotterdam, Rotterdam, NetherlandsThe Rotterdam Transplant Group, Department of Internal Medicine–Nephrology & Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, NetherlandsRotterdam Transplant Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, NetherlandsDepartment of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, NetherlandsThe Rotterdam Transplant Group, Department of Internal Medicine–Nephrology & Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, NetherlandsRotterdam Transplant Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, NetherlandsThe Rotterdam Transplant Group, Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, NetherlandsDepartment of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, ChinaThe Rotterdam Transplant Group, Department of Internal Medicine–Nephrology & Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, NetherlandsRotterdam Transplant Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, NetherlandsThe Rotterdam Transplant Group, Department of Clinical Pharmacology, University Medical Center Rotterdam, Rotterdam, NetherlandsThe Rotterdam Transplant Group, Department of Internal Medicine–Nephrology & Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, NetherlandsRotterdam Transplant Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, NetherlandsThe Rotterdam Transplant Group, Department of Internal Medicine–Nephrology & Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, NetherlandsRotterdam Transplant Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, NetherlandsThe Rotterdam Transplant Group, Department of Internal Medicine–Nephrology & Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, NetherlandsRotterdam Transplant Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, NetherlandsBackground: FoxP3+ follicular regulatory T cells (Tfr) have been identified as the cell population controlling T follicular helper (Tfh) cells and B cells which, are both involved in effector immune responses against transplanted tissue.Methods: To understand the biology of Tfr cells in kidney transplant patients treated with tacrolimus and mycophenolate mofetil (MMF) combination immunosuppression, we measured circulating (c)Tfh and cTfr cells in peripheral blood by flow cytometry in n = 211 kidney transplant recipients. At the time of measurement patients were 5–7 years after transplantation. Of this cohort of patients, 23.2% (49/211) had been previously treated for rejection. Median time after anti-rejection therapy was 4.9 years (range 0.4–7 years). Age and gender matched healthy individuals served as controls.Results: While the absolute numbers of cTfh cells were comparable between kidney transplant recipients and healthy controls, the numbers of cTfr cells were 46% lower in immunosuppressed recipients (p < 0.001). More importantly, in transplanted patients, the ratio of cTfr to cTfh was decreased (median; 0.10 vs. 0.06), indicating a disruption of the balance between cTfr and cTfh cells. This shifted balance was observed for both non-rejectors and rejectors. Previous pulse methylprednisolone or combined pulse methylprednisolone + intravenous immunoglobulin anti-rejection therapy led to a non-significant 30.6% (median) and 51.2% (median) drop in cTfr cells, respectively when compared to cTfr cell numbers in transplant patients who did not receive anti-rejection therapy. A history of alemtuzumab therapy did lead to a significant decrease in cTfr cells of 85.8% (median) compared with patients not treated with anti-rejection therapy (p < 0.0001). No association with tacrolimus or MMF pre-dose concentrations was found.Conclusion: This cross-sectional study reveals that anti-rejection therapy with alemtuzumab significantly lowers the number of cTfr cells in kidney transplant recipients. The observed profound effects by these agents might dysregulate cTfr functions.https://www.frontiersin.org/article/10.3389/fimmu.2020.01972/fullkidney transplantationantibody mediated rejectionanti-rejection therapydonor specific antibodiesflow cytometrycirculating Tfr |
| spellingShingle | Qian Niu Qian Niu Aleixandra Mendoza Rojas Aleixandra Mendoza Rojas Aleixandra Mendoza Rojas Marjolein Dieterich Marjolein Dieterich Dave L. Roelen Marian C. Clahsen-van Groningen Marian C. Clahsen-van Groningen Marian C. Clahsen-van Groningen Lanlan Wang Teun van Gelder Teun van Gelder Teun van Gelder Dennis A. Hesselink Dennis A. Hesselink Nicole M. van Besouw Nicole M. van Besouw Carla C. Baan Carla C. Baan Immunosuppression Has Long-Lasting Effects on Circulating Follicular Regulatory T Cells in Kidney Transplant Recipients Frontiers in Immunology kidney transplantation antibody mediated rejection anti-rejection therapy donor specific antibodies flow cytometry circulating Tfr |
| title | Immunosuppression Has Long-Lasting Effects on Circulating Follicular Regulatory T Cells in Kidney Transplant Recipients |
| title_full | Immunosuppression Has Long-Lasting Effects on Circulating Follicular Regulatory T Cells in Kidney Transplant Recipients |
| title_fullStr | Immunosuppression Has Long-Lasting Effects on Circulating Follicular Regulatory T Cells in Kidney Transplant Recipients |
| title_full_unstemmed | Immunosuppression Has Long-Lasting Effects on Circulating Follicular Regulatory T Cells in Kidney Transplant Recipients |
| title_short | Immunosuppression Has Long-Lasting Effects on Circulating Follicular Regulatory T Cells in Kidney Transplant Recipients |
| title_sort | immunosuppression has long lasting effects on circulating follicular regulatory t cells in kidney transplant recipients |
| topic | kidney transplantation antibody mediated rejection anti-rejection therapy donor specific antibodies flow cytometry circulating Tfr |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.01972/full |
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