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Endocrine, Metabolic & Immune Disorders - Drug Targets

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ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

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Research Article

Acute Versus Chronic Administration of Calcineurin-Inhibitors Differentially Affect T-Cell Function

Author(s): Julia Kirchhof, Benjamin Wilde*, Justine Schmidt, Nils Mülling, Liubov Petrakova, Alexandra Brinkhoff, Manfred Schedlowski and Oliver Witzke

Volume 21, Issue 6, 2021

Published on: 31 August, 2020

Page: [1083 - 1089] Pages: 7

DOI: 10.2174/1871530320999200831161710

Price: $65

Abstract

Background: Calcineurin-inhibitors (CNI) are used in renal transplant patients (RTX) to prevent rejection. CNI mainly suppress T-cell mediated immunity but very little is known about the impact of long-term treatment with CNI on T-cell function.

Objective: We investigated the immunological effects of long-term CNI intake in RTX patients in comparison to short-term CNI administration in healthy controls (HC).

Methods: Blood was drawn from 30 RTX patients with long-term CNI treatment. In addition, blood was sampled from HC with short-term CNI treatment (four dosages) before the first and 2 hours after the last CsA intake. T-cells were analyzed for cytokine production, proliferation, and CD25 expression.

Results: Short-term CNI reduced T-cell derived IL-2 and IFNγ as well as T-cell proliferation in HC. IFNγ was not suppressed in patients with long-term CNI treatment. IL-2 production, CD25 expression, and T-cell proliferation were enhanced in long-term CNI patients.

Conclusion: Suppression of IFNγ/IL-2 and T-cell proliferation is weaker during long-term CNI treatment in patients compared to short-term treatment in healthy subjects. Enhanced CD25 expression may lower the threshold for T-cell activation during long-term CNI treatment.

Keywords: CD25, cyclosporine A, interleukin-2, renal transplantation, T-Cell, tacrolimus.

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[1]
Azzi, J.R.; Sayegh, M.H.; Mallat, S.G. Calcineurin inhibitors: 40 years later, can’t live without. J. Immunol., 2013, 191(12), 5785-5791.
[http://dx.doi.org/10.4049/jimmunol.1390055] [PMID: 24319282]
[2]
Halloran, P.F. Immunosuppressive drugs for kidney transplantation. N. Engl. J. Med., 2004, 351(26), 2715-2729.
[http://dx.doi.org/10.1056/NEJMra033540] [PMID: 15616206]
[3]
Liu, J.; Farmer, J.D., Jr; Lane, W.S.; Friedman, J.; Weissman, I.; Schreiber, S.L. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell, 1991, 66(4), 807-815.
[http://dx.doi.org/10.1016/0092-8674(91)90124-H] [PMID: 1715244]
[4]
Kang, H.G.; Zhang, D.; Degauque, N.; Mariat, C.; Alexopoulos, S.; Zheng, X.X. Effects of cyclosporine on transplant tolerance: the role of IL-2. Am. J. Transplant., 2007, 7(8), 1907-1916.
[http://dx.doi.org/10.1111/j.1600-6143.2007.01881.x] [PMID: 17617853]
[5]
Merino, D.; San Segundo, D.; Medina, J.M.; Rodrigo, E.; Asensio, E.; Irure, J.; Fernández-Fresnedo, G.; Arias, M.A.; López-Hoyos, M. Different in vitro proliferation and cytokine-production inhibition of memory T-cell subsets after calcineurin and mammalian target of rapamycin inhibitors treatment. Immunology, 2016, 148(2), 206-215.
[http://dx.doi.org/10.1111/imm.12603] [PMID: 26931075]
[6]
Tsuda, K.; Yamanaka, K.; Kitagawa, H.; Akeda, T.; Naka, M.; Niwa, K.; Nakanishi, T.; Kakeda, M.; Gabazza, E.C.; Mizutani, H. Calcineurin inhibitors suppress cytokine production from memory T cells and differentiation of naïve T cells into cytokine-producing mature T cells. PLoS One, 2012, 7(2), e31465.
[http://dx.doi.org/10.1371/journal.pone.0031465] [PMID: 22359594]
[7]
Liu, J. FK506 and cyclosporin, molecular probes for studying intracellular signal transduction. Immunol. Today, 1993, 14(6), 290-295.
[http://dx.doi.org/10.1016/0167-5699(93)90048-P] [PMID: 7691065]
[8]
Schreiber, S.L.; Crabtree, G.R. The mechanism of action of cyclosporin A and FK506. Immunol. Today, 1992, 13(4), 136-142.
[http://dx.doi.org/10.1016/0167-5699(92)90111-J] [PMID: 1374612]
[9]
Riella, L.V.; Alegre, M-L. Novel Role of Calcineurin Inhibitors in Curbing T Cells’ Sweet Tooth. Am. J. Transplant., 2018, 18(1), 3-3.
[http://dx.doi.org/10.1111/ajt.14606] [PMID: 29267999]
[10]
Vaeth, M.; Maus, M.; Klein-Hessling, S.; Freinkman, E.; Yang, J.; Eckstein, M.; Cameron, S.; Turvey, S.E.; Serfling, E.; Berberich-Siebelt, F.; Possemato, R.; Feske, S. Store-Operated Ca2+ Entry Controls Clonal Expansion of T Cells through Metabolic Reprogramming. Immunity, 2017, 47(4), 664-679.e6.
[http://dx.doi.org/10.1016/j.immuni.2017.09.003] [PMID: 29030115]
[11]
Daniel, V.; Naujokat, C.; Sadeghi, M.; Wiesel, M.; Hergesell, O.; Opelz, G. Association of circulating interleukin (IL)-12- and IL-10-producing dendritic cells with time posttransplant, dose of immunosuppression, and plasma cytokines in renal-transplant recipients. Transplantation, 2005, 79(11), 1498-1506.
[http://dx.doi.org/10.1097/01.TP.0000163470.83217.E6] [PMID: 15940038]
[12]
Daniel, V.; Naujokat, C.; Sadeghi, M.; Renner, F.C.; Weimer, R.; Opelz, G. Association of high IFN-γ plasma levels with low B-cell counts in renal transplant recipients with stable long-term graft function. Clin. Transplant., 2010, 24(2), 281-289.
[http://dx.doi.org/10.1111/j.1399-0012.2009.01067.x] [PMID: 19712086]
[13]
Albring, A.; Wendt, L.; Harz, N.; Engler, H.; Wilde, B.; Kribben, A.; Lindemann, M.; Schedlowski, M.; Witzke, O. Relationship between pharmacokinetics and pharmacodynamics of calcineurin inhibitors in renal transplant patients. Clin. Transplant., 2015, 29(4), 294-300.
[http://dx.doi.org/10.1111/ctr.12504] [PMID: 25557538]
[14]
de Mattos, A.M.; Olyaei, A.J.; Bennett, W.M. Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future. Am. J. Kidney Dis., 2000, 35(2), 333-346.
[http://dx.doi.org/10.1016/S0272-6386(00)70348-9] [PMID: 10676738]
[15]
Naesens, M.; Kuypers, D.R.; Sarwal, M. Calcineurin inhibitor nephrotoxicity. Clin. J. Am. Soc. Nephrol., 2009, 4(2), 481-508.
[http://dx.doi.org/10.2215/CJN.04800908] [PMID: 19218475]
[16]
Gijtenbeek, J.M.; van den Bent, M.J.; Vecht, C.J. Cyclosporine neurotoxicity: a review. J. Neurol., 1999, 246(5), 339-346.
[http://dx.doi.org/10.1007/s004150050360] [PMID: 10399863]
[17]
Albring, A.; Wendt, L.; Benson, S.; Nissen, S.; Yavuz, Z.; Engler, H.; Witzke, O.; Schedlowski, M. Preserving learned immunosuppressive placebo response: perspectives for clinical application. Clin. Pharmacol. Ther., 2014, 96(2), 247-255.
[http://dx.doi.org/10.1038/clpt.2014.75] [PMID: 24699032]
[18]
Sadeghi, M.; Daniel, V.; Naujokat, C.; Schmidt, J.; Mehrabi, A.; Zeier, M.; Opelz, G. Evidence for IFN-γ up- and IL-4 downregulation late post-transplant in patients with good kidney graft outcome. Clin. Transplant., 2007, 21(4), 449-459.
[http://dx.doi.org/10.1111/j.1399-0012.2007.00665.x] [PMID: 17645703]
[19]
Rostaing, L.; Puyoo, O.; Tkaczuk, J.; Peres, C.; Rouzaud, A.; Cisterne, J.M.; de Preval, C.; Ohayon, E.; Durand, D.; Abbal, M. Differences in Type 1 and Type 2 intracytoplasmic cytokines, detected by flow cytometry, according to immunosuppression (cyclosporine A vs. tacrolimus) in stable renal allograft recipients. Clin. Transplant., 1999, 13(5), 400-409.
[http://dx.doi.org/10.1034/j.1399-0012.1999.130506.x] [PMID: 10515221]
[20]
Häringer, B.; Lozza, L.; Steckel, B.; Geginat, J. Identification and characterization of IL-10/IFN-γ-producing effector-like T cells with regulatory function in human blood. J. Exp. Med., 2009, 206(5), 1009-1017.
[http://dx.doi.org/10.1084/jem.20082238] [PMID: 19414553]
[21]
Bouvy, A.P.; Klepper, M.; Kho, M.M.; Ijzermans, J.N.; Betjes, M.G.; Weimar, W.; Baan, C.C. T cells Exhibit Reduced Signal Transducer and Activator of Transcription 5 Phosphorylation and Upregulated Coinhibitory Molecule Expression After Kidney Transplantation. Transplantation, 2015, 99(9), 1995-2003.
[http://dx.doi.org/10.1097/TP.0000000000000674] [PMID: 25769075]
[22]
van de Wetering, J.; Koumoutsakos, P.; Peeters, A.; van der Mast, B.J.; de Kuiper, P.; IJzermans, J.N.; Weimar, W.; Baan, C.C. Discontinuation of calcineurin inhibitors treatment allows the development of FOXP3+ regulatory T-cells in patients after kidney transplantation. Clin. Transplant., 2011, 25(1), 40-46.
[http://dx.doi.org/10.1111/j.1399-0012.2010.01311.x] [PMID: 20636406]

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