1. In vitro and in vivo evidence that the switch from calcineurin to mTOR inhibitors may be a strategy for immunosuppression in Epstein-Barr virus-associated post-transplant lymphoproliferative disorder.
- Author
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Thieme CJ, Schulz M, Wehler P, Anft M, Amini L, Blàzquez-Navarro A, Stervbo U, Hecht J, Nienen M, Stittrich AB, Choi M, Zgoura P, Viebahn R, Schmueck-Henneresse M, Reinke P, Westhoff TH, Roch T, and Babel N
- Subjects
- Humans, Herpesvirus 4, Human, Tacrolimus pharmacology, Tacrolimus therapeutic use, Calcineurin genetics, MTOR Inhibitors, Cyclosporine pharmacology, Cyclosporine therapeutic use, Mycophenolic Acid therapeutic use, Immunosuppression Therapy, Immunosuppressive Agents therapeutic use, Sirolimus pharmacology, Sirolimus therapeutic use, Prednisolone pharmacology, Prednisolone therapeutic use, TOR Serine-Threonine Kinases, Epstein-Barr Virus Infections drug therapy, Lymphoproliferative Disorders drug therapy, Lymphoproliferative Disorders etiology, Lymphoproliferative Disorders prevention & control
- Abstract
Post-transplant lymphoproliferative disorder is a life-threatening complication of immunosuppression following transplantation mediated by failure of T cells to control Epstein-Barr virus (EBV)-infected and transformed B cells. Typically, a modification or reduction of immunosuppression is recommended, but insufficiently defined thus far. In order to help delineate this, we characterized EBV-antigen-specific T cells and lymphoblastoid cell lines from healthy donors and in patients with a kidney transplant in the absence or presence of the standard immunosuppressants tacrolimus, cyclosporin A, prednisolone, rapamycin, and mycophenolic acid. Phenotypes of lymphoblastoid cell-lines and T cells, T cell-receptor-repertoire diversity, and T-cell reactivity upon co-culture with autologous lymphoblastoid cell lines were analyzed. Rapamycin and mycophenolic acid inhibited lymphoblastoid cell-line proliferation. T cells treated with prednisolone and rapamycin showed nearly normal cytokine production. Proliferation and the viability of T cells were decreased by mycophenolic acid, while tacrolimus and cyclosporin A were strong suppressors of T-cell function including their killing activity. Overall, our study provides a basis for the clinical decision for the modification and reduction of immunosuppression and adds information to the complex balance of maintaining anti-viral immunity while preventing acute rejection. Thus, an immunosuppressive regime based on mTOR inhibition and reduced or withdrawn calcineurin inhibitors could be a promising strategy for patients with increased risk of or manifested EBV-associated post-transplant lymphoproliferative disorder., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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