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High Mutation Frequency of the PIGA Gene in T Cells Results In High Mutation Frequency of the PIGA Gene in T Cells Results in Reconstitution of GPI A nchor−/CD52− T Cells That Can Give Early Immune Protection after This information is current as Alemtuzumab-Based T Cell−Depleted of October 1, 2021. Allogeneic Stem Cell Transplantation Floris C. Loeff, J. H. Frederik Falkenburg, Lois Hageman, Wesley Huisman, Sabrina A. J. Veld, H. M. Esther van Egmond, Marian van de Meent, Peter A. von dem Borne, Hendrik Veelken, Constantijn J. M. Halkes and Inge Jedema Downloaded from J Immunol published online 2 February 2018 http://www.jimmunol.org/content/early/2018/02/02/jimmun ol.1701018 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2018/02/02/jimmunol.170101 Material 8.DCSupplemental Why The JI? Submit online. by guest on October 1, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published February 2, 2018, doi:10.4049/jimmunol.1701018 The Journal of Immunology High Mutation Frequency of the PIGA Gene in T Cells Results in Reconstitution of GPI Anchor2/CD522 T Cells That Can Give Early Immune Protection after Alemtuzumab- Based T Cell–Depleted Allogeneic Stem Cell Transplantation Floris C. Loeff,* J. H. Frederik Falkenburg,* Lois Hageman,* Wesley Huisman,*,† Sabrina A. J. Veld,* H. M. Esther van Egmond,* Marian van de Meent,* Peter A. von dem Borne,* Hendrik Veelken,* Constantijn J. M. Halkes,*,1 and Inge Jedema*,1 Alemtuzumab (ALM) is used for T cell depletion in the context of allogeneic hematopoietic stem cell transplantation (alloSCT) to Downloaded from prevent acute graft-versus-host disease and graft rejection. Following ALM-based T cell–depleted alloSCT, relatively rapid recovery of circulating T cells has been described, including T cells that lack membrane expression of the GPI-anchored ALM target Ag CD52. We show, in a cohort of 89 human recipients of an ALM-based T cell–depleted alloSCT graft, that early lymphocyte reconstitution always coincided with the presence of large populations of T cells lacking CD52 membrane expression. In contrast, loss of CD52 expression was not overt within B cells or NK cells. We show that loss of CD52 expression from the T cell membrane resulted from loss of GPI anchor expression caused by a highly polyclonal mutational landscape in the http://www.jimmunol.org/ PIGA gene. This polyclonal mutational landscape in the PIGA gene was also found in CD522 T cells present at a low frequency in peripheral blood of healthy donors. Finally, we demonstrate that the GPI2/CD522 T cell populations that arise after ALM-based T cell–depleted alloSCT contain functional T cells directed against multiple viral targets that can play an important role in immune protection early after ALM-based T cell–depleted transplantation. The Journal of Immunology, 2018, 200: 000–000. llogeneic hematopoietic stem cell transplantation reduce the risk for graft rejection and GvHD. Postponed appli- (alloSCT) is being used in the treatment of patients with a cation of donor lymphocyte infusions is used to induce therapeutic variety of malignant and nonmalignant hematological GvT and conversion to full donor chimerism (4, 5). A by guest on October 1, 2021 diseases. The goal of alloSCT is to replace a patient’s hemato- Alemtuzumab (ALM; Campath-1H), a humanized therapeutic poiesis (including the malignancy) with cells derived from a IgG1 Ab, has been successfully used for in vivo and in vitro T cell healthy donor by administration of a hematopoietic stem cell depletion in the alloSCT setting for several decades (6, 7). ALM graft. T cells derived from patient and donor play a major role in targets the GPI-anchored protein CD52 that is expressed on all the effectiveness and toxicity of this treatment. Although recog- mature lymphocytes but not (or only marginally) on hematopoietic nition of residual malignant cells by donor T cells can induce a stem cells (8). Although ALM induces profound depletion therapeutic graft-versus-tumor effect (GvT) (1), recognition of of lymphocytes, relatively rapid recovery of circulating T cells can nonhematopoietic healthy tissue by these donor T cells can result be observed after ALM-based in vitro T cell–depleted alloSCT. in detrimental graft-versus-host disease (GvHD) (2, 3). In contrast, Moreover, reconstitution of populations of T cells completely recognition of donor hematopoiesis by residual patient T cells lacking CD52 membrane expression has been described (9, 10). may induce graft rejection. Depletion strategies, for patient and The mechanism underlying this lack of CD52 expression and the donor T cells before transplantation, have been developed to effect on the functionality of these T cells are not known. *Department of Hematology, Leiden University Medical Center, 2333ZA Leiden, the designed, performed, analyzed, and interpreted experiments, designed and supervised Netherlands; and †Department of Hematopoiesis, Sanquin Research, 1066CX the study, and wrote the manuscript. All authors revised and edited the manuscript. Amsterdam, the Netherlands The sequences presented in this article have been submitted to the European Nucle- 1C.J.M.H. and I.J. share senior authorship. otide Archive database (http://www.ebi.ac.uk/ena/data/view/PRJEB24004) under accession number PRJEB24004. ORCIDs: 0000-0001-7059-2038 (F.C.L.); 0000-0002-5699-7087 (W.H.); 0000-0002- 7470-7346 (P.A.v.d.B.). Address correspondence and reprint requests to Floris C. Loeff, Department of Hematology, Laboratory for Experimental Hematology, Leiden University Medical Received for publication July 13, 2017. Accepted for publication January 9, 2018. Center, P.O. Box 9600, zone C2-R, 2300 RC Leiden, the Netherlands. E-mail address: This work was supported by the Frank Sanderse Stichting and the Doelfonds Leu- [email protected] kemie van de Bontius Stichting. W.H. was supported by the Sanquin Blood Supply The online version of this article contains supplemental material. Foundation (PPOC 15-37). Abbreviations used in this article: alloSCT, allogeneic hematopoietic stem cell F.C.L. designed, performed, analyzed, and interpreted experiments and wrote the transplantation; ALM, alemtuzumab; EBV-LCL, EBV-transformed lymphoblastoid manuscript; J.H.F.F. obtained patient consent and samples, recorded clinical data, cell; GvHD, graft-versus-host disease; GvT, graft-versus-tumor effect; MA, myeloa- designed and supervised the study, and wrote the manuscript; L.H., W.H., S.A.J.V., blative; NMA, nonmyeloablative; PacBlue, Pacific Blue; PB, peripheral blood; H.M.E.v.E., and M.v.d.M. performed experiments; P.A.v.d.B. and H.V. obtained pa- PETxR, PE–Texas Red; PNH, paroxysmal nocturnal hemoglobinuria; tNGFR, trun- tient consent and samples and recorded clinical data; C.J.M.H. designed and inter- cated form of the nerve growth factor receptor; UD, unrelated donor; wt, wild-type. preted experiments, obtained patient consent and samples, recorded and analyzed clinical data, designed and supervised the study, and wrote the manuscript; and I.J. Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1701018 2 PIGA MUTATIONS CAUSE CD52 LOSS IN DONOR T CELLS The aims of this study were to comprehensively analyze to what an unrelated donor (UD), patients received 15 mg of ALM (MabCampath; extent CD522 lymphocytes contribute to early lymphocyte recon- Sanofi Genzyme, Naarden, the Netherlands) i.v. at days 26and25. NMA 2 2 stitution in recipients of an ALM-based T cell–depleted alloSCT and conditioning consisted of 15 mg of ALM i.v. at days 4and 3, fludar- abine, and i.v. busulfan. Nine NMA-conditioned patients with a UD also to unravel the mechanism underlying the loss of CD52 membrane received antithymocyte globulin (thymoglobulin, 1 or 2 mg/kg at day 22, expression. We show, in a cohort of 89 patients with hematological Supplemental Table I). Patients received an allogeneic G-CSF–mobilized diseases treated with an ALM-based T cell–depleted alloSCT, that peripheral stem cell graft (n = 86) or a bone marrow graft (n = 3). All grafts reconstitution of CD522 cells is common within the CD4 and the were subjected to T cell depletion by the addition of 20 mg of ALM “to the bag” (11). Cyclosporin, as posttransplantation immune suppression, was only CD8 T cell compartments, but not within the B cell and NK cell given to MA-conditioned patients with a UD, starting at day 21andtapered compartments. We demonstrate that loss of CD52 expression from off from day 30 onward. PB was collected for direct routine clinical eval- the membrane of these cells did not result from loss of CD52 gene uation, and PBMCs were isolated by Ficoll-isopaque separation and cry- expression but, instead, from loss of GPI anchor expression. In turn, opreserved for later scientific evaluation. loss of GPI anchor expression resulted from a highly polyclonal CD52 and GPI anchor expression analysis mutational landscape in the PIGA gene, one of the genes essential 2 2 PBMCs were thawed, and CD52 membrane expression was analyzed on for GPI anchor biosynthesis. We show that GPI /CD52 PIGA + + + + CD4 and CD8 T cells (gating on CD3 CD4 or CD3 CD8 cells, re- mutant T cells are also present at low frequencies in peripheral blood 2 + 2 2 spectively), NK cells (gating on CD3 CD56 cells), and B cells (gating on (PB) of healthy donors.
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