Abstract
The role of killer immunoglobulin-like receptor–ligand mismatch (KIR–ligand mismatch) between donors and recipients undergoing cord blood transplantation (CBT) is controversial. If each immunosuppressant differently affects natural killer (NK) cell function, the effect of KIR–ligand mismatch may be altered depending on the type of graft versus host disease (GVHD) prophylaxis. To verify this hypothesis, the difference in the effect of KIR–ligand mismatch was retrospectively assessed between patients who received CBT for acute leukemia, myelodysplastic syndrome, or chronic myeloid leukemia, as well as GVHD prophylaxis comprising tacrolimus plus methotrexate (MTX) or mycophenolate mofetil (MMF). In the MMF group (n = 1363), KIR–ligand mismatch augmented the incidence of non-relapse mortality (NRM; hazard ratio [HR], 1.40; P = 0.008), which worsened overall survival (OS; HR, 1.30, P = 0.0077). In the analysis of each KIR–ligand mismatch type, HLA-C2 mismatch had a favorable effect on relapse incidence (HR, 0.56; P = 0.0043) and OS (HR, 0.72; P = 0.037) only in the MTX group. In the MMF group, HLA-A3/A11 mismatch worsened NRM (HR, 1.93; P < 0.001) and OS (HR, 1.48; P = 0.014). These results imply that the effects of KIR–ligand mismatch differ with the type of GVHD prophylaxis and that assessing the KIR–ligand mismatch status is important for CBT.
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References
Leung W. Use of NK cell activity in cure by transplant. Br J Haematol. 2011;155:14–29.
Ruggeri L, Capanni M, Casucci M, Volpi I, Tosti A, Perruccio K, et al. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Blood. 1999;94:333–9.
Giebel S, Locatelli F, Lamparelli T, Velardi A, Davies S, Frumento G, et al. Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors. Blood. 2003;102:814–9.
Morishima Y, Yabe T, Matsuo K, Kashiwase K, Inoko H, Saji H, et al. Effects of HLA allele and killer immunoglobulin-like receptor ligand matching on clinical outcome in leukemia patients undergoing transplantation with T-cell-replete marrow from an unrelated donor. Biol Blood Marrow Transplant. 2007;13:315–28.
Yabe T, Matsuo K, Hirayasu K, Kashiwase K, Kawamura-Ishii S, Tanaka H, et al. Donor killer immunoglobulin-like receptor (KIR) genotype-patient cognate KIR ligand combination and antithymocyte globulin preadministration are critical factors in outcome of HLA-C-KIR ligand-mismatched T cell-replete unrelated bone marrow transplantatio. Biol Blood Marrow Transplant. 2008;14:75–87.
Willemze R, Rodrigues CA, Labopin M, Sanz G, Michel G, Socié G, et al. KIR-ligand incompatibility in the graft-versus-host direction improves outcomes after umbilical cord blood transplantation for acute leukemia. Leukemia. 2009;23:492–500.
Brunstein CG, Wagner JE, Weisdorf DJ, Cooley S, Noreen H, Barker JN, et al. Negative effect of KIR alloreactivity in recipients of umbilical cord blood transplant depends on transplantation conditioning intensity. Blood. 2009;113:5628–34.
Tanaka J, Morishima Y, Takahashi Y, Yabe T, Oba K, Takahashi S, et al. Effects of KIR ligand incompatibility on clinical outcomes of umbilical cord blood transplantation without ATG for acute leukemia in complete remission. Blood Cancer J. 2013;3:e164.
Rocha V, Ruggeri A, Spellman S, Wang T, Sobecks R, Locatelli F, et al. Killer cell immunoglobulin-like receptor-ligand matching and outcomes after unrelated cord blood transplantation in acute myeloid leukemia. Biol Blood Marrow Transplant. 2016;22:1284–9.
Yokoyama H, Kanda J, Kawahara Y, Uchida N, Tanaka M, Takahashi S, et al. Reduced leukemia relapse through cytomegalovirus reactivation in killer cell immunoglobulin-like receptor-ligand-mismatched cord blood transplantation. Bone Marrow Transplant. 2021;56:1352–63.
Wang H, Grzywacz B, Sukovich D, McCullar V, Cao Q, Lee AB, et al. The unexpected effect of cyclosporin A on CD56+CD16- and CD56+CD16+ natural killer cell subpopulations. Blood. 2007;110:1530–9.
Ohata K, Espinoza JL, Lu X, Kondo Y, Nakao S. Mycophenolic acid inhibits natural killer cell proliferation and cytotoxic function: a possible disadvantage of including mycophenolate mofetil in the graft-versus-host disease prophylaxis regimen. Biol Blood Marrow Transplant. 2011;17:205–13.
Atsuta Y, Suzuki R, Yoshimi A, Gondo H, Tanaka J, Hiraoka A, et al. Unification of hematopoietic stem cell transplantation registries in Japan and establishment of the TRUMP System. Int J Hematol. 2007;86:269–74.
Atsuta Y. Introduction of Transplant Registry Unified Management Program 2 (TRUMP2): scripts for TRUMP data analyses, part I (variables other than HLA-related data). Int J Hematol. 2016;103:3–10.
Kanda J. Scripts for TRUMP data analyses. Part II (HLA-related data): statistical analyses specific for hematopoietic stem cell transplantation. Int J Hematol. 2016;103:11–9.
Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant. 2009;15:1628–33.
Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.
Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295:2097–100.
Farag SS, Bacigalupo A, Eapen M, Hurley C, Dupont B, Caligiuri MA, et al. The effect of KIR ligand incompatibility on the outcome of unrelated donor transplantation: a report from the center for international blood and marrow transplant research, the European blood and marrow transplant registry, and the Dutch registry. Biol Blood Marrow Transplant. 2006;12:876–84.
Hsu KC, Gooley T, Malkki M, Pinto-Agnello C, Dupont B, Bignon J-D, et al. KIR ligands and prediction of relapse after unrelated donor hematopoietic cell transplantation for hematologic malignancy. Biol Blood Marrow Transplant. 2006;12:828–36.
Davies SM, Ruggieri L, DeFor T, Wagner JE, Weisdorf DJ, Miller JS, et al. Evaluation of KIR ligand incompatibility in mismatched unrelated donor hematopoietic transplants. Killer immunoglobulin-like receptor. Blood. 2002;100:3825–7.
Beelen DW, Ottinger HD, Ferencik S, Elmaagacli AH, Peceny R, Trenschel R, et al. Genotypic inhibitory killer immunoglobulin-like receptor ligand incompatibility enhances the long-term antileukemic effect of unmodified allogeneic hematopoietic stem cell transplantation in patients with myeloid leukemias. Blood. 2005;105:2594–600.
Sivula J, Volin L, Porkka K, Vettenranta K, Itälä M, Partanen J, et al. Killer-cell immunoglobulin-like receptor ligand compatibility in the outcome of Finnish unrelated donor hematopoietic stem cell transplantation. Transpl Immunol. 2007;18:62–6.
Terakura S, Kuwatsuka Y, Yamasaki S, Wake A, Kanda J, Inamoto Y, et al. GvHD prophylaxis after single-unit reduced intensity conditioning cord blood transplantation in adults with acute leukemia. Bone Marrow Transplant. 2017;52:1261–7.
Terakura S, Wake A, Inamoto Y, Murata M, Sakai R, Yamaguchi T, et al. Exploratory research for optimal GvHD prophylaxis after single unit CBT in adults: short-term methotrexate reduced the incidence of severe GvHD more than mycophenolate mofetil. Bone Marrow Transplant. 2017;52:423–30.
Lowe EJ, Turner V, Handgretinger R, Horwitz EM, Benaim E, Hale GA, et al. T-cell alloreactivity dominates natural killer cell alloreactivity in minimally T-cell-depleted HLA-non-identical paediatric bone marrow transplantation. Br J Haematol. 2003;123:323–6.
Cooley S, McCullar V, Wangen R, Bergemann TL, Spellman S, Weisdorf DJ, et al. KIR reconstitution is altered by T cells in the graft and correlates with clinical outcomes after unrelated donor transplantation. Blood. 2005;106:4370–6.
Nguyen S, Achour A, Souchet L, Vigouroux S, Chevallier P, Furst S, et al. Clinical impact of NK-cell reconstitution after reduced intensity conditioned unrelated cord blood transplantation in patients with acute myeloid leukemia: analysis of a prospective phase II multicenter trial on behalf of the Société Française de Greffe d. Bone Marrow Transplant. 2017;52:1428–35.
Dekojová T, Houdová L, Fatka J, Pitule P, Ostašov P, Caputo VS, et al. Dynamic changes of inhibitory killer-immunoglobulin-like receptors on NK cells after allogeneic hematopoietic stem cell transplantation: an initial study. J Clin Med. 2020;9:E3502.
Zhao XY, Yu XX, Xu ZL, Cao XH, Huo MR, Zhao XS, et al. Donor and host coexpressing KIR ligands promote NK education after allogeneic hematopoietic stem cell transplantation. Blood Adv. 2019;3:4312–25.
Gumperz JE, Valiante NM, Parham P, Lanier LL, Tyan D. Heterogeneous phenotypes of expression of the NKB1 natural killer cell class I receptor among individuals of different human histocompatibility leukocyte antigens types appear genetically regulated, but not linked to major histocompatibililty complex haplotype. J Exp Med. 1996;183:1817–27.
Gardiner CM, Guethlein LA, Shilling HG, Pando M, Carr WH, Rajalingam R, et al. Different NK cell surface phenotypes defined by the DX9 antibody are due to KIR3DL1 gene polymorphism. J Immunol. 2001;166:2992–3001.
Boudreau JE, Mulrooney TJ, Le Luduec J-B, Barker E, Hsu KC. KIR3DL1 and HLA-B density and binding calibrate NK education and response to HIV. J Immunol. 2016;196:3398–410.
Boudreau JE, Giglio F, Gooley TA, Stevenson PA, Le Luduec J-B, Shaffer BC, et al. KIR3DL1/HLA-B subtypes govern acute myelogenous leukemia relapse after hematopoietic cell transplantation. J Clin Oncol. 2017;35:2268–78.
Petersdorf EW, Carrington M, O’hUigin C, Bengtsson M, De Santis D, Dubois V, et al. Role of HLA-B exon 1 in graft-versus-host disease after unrelated haemopoietic cell transplantation: a retrospective cohort study. Lancet Haematol. 2020;7:e50–e60.
Petersdorf EW, Gooley T, Volt F, Kenzey C, Madrigal A, McKallor C, et al. Use of the HLA-B leader to optimize cord-blood transplantation. Haematologica. 2020; https://doi.org/10.3324/haematol.2020.264424.
Acknowledgements
The authors would like to thank all the physicians and data managers who provided valuable data available from the Japanese Society for Transplantation and Cellular Therapy. The authors would also like to thank the staff at the Japanese Data Center for Hematopoietic Cell Transplantation for their contributions.
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HY, MH, YT, ST, and SM designed the study. NU, MT, MO, YO, DO, YK, AW, MS, HK, YM, and KO collected the data. TK, JK, TF, and YA managed the data. HY, MH, YT, ST, and SM analyzed and interpreted the data. HY wrote the first draft of the manuscript. ST and SM were responsible for the GvHD Working Group and HLA Working Group of JSHCT. All the authors reviewed and revised the manuscript.
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Yokoyama, H., Hirayama, M., Takahashi, Y. et al. Altered effect of killer immunoglobulin-like receptor–ligand mismatch by graft versus host disease prophylaxis in cord blood transplantation. Bone Marrow Transplant 56, 3059–3067 (2021). https://doi.org/10.1038/s41409-021-01469-6
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DOI: https://doi.org/10.1038/s41409-021-01469-6