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Immune Recovery

Sequential recovery of NK cell receptor repertoire after allogeneic hematopoietic SCT

Bone Marrow Transplantation volume 45, pages 1022–1030 (2010)Cite this article

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Abstract

Alloreactivity of natural killer (NK) cells contributes to the GVL reaction after allogeneic hematopoietic SCT (allo-HSCT). However, various procedure-related factors may affect NK cell maturation and their ability to recognize and kill leukemic cells. In this study, we prospectively evaluated expression of NK cell inhibitory receptors in 83 adults treated with myeloablative, killer cell Ig-like receptor (KIR)-ligand-matched allo-HSCT. NK cell maturation was evaluated by comparing the phenotypic patterns after allo-HSCT with the donor ones. The frequencies of KIR3DL1 were comparable to the donor ones on day +28, while they decreased significantly starting from day +100. The expression of KIR2DL2/3 was significantly lower in patients compared with donors up to day +100. The expression of KIR2DL1, despite continues growth, remained significantly decreased for 1 year after allo-HSCT. NKG2A was over-expressed up to day +180. Within 1 year after allo-HSCT, the NK cell phenotypic pattern tended to recapitulate the donor type. The process was disturbed by the use of steroids with significant differences observed on days +56 (P=0.01) and +100 (P=0.04). Up to day +100, reconstitution of NK cell receptor repertoire correlated with the absolute numbers of circulating CD3+, CD3+CD4+ and CD3+CD8+ cells. Our observations should be taken into account when trying to predict potential benefit from NK cell alloreactivity.

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References

  1. Farag SS, Fehniger TA, Ruggeri L, Velardi A, Caligiuri MA . Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect. Blood 2002; 100: 1935–1947.

    Article  CAS  Google Scholar 

  2. Valiante NM, Uhrberg M, Shilling HG, Lienert-Weidenbach K, Arnett KL, D’Andrea A et al. Functionally and structurally distinct NK cell receptor repertoires in the peripheral blood of two human donors. Immunity 1997; 7: 739–751.

    Article  CAS  PubMed  Google Scholar 

  3. Shilling HG, Guethlein LA, Cheng NW, Gardiner CM, Rodriguez R, Tyan D et al. Allelic polymorphism synergizes with variable gene content to individualize human KIR genotype. J Immunol 2002; 168: 2307–2315.

    Article  CAS  PubMed  Google Scholar 

  4. 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: 2097–2100.

    Article  CAS  Google Scholar 

  5. 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: 814–819.

    Article  CAS  Google Scholar 

  6. 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.

    Article  CAS  PubMed  Google Scholar 

  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: 2594–2600.

    Article  CAS  PubMed  Google Scholar 

  8. Elmaagacli AH, Ottinger H, Koldehoff M, Peceny R, Steckel NK, Trenschel R et al. Reduced risk for molecular disease in patients with chronic myeloid leukemia after transplantation from a KIR-mismatched donor. Transplantation 2005; 79: 1741–1747.

    Article  CAS  PubMed  Google Scholar 

  9. De Santis D, Bishara A, Witt CS, Nagler A, Brautbar C, Slavin S et al. Natural killer cell HLA-C epitopes and killer cell immunoglobulin-like receptors both influence outcome of mismatched unrelated donor bone marrow transplants. Tissue Antigens 2005; 65: 519–528.

    Article  CAS  PubMed  Google Scholar 

  10. Schaffer M, Malmberg KJ, Ringden O, Ljunggren HG, Remberger M . Increased infection-related mortality in KIR-ligand-mismatched unrelated allogeneic hematopoietic stem-cell transplantation. Transplantation 2004; 78: 1081–1085.

    Article  PubMed  Google Scholar 

  11. 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: 3825–3827.

    Article  CAS  PubMed  Google Scholar 

  12. Bornhauser M, Schwerdtfeger R, Martin H, Frank KH, Theuser C, Ehninger G . Role of KIR ligand incompatibility in hematopoietic stem cell transplantation using unrelated donors. Blood 2004; 103: 2860–2861.

    Article  PubMed  Google Scholar 

  13. Kroger N, Binder T, Zabelina T, Wolschke C, Schieder H, Renges H et al. Low number of donor activating killer immunoglobulin-like receptors (KIR) genes but not KIR-ligand mismatch prevents relapse and improves disease-free survival in leukemia patients after in vivo T-cell depleted unrelated stem cell transplantation. Transplantation 2006; 82: 1024–1030.

    Article  PubMed  Google Scholar 

  14. Bishara A, De Santis D, Witt CC, Brautbar C, Christiansen FT, Or R et al. The beneficial role of inhibitory KIR genes of HLA class I NK epitopes in haploidentically mismatched stem cell allografts may be masked by residual donor-alloreactive T cells causing GVHD. Tissue Antigens 2004; 63: 204–211.

    Article  CAS  PubMed  Google Scholar 

  15. Farag SS, Bacigalupo A, Eapen M, Hurley C, Dupont B, Caligiuri MA . 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: 876–884.

    Article  CAS  Google Scholar 

  16. 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: 315–328.

    Article  CAS  PubMed  Google Scholar 

  17. 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: 62–66.

    Article  CAS  PubMed  Google Scholar 

  18. Huang XJ, Zhao XY, Liu DH, Liu KY, Xu LP . Deleterious effects of KIR ligand incompatibility on clinical outcomes in haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion. Leukemia 2007; 21: 848–851.

    Article  CAS  PubMed  Google Scholar 

  19. Locatelli F, Velardi A, Giebel S . The role of NK alloreactivity on the outcome of patients who received transplants from unrelated volunteers is influenced by different disease-and transplant-related variables. Blood 2004; 103: 2862.

    CAS  Google Scholar 

  20. 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: 4370–4376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Vago L, Forno B, Sormani MP, Crocchiolo R, Zino E, Di Terlizzi S et al. Temporal, quantitative, and functional characteristics of single-KIR-positive alloreactive natural killer cell recovery account for impaired graft-versus-leukemia activity after haploidentical hematopoietic stem cell transplantation. Blood 2008; 112: 3488–3499.

    Article  CAS  PubMed  Google Scholar 

  22. Nguyen S, Dhedin N, Vernant JP, Kuentz M, Al Jijakli A, Rouas-Freiss N et al. NK-cell reconstitution after haploidentical hematopoietic stem-cell transplantations: immaturity of NK cells and inhibitory effect of NKG2A override GvL effect. Blood 2005; 105: 4135–4142.

    Article  CAS  PubMed  Google Scholar 

  23. Zhao XY, Huang XJ, Liu KY, Xu LP, Liu DH . Reconstitution of natural killer cell receptor repertoires after unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation: analyses of CD94:NKG2A and killer immunoglobulin-like receptor expression and their associations with clinical outcome. Biol Blood Marrow Transplant 2007; 13: 734–744.

    Article  CAS  PubMed  Google Scholar 

  24. Shilling HG, McQueen KL, Cheng NW, Shizuru JA, Negrin RS, Parham P . Reconstitution of NK cell receptor repertoire following HLA-matched hematopoietic cell transplantation. Blood 2003; 101: 3730–3740.

    Article  CAS  PubMed  Google Scholar 

  25. Holowiecki J, Giebel S, Wojnar J, Krawczyk-Kulis M, Markiewicz M, Holowiecka-Goral A et al. Treosulfan and fludarabine low-toxicity conditioning for allogeneic haematopoietic stem cell transplantation in chronic myeloid leukaemia. Br J Haematol 2008; 142: 284–292.

    Article  CAS  PubMed  Google Scholar 

  26. Casper J, Knauf W, Blau I, Ruutu T, Volin L, Wandt H et al. Treosulfan/fludarabine: a new conditioning regimen in allogeneic transplantation. Ann Hematol 2004; 83 (Suppl 1): 70–71.

    Google Scholar 

  27. Giebel S, Nowak I, Wojnar J, Markiewicz M, Dziaczkowska J, Wylezol I et al. Impact of activating killer immunoglobulin-like receptor genotype on outcome of unrelated donor—hematopoietic cell transplantation. Transpl Proc 2006; 38: 287–291.

    Article  CAS  Google Scholar 

  28. Giebel S, Nowak I, Dziaczkowska J, Czerw T, Wojnar J, Krawczyk-Kulis M et al. Activating killer immunoglobulin-like receptor incompatibilities enhance graft-versus host disease and affect survival after allogeneic hematopoietic stem cell transplantation. Eur J Haematol 2009; 83: 343–356.

    Article  CAS  PubMed  Google Scholar 

  29. Gooley TA, Leisenring W, Crowley J, Storer BE . Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 1999; 18: 695–706.

    Article  CAS  PubMed  Google Scholar 

  30. Niederwieser D, Gastl G, Rumpold H, Marth C, Kraft D, Huber C . Rapid reappearance of large granular lymphocytes (LGL) with concomitant reconstitution of natural killer (NK) activity after human bone marrow transplantation (BMT). Br J Haematol 1987; 65: 301–305.

    Article  CAS  PubMed  Google Scholar 

  31. Savani BN, Mielke S, Adams S, Uribe M, Rezvani K, Yong AS et al. Rapid natural killer cell recovery determines outcome after T-cell-depleted HLA-identical stem cell transplantation in patients with myeloid leukemias but not with acute lymphoblastic leukemia. Leukemia 2007; 21: 2145–2152.

    Article  CAS  PubMed  Google Scholar 

  32. Jacobs R, Stoll M, Stratmann G, Leo R, Link H, Schmidt RE . CD16- CD56+ natural killer cells after bone marrow transplantation. Blood 1992; 79: 3239–3244.

    CAS  PubMed  Google Scholar 

  33. Fehniger TA, Shah MH, Turner MJ, VanDeusen JB, Whitman SP, Cooper MA et al. Differential cytokine and chemokine gene expression by human NK cells following activation with IL-18 or IL-15 in combination with IL-12: implications for the innate immune response. J Immunol 1999; 162: 4511–4520.

    CAS  PubMed  Google Scholar 

  34. Fischer JC, Ottinger H, Ferencik S, Sribar M, Punzel M, Beelen DW et al. Relevance of C1 and C2 epitopes for hemopoietic stem cell transplantation: role for sequential acquisition of HLA-C-specific inhibitory killer Ig-like receptor. J Immunol 2007; 178: 3918–3923.

    Article  CAS  PubMed  Google Scholar 

  35. Nguyen S, Kuentz M, Vernant JP, Dhedin N, Bories D, Debré P et al. Involvement of mature donor T cells in the NK cell reconstitution after haploidentical hematopoietic stem-cell transplantation. Leukemia 2008; 22: 344–352.

    Article  CAS  PubMed  Google Scholar 

  36. Giebel S, Dziaczkowska J, Wojnar J, Krawczyk-Kulis M, Markiewicz M, Kruzel T et al. The impact of immunosuppressive therapy on an early quantitative NK cell reconstitution after allogeneic haematopoietic cell transplantation. Ann Transplant 2005; 10: 29–33.

    PubMed  Google Scholar 

  37. Vitale C, Chiossone L, Cantoni C, Morreale G, Cottalasso F, Moretti S et al. The corticosteroid-induced inhibitory effect on NK cell function reflects down-regulation and/or dysfunction of triggering receptors involved in natural cytotoxicity. Eur J Immunol 2004; 34: 3028–3038.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was performed in the Department of Hematology and Bone Marrow Transplantation of the Silesian Medical University in Katowice. Contributions of colleagues involved in clinical care were Dr Miroslaw Markiewicz, Dr Iwona Wylezol, Dr Lucja Kachel, Dr Maria Sadus-Wojciechowska and Dr Marek Seweryn, as well as for immunphenotyping was Dr Krystyna Jagoda, is appreciated. This study was supported by the grant No. 2 PO5B 155 28 from the Polish Ministry of Science and Higher Education.

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Authors and Affiliations

  1. Department of Clinical and Experimental Oncology, Division of Bone Marrow Transplantation and Lymphoma, Comprehensive Cancer Centre, Maria Sklodowska-Curie Memorial Institute—Gliwice Branch, Gliwice, Poland

    S Giebel, A Holowiecka & J Holowiecki

  2. Department of Hematology and Bone Marrow Transplantation, Silesian Medical University, Katowice, Poland

    S Giebel, J Dziaczkowska, T Czerw, J Wojnar, M Krawczyk-Kulis, A Holowiecka, S Kyrcz-Krzemien & J Holowiecki

  3. Department of Clinical Immunology, Laboratory of Immunogenetics and Tissue Immunology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland

    I Nowak & P Kusnierczyk

  4. Department of Mathematics, University of Pavia, Pavia, Italy

    A Segatti

  5. Jan Dlugosz Pedagogical University, Czestochowa, Poland

    P Kusnierczyk

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  1. S Giebel
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Correspondence to S Giebel.

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Giebel, S., Dziaczkowska, J., Czerw, T. et al. Sequential recovery of NK cell receptor repertoire after allogeneic hematopoietic SCT. Bone Marrow Transplant 45, 1022–1030 (2010). https://doi.org/10.1038/bmt.2009.384

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