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NK cells in allogeneic bone marrow transplantation

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Abstract

NK cells, until recently an ignored subset of lymphocytes, have begun to emerge as important cytotoxic effectors. It is now accepted that NK cells together with T cells constitute major actors in graft-versus-leukemia reaction after allogeneic bone marrow transplantation (BMT). Over the last several years the mechanisms regulating the activation of NK cells have been the subject of intense investigations encouraged by the clinical implications that these studies will have. This article provides a general overview of NK-cells biology and regulation pertinent to their function in allogeneic BMT, followed by a review of the in vivo preclinical and clinical evidence for the beneficial effect of NK cells in the adoptive immunotherapy of leukemia.

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References

  1. Asai O, Longo DL, Tian ZG, Hornung RL, Taub DD, Ruscetti FW, Murphy WJ (1998) Suppression of graft-versus-host disease and amplification of graft-versus-tumor effects by activated natural killer cells after allogeneic bone marrow transplantation. J Clin.Invest 101:1835–1842

    CAS  Google Scholar 

  2. Ashkar AA, Di Santo JP, Croy BA (2000) Interferon gamma contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy. J Exp Med 192:259–270

    Article  CAS  PubMed  Google Scholar 

  3. Bakker AB, Wu J, Phillips JH, Lanier LL (2000) NK cell activation: distinct stimulatory pathways counterbalancing inhibitory signals. Hum Immunol 61:18–27

    Article  CAS  PubMed  Google Scholar 

  4. Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T (1999) Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285:727–729

    Article  PubMed  Google Scholar 

  5. Bensussan A (1998) The human natural killer lymphocyte receptors for MHC class I molecules. Eur Cytokine Netw 9:577–583

    CAS  PubMed  Google Scholar 

  6. BlEry M., Olcese L, Vivier E (2000) Early signaling via inhibitory and activating NK receptors. Hum Immunol 61:51–64

    CAS  PubMed  Google Scholar 

  7. Bolland S, Ravetch JV (1999) Inhibitory pathways triggered by ITIM-containing receptors. Adv Immunol 72:149–177

    CAS  PubMed  Google Scholar 

  8. Carayol G, Giron-Michel J, Azzarone B, Castagna L, Cambier N, Mishal Z, Bourhis JH, Chouaib S, Caignard A (2000) Altered natural killer cell differentiation in CD34+ progenitors from chronic myeloid leukemia patients. Oncogene 19:2758–2766

    Article  CAS  PubMed  Google Scholar 

  9. Carayol G., Robin C,.Bourhis JH, Bennaceur-Griscelli A, Chouaib S, Coulombel L, Caignard A (1998) NK cells differentiated from bone marrow, cord blood and peripheral blood stem cells exhibit similar phenotype and functions. Eur J Immunol 28:1991–2002

    CAS  PubMed  Google Scholar 

  10. Champlin RE., Passweg JR, Zhang MJ, Rowlings PA, Pelz CJ, Atkinson KA, Barrett AJ, Cahn JY, Drobyski WR, Gale RP, Goldman JM, Gratwohl A, Gordon-Smith EC, Henslee-Downey PJ, Herzig RH, Klein JP, Marmont AM, O'Reilly RJ, Ringden O, Slavin S, Sobocinski KA, Speck B, Weiner RS, Horowitz MM (2000) T-cell depletion of bone marrow transplants for leukemia from donors other than HLA-identical siblings: advantage of T-cell antibodies with narrow specificities. Blood 95:3996–4003

    CAS  PubMed  Google Scholar 

  11. Colonna,M., Navarro F, Bellon T, Llano M, Garcia P, Samaridis J, Angman L, Cella M, Lopez-Botet M (1997) A common inhibitory receptor for major histocompatibility complex class I molecules on human lymphoid and myelomonocytic cells. J Exp.Med 186:1809–1818

    CAS  PubMed  Google Scholar 

  12. Colonna M, Samaridis J (1995) Cloning of immunoglobulin-superfamily members associated with HLA-C and HLA-B recognition by human natural killer cells. Science 268:405–408

    CAS  PubMed  Google Scholar 

  13. Cooper MA, Fehniger TA, Caligiuri MA (2001) The biology of human natural killer-cell subsets. Trends Immunol 22:633–640

    CAS  PubMed  Google Scholar 

  14. Crocker PR, Varki A (2001) Siglecs, sialic acids and innate immunity. Trends Immunol 22:337–342

    Article  CAS  PubMed  Google Scholar 

  15. Cosman D, Mullberg J, Sutherland CL, Chin W, Armitage R, Fanslow W, Kubin M, Chalupny NJ (2001) ULBPs, novel MHC class I–related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 14:123–133

    CAS  PubMed  Google Scholar 

  16. Costello RT, Sivori S, Marcenaro E, Lafage-Pochitaloff M, Mozziconacci MJ, Reviron D, Gastaut JA, Pende D, Olive D, Moretta A (2002) Defective expression and function of natural killer cell-triggering receptors in patients with acute myeloid leukemia. Blood 99:3661–3667

    Article  CAS  PubMed  Google Scholar 

  17. Dietrich J, Cella M, Colonna M (2001) Ig-like transcript 2 (ILT2)/leukocyte Ig-like receptor 1 (LIR1) inhibits TCR signaling and actin cytoskeleton reorganization. J Immunol 166:2514–2521

    CAS  PubMed  Google Scholar 

  18. Djeu JY, Jiang K, Wei S (2002) A view to a kill: signals triggering cytotoxicity. Clin Cancer Res 8:636–640

    CAS  PubMed  Google Scholar 

  19. Dorfman JR, Raulet DH (1998) Acquisition of Ly49 receptor expression by developing natural killer cells. J Exp Med 187:609–618

    Article  CAS  PubMed  Google Scholar 

  20. Drobyski WR, Klein J, Flomenberg N, Pietryga D, Vesole DH, Margolis DA, Keever–Taylor CA (2002) Superior survival associated with transplantation of matched unrelated versus one-antigen-mismatched unrelated or highly human leukocyte antigen-disparate haploidentical family donor marrow grafts for the treatment of hematologic malignancies: establishing a treatment algorithm for recipients of alternative donor grafts. Blood 99:806–814

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. Fehniger TA, Caligiuri MA (2001) Interleukin 15: biology and relevance to human disease. Blood 97:14–32

    CAS  PubMed  Google Scholar 

  23. Gumperz JE, Valiante NM, Parham P, Lanier LL, Tyan D (1996) 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 183:1817–1827

    PubMed  Google Scholar 

  24. Held W, Kunz B (1998) An allele-specific, stochastic gene expression process controls the expression of multiple Ly49 family genes and generates a diverse, MHC-specific NK cell receptor repertoire. Eur J Immunol 28:2407–2416

    Google Scholar 

  25. Hessner MJ, Endean DJ, Casper JT, Horowitz MM, Keever–Taylor CA, Roth M, Flomenberg N, Drobyski WR (1995) Use of unrelated marrow grafts compensates for reduced graft-versus-leukemia reactivity after T-cell-depleted allogeneic marrow transplantation for chronic myelogenous leukemia. Blood 86:3987–3996

    CAS  PubMed  Google Scholar 

  26. Jamieson AM, Diefenbach A, McMahon CW, Xiong N, Carlyle JR, Raulet DH (2002) The role of the NKG2D immunoreceptor in immune cell activation and natural killing. Immunity 17:19–29

    CAS  PubMed  Google Scholar 

  27. Johansson MH, Bieberich C, Jay G, Karre K, Hoglund P (1997) Natural killer cell tolerance in mice with mosaic expression of major histocompatibility complex class I transgene. J Exp Med 186:353–364

    Article  CAS  PubMed  Google Scholar 

  28. Lanier LL (2000) Turning on natural killer cells. J Exp Med 191:1259–1262

    Article  CAS  PubMed  Google Scholar 

  29. Lanier LL, Bakker AB (2000) The ITAM–bearing transmembrane adaptor DAP12 in lymphoid and myeloid cell function. Immunol Today 21:611–614

    Article  CAS  PubMed  Google Scholar 

  30. Leibson PJ (1998) Cytotoxic lymphocyte recognition of HLA-E: utilizing a nonclassical window to peer into classical MHC. Immunity 9:289–294

    CAS  PubMed  Google Scholar 

  31. Lopez-Botet M, Bellon T (1999) Natural killer cell activation and inhibition by receptors for MHC class I. Curr Opin Immunol 11:301–307

    CAS  PubMed  Google Scholar 

  32. Love PE, Shores EW (2000) ITAM multiplicity and thymocyte selection: how low can you go? Immunity 12:591–597

  33. Mandelboim O, Lieberman N, Lev M, Paul L, Arnon TI, Bushkin Y, Davis DM, Strominger JL, Yewdell JW, Porgador A (2001) Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells. Nature 409:1055–1060

    Article  CAS  PubMed  Google Scholar 

  34. Miller JS (2002) Biology of natural killer cells in cancer and infection. Cancer Invest 20:405–419

    Article  PubMed  Google Scholar 

  35. Moretta A, Biassoni R, Bottino C, Mingari MC, Moretta L (2000) Natural cytotoxicity receptors that trigger human NK-cell-mediated cytolysis. Immunol Today 21:228–234

    CAS  PubMed  Google Scholar 

  36. Moretta A, Bottino C, Pende D, Tripodi G, Tambussi G, Viale O, Orengo A, Barbaresi M, Merli A, Ciccone E, Moretta L (1990) Identification of four subsets of human CD3−CD16+ natural killer (NK) cells by the expression of clonally distributed functional surface molecules: correlation between subset assignment of NK clones and ability to mediate specific alloantigen recognition. J Exp Med 172:1589–1598

    CAS  PubMed  Google Scholar 

  37. Mrozek E, Anderson P, Caligiuri MA (1996) Role of interleukin-15 in the development of human CD56+ natural killer cells from CD34+ hematopoietic progenitor cells. Blood 87:2632–2640

    CAS  PubMed  Google Scholar 

  38. Nakajima H, Colonna M (2000) 2B4: an NK cell activating receptor with unique specificity and signal transduction mechanism. Hum Immunol 61:39–43

    CAS  PubMed  Google Scholar 

  39. Parolini S, Bottino C, Falco M, Augugliaro R, Giliani S, Franceschini R, Ochs HD, Wolf H, Bonnefoy JY, Biassoni R, Moretta L, Notarangelo LD, Moretta A (2000) X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells. J Exp Med 192:337–346

    CAS  PubMed  Google Scholar 

  40. Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, Gross JA, Johnston J, Madden K, Xu W, West J, Schrader S, Burkhead S, Heipel M, Brandt C, Kuijper JL, Kramer J, Conklin D, Presnell SR, Berry J, Shiota F, Bort S, Hambly K, Mudri S, Clegg C, Moore M, Grant FJ, Lofton-Day C, Gilbert T, Rayond F, Ching A, Yao L, Smith D, Webster P, Whitmore T, Maurer M, Kaushansky K, Holly RD, Foster D (2000) Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 408:57–63

    Google Scholar 

  41. Pende D, Parolini S, Pessino A, Sivori S, Augugliaro R, Morelli L, Marcenaro E, Accame L, Malaspina A, Biassoni R, Bottino C, Moretta L, Moretta A (1999) Identification and molecular characterization of NKp30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells. J Exp Med 190:1505–1516

    Article  CAS  PubMed  Google Scholar 

  42. Raulet DH, Held W, Correa I, Dorfman JR, Wu MF, Corral L (1997) Specificity, tolerance and developmental regulation of natural killer cells defined by expression of class I–specific Ly49 receptors. Immunol Rev 155:41–52

    CAS  PubMed  Google Scholar 

  43. Raulet DH, Vance RE, McMahon CW (2001) Regulation of the natural killer cell receptor repertoire. Annu Rev Immunol 19:291–330

    Article  CAS  PubMed  Google Scholar 

  44. Roth C, Carlyle JR, Takizawa H, Raulet DH (2000) Clonal acquisition of inhibitory Ly49 receptors on developing NK cells is successively restricted and regulated by stromal class I MHC. Immunity 13:143–153

    CAS  PubMed  Google Scholar 

  45. Ruggeri L, Capanni M, Casucci M, Volpi I, Tosti A, Perruccio K, Urbani E, Negrin RS, Martelli MF, Velardi A (1999) Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Blood 94:333–339

    CAS  PubMed  Google Scholar 

  46. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, Posati S, Rogaia D, Frassoni F, Aversa F, Martelli MF, Velardi A (2002) Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295:2097–2100

    Article  CAS  PubMed  Google Scholar 

  47. Salcedo M, Diehl AD, Olsson–Alheim MY, Sundback J, Van Kaer L, Karre K, Ljunggren HG (1997) Altered expression of Ly49 inhibitory receptors on natural killer cells from MHC class I–deficient mice. J Immunol 158:3174–3180

    CAS  PubMed  Google Scholar 

  48. Sasazuki T, Juji T, Morishima Y, Kinukawa N, Kashiwabara H, Inoko H, Yoshida T, Kimura A, Akaza T, Kamikawaji N, Kodera Y, Takaku F. 1998. Effect of matching of class I HLA alleles on clinical outcome after transplantation of hematopoietic stem cells from an unrelated donor. Japan Marrow Donor Program. N Engl J Med 339:1177–1185

    Google Scholar 

  49. Sivakumar PV, Gunturi A, Salcedo M, Schatzle JD, Lai WC, Kurepa Z, Pitcher L, Seaman MS, Lemonnier FA, Bennett M, Forman J, Kumar V (1999) Cutting edge: expression of functional CD94/NKG2A inhibitory receptors on fetal NK1.1+Ly-49− cells: a possible mechanism of tolerance during NK cell development. J Immunol 162:6976–6980

    CAS  PubMed  Google Scholar 

  50. Sivori S, Falco M, Marcenaro E, Parolini S, Biassoni R, Bottino C, Moretta L, Moretta A (2002) Early expression of triggering receptors and regulatory role of 2B4 in human natural killer cell precursors undergoing in vitro differentiation. Proc Natl Acad Sci USA 99:4526–4531

    Article  CAS  PubMed  Google Scholar 

  51. Sivori S, Vitale M, Morelli L, Sanseverino L, Augugliaro R, Bottino C, Moretta L, Moretta A (1997) p46, a novel natural killer cell-specific surface molecule that mediates cell activation. J Exp Med 186:1129–1136

    Article  CAS  PubMed  Google Scholar 

  52. Valiante NM, Uhrberg M, Shilling HG, Lienert–Weidenbach K, Arnett KL, D'Andrea A, Phillips JH, Lanier LL, Parham P (1997) Functionally and structurally distinct NK cell receptor repertoires in the peripheral blood of two human donors. Immunity 7:739–751

    PubMed  Google Scholar 

  53. Vitale M, Bottino C, Sivori S, Sanseverino L, Castriconi R, Marcenaro E, Augugliaro R, Moretta L, Moretta A (1998) NKp44, a novel triggering surface molecule specifically expressed by activated natural killer cells, is involved in non-major histocompatibility complex-restricted tumor cell lysis. J Exp Med 187:2065–2072

    Article  CAS  PubMed  Google Scholar 

  54. Vitale M, Falco M, Castriconi R, Parolini S, Zambello R, Semenzato G, Biassoni R, Bottino C, Moretta L, Moretta A (2001) Identification of NKp80, a novel triggering molecule expressed by human NK cells. Eur J Immunol 31:233–242

    Article  CAS  PubMed  Google Scholar 

  55. Vivier E, Tomasello E, Paul P (2002) Lymphocyte activation via NKG2D: towards a new paradigm in immune recognition? Curr Opin Immunol 14:306–311

  56. Voutsadakis IA (2002) Gemtuzumab Ozogamicin (CMA-676, Mylotarg) for the treatment of CD33+ acute myeloid leukemia. Anticancer Drugs 13:685–692

    Article  CAS  PubMed  Google Scholar 

  57. Witt CS, Dewing C, Sayer DC, Uhrberg M, Parham P, Christiansen FT (1999) Population frequencies and putative haplotypes of the killer cell immunoglobulin-like receptor sequences and evidence for recombination. Transplantation 68:1784–1789

    PubMed  Google Scholar 

  58. Wu MF, Raulet DH (1997) Class I deficient hemopoietic cells and nonhemopoietic cells dominantly induce unresponsiveness of natural killer cells to class I–deficient bone marrow cell grafts. J Immunol 158:1628–1633

    CAS  PubMed  Google Scholar 

  59. Zeis M, Uharek L, Glass B, Steinmann J, Dreger P, Gassmann W, Schmitz N (1997) Allogeneic MHC–mismatched activated natural killer cells administered after bone marrow transplantation provide a strong graft-versus-leukaemia effect in mice. Br J Haematol 96:757–761

    CAS  PubMed  Google Scholar 

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  1. 121 Ippokratous Street, 11472, Athens, Greece

    Ioannis A. Voutsadakis

  2. Division of Hematology and INSERM U487, Institut Gustave-Roussy, Villejuif, France

    Ioannis A. Voutsadakis

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Voutsadakis, I.A. NK cells in allogeneic bone marrow transplantation. Cancer Immunol Immunother 52, 525–534 (2003). https://doi.org/10.1007/s00262-003-0378-7

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