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Immune Modulation

Immunomodulation of early engrafted natural killer cells with interleukin-2 and interferon-α in autologous stem cell transplantation

Bone Marrow Transplantation volume 28, pages 673–680 (2001)Cite this article

Abstract

High relapse rates during the first year after autologous stem cell transplantation (ASCT) for multiple myeloma or non-Hodgkin lymphoma are due to the failure of high-dose chemotherapy to eradicate minimal residual disease. Post-ASCT immunorecovery studies have shown that quantities of natural killer (NK) cells return to normal within 1 month post-ASCT in contrast to the recovery of T and B cell populations (up to 1 year). Preclinical studies have demonstrated that NK cells have potent antitumor activity. IL-2 and IFN-α enhance NK-cell activity. We investigated the efficacy of IL-2 and IFN-α to up-regulate NK-cell cytotoxicity at 14 days post ASCT. Twenty patients undergoing ASCT had PBMCs collected pretransplantation and at 14 days post transplantation. PBMCs (effector cells) from each blood sample were incubated in vitrowith IFN-α and IL-2 at 10000 IU/ml. NK cell activity was determined by sodium chromate 51Cr release assay for lysis of K562 target cells. IL-2 and IFN-α each increased lysis of K562 cells compared with placebo (effector-to-target ratio, 50:1, P < 0.001). Increased NK cell activity occurred in samples from all patients. IL-2 and IFN-α up-regulated NK cell activity at 14 days post ASCT. They may be useful as immunomodulators as early as 14 days post ASCT to eradicate or control minimal residual disease. Bone Marrow Transplantation (2001) 28, 673–680.

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References

  1. Löwenberg B, Verdonck LJ, Dekker AW et al. Autologous bone marrow transplantation in acute myeloid leukemia in first remission: results of a Dutch prospective study J Clin Oncol 1990 8: 287–294

    Article  Google Scholar 

  2. Klingemann HG, Phillips GL . Immunotherapy after bone marrow transplantation Bone Marrow Transplant 1991 8: 73–81

    CAS  PubMed  Google Scholar 

  3. Petersen FB, Appelbaum FR, Hill R et al. Autologous marrow transplantation for malignant lymphoma: a report of 101 cases from Seattle J Clin Oncol 1990 8: 638–647

    Article  CAS  Google Scholar 

  4. Bengtsson M, Smedmyr B, Festin R et al. B lymphocyte regeneration in marrow and blood after autologous bone marrow transplantation: increased numbers of B cells carrying activation and progression markers Leuk Res 1989 13: 791–797

    Article  CAS  Google Scholar 

  5. Small TN, Keever CA, Weiner-Fedus S et al. B-cell differentiation following autologous, conventional, or T-cell depleted bone marrow transplantation: a recapitulation of normal B-cell ontogeny Blood 1990 76: 1647–1656

    CAS  Google Scholar 

  6. Guillaume T, Rubinstein DB, Symann M . Immune reconstitution and immunotherapy after autologous hematopoietic stem cell transplantation Blood 1998 92: 1471–1490

    CAS  Google Scholar 

  7. Marin GH, Mendez MC, Menna ME et al. Immune recovery after bone marrow and peripheral blood stem cell transplantation Transplant Proc 1999 31: 2582–2584

    Article  CAS  Google Scholar 

  8. Parrado A, Casares S, Prieto J et al. Repopulation of circulating T, B and NK lymphocytes following bone marrow and blood stem cell transplantation Hematol Cell Ther 1997 39: 301–306

    Article  CAS  Google Scholar 

  9. Olsen GA, Gockerman JP, Bast RC Jr et al. Altered immunologic reconstitution after standard-dose chemotherapy or high-dose chemotherapy with autologous bone marrow support Transplantation 1988 46: 57–60

    Article  CAS  Google Scholar 

  10. Sugita K, Soiffer RJ, Murray C et al. The phenotype and reconstitution of immunoregulatory T cell subsets after T cell-depleted allogeneic and autologous bone marrow transplantation Transplantation 1994 57: 1465–1473

    Article  CAS  Google Scholar 

  11. Bengtsson M, Totterman TH, Smedmyr B et al. Regeneration of functional and activated NK and T sub-subset cells in the marrow and blood after autologous bone marrow transplantation: a prospective phenotypic study with 2/3-color FACS analysis Leukemia 1989 3: 68–75

    CAS  Google Scholar 

  12. Henon PR, Liang H, Beck-Wirth G et al. Comparison of hematopoietic and immune recovery after autologous bone marrow or blood stem cell transplants Bone Marrow Transplant 1992 9: 285–291

    CAS  Google Scholar 

  13. Ashihara E, Shimazaki C, Yamagata N et al. Reconstitution of lymphocyte subsets after peripheral blood stem cell transplantation: two-color flow cytometric analysis Bone Marrow Transplant 1994 13: 377–381

    CAS  PubMed  Google Scholar 

  14. Timonen T, Ortaldo JR, Herberman RB . Characteristics of human large granular lymphocytes and relationship to natural killer and K cells J Exp Med 1981 153: 569–582

    Article  CAS  Google Scholar 

  15. Trinchieri G . Biology of natural killer cells Adv Immunol 1989 47: 187–376

    Article  CAS  Google Scholar 

  16. Mori S, Yamaguchi K, Morita H, Mohri N . Distribution of HNK-1+ cells in malignant lymphomas Acta Pathol Jpn 1985 35: 339–350

    CAS  PubMed  Google Scholar 

  17. Swerdlow SH, Murray LJ . Natural killer (Leu 7+) cells in reactive lymphoid tissues and malignant lymphomas Am J Clin Pathol 1984 81: 459–463

    Article  CAS  Google Scholar 

  18. Si L, Whiteside TL . Tissue distribution of human NK cells studied with anti-Leu-7 monoclonal antibody J Immunol 1983 130: 2149–2155

    CAS  PubMed  Google Scholar 

  19. Porwit-Ksiazek A, Ksiazek T, Biberfeld P . Leu 7+ (HNK-1+) cells. I. Selective compartmentalization of Leu 7+ cells with different immunophenotypes in lymphatic tissues and blood Scand J Immunol 1983 18: 485–493

    Article  CAS  Google Scholar 

  20. Mori S, Mohri N, Morita H et al. The distribution of cells expressing a natural killer cell marker (HNK-1) in normal human lymphoid organs and malignant lymphomas Virch Arch B Cell Pathol Incl Mol Pathol 1983 43: 253–263

    Article  CAS  Google Scholar 

  21. Lattime EC, Pecoraro GA, Stutman O . The activity of natural cytotoxic cells is augmented by interleukin 2 and interleukin 3 J Exp Med 1983 157: 1070–1075

    Article  CAS  Google Scholar 

  22. Oshimi K, Oshimi Y, Yamada O, Mizoguchi H . Lysis of lymphoma cells by autologous and allogeneic natural killer cells Blood 1985 65: 638–643

    CAS  PubMed  Google Scholar 

  23. Wong EK, Eaves C, Klingemann HG . Comparison of natural killer activity of human bone marrow and blood cells in cultures containing IL-2, IL-7 and IL-12 Bone Marrow Transplant 1996 18: 63–71

    CAS  PubMed  Google Scholar 

  24. Morgan DA, Ruscetti FW, Gallo R . Selective in vitro growth of T lymphocytes from normal human bone marrows Science 1976 193: 1007–1008

    Article  CAS  Google Scholar 

  25. Smith KA . Lowest dose interleukin-2 immunotherapy Blood 1993 81: 1414–1423

    CAS  PubMed  Google Scholar 

  26. Djeu JY, Heinbaugh JA, Holden HT, Herberman RB . Augmentation of mouse natural killer cell activity by interferon and interferon inducers J Immunol 1979 122: 175–181

    CAS  PubMed  Google Scholar 

  27. Silva A, Bonavida B, Targan S . Mode of action of interferon-mediated modulation of natural killer cytotoxic activity: recruitment of pre-NK cells and enhanced kinetics of lysis J Immunol 1980 125: 479–484

    CAS  PubMed  Google Scholar 

  28. Edwards BS, Hawkins MJ, Borden EC . Comparative in vivo and in vitro activation of human natural killer cells by two recombinant alpha-interferons differing in antiviral activity Cancer Res 1984 44: 3135–3139

    CAS  PubMed  Google Scholar 

  29. Lee SH, Kelley S, Chiu H, Stebbing N . Stimulation of natural killer cell activity and inhibition of proliferation of various leukemic cells by purified human leukocyte interferon subtypes Cancer Res 1982 42: 1312–1316

    CAS  PubMed  Google Scholar 

  30. Anderson TM, Ibayashi Y, Tokuda Y et al. Effects of systemic recombinant interleukin-2 on natural killer and lymphokine activated killer activity of human tumor infiltrating lymphocytes Cancer Res 1988 48: 1180–1183

    CAS  PubMed  Google Scholar 

  31. Itoh K, Tilden AB, Balch CM . Interleukin 2 activation of cytotoxic T-lymphocytes infiltrating into human metastatic melanomas Cancer Res 1986 46: 3011–3017

    CAS  PubMed  Google Scholar 

  32. Ellis TM, McKenzie RS, Simms PE et al. Induction of human lymphokine-activated killer cells by IFN-alpha and IFN-gamma J Immunol 1989 143: 4282–4286

    CAS  PubMed  Google Scholar 

  33. Senik A, Gresser I, Maury C et al. Enhancement by interferon of natural killer cell activity in mice Cell Immunol 1979 44: 186–200

    Article  CAS  Google Scholar 

  34. Targan S, Stebbing N . In vitro interactions of purified cloned human interferons on NK cells: enhanced activation J Immunol 1982 129: 934–935

    CAS  PubMed  Google Scholar 

  35. Divine M, Boutolleau D, Delfau-Larue MH et al. Poor lymphocyte recovery following CD34-selected autologous peripheral blood stem cell transplantation for non-Hodgkin'slymphoma Br J Haematol 1999 105: 349–360

    Article  CAS  Google Scholar 

  36. Talmadge JE, Reed E, Ino K et al. Rapid immunologic reconstitution following transplantation with mobilized peripheral blood stem cells as compared to bone marrow Bone Marrow Transplant 1997 19: 161–172

    Article  CAS  Google Scholar 

  37. Storek J, Saxon A . Reconstitution of B cell immunity following bone marrow transplantation Bone Marrow Transplant 1992 9: 395–408

    CAS  Google Scholar 

  38. Miller RA, Daley J, Ghalie R, Kaizer H . Clonal analysis of T-cell deficiencies in autotransplant recipients Blood 1991 77: 1845–1850

    CAS  Google Scholar 

  39. Cayeux S, Meuer S, Pezzutto A et al. T-cell ontogeny after autologous bone marrow transplantation: failure to synthesize interleukin-2 (IL-2) and lack of CD2- and CD3-mediated proliferation by both CD4− and CD8+ cells even in the presence of exogenous IL-2 Blood 1989 74: 2270–2277

    CAS  Google Scholar 

  40. Anderson KC, Ritz J, Takvorian T et al. Hematologic engraftment and immune reconstitution posttransplantation with anti-B1 purged autologous bone marrow Blood 1987 69: 597–604

    CAS  PubMed  Google Scholar 

  41. Roberts MM, To LB, Gillis D et al. Immune reconstitution following peripheral blood stem cell transplantation, autologous bone marrow transplantation and allogeneic bone marrow transplantation Bone Marrow Transplant 1993 12: 469–475

    CAS  Google Scholar 

  42. Koehne G, Zeller W, Stockschlaeder M, Zander AR . Phenotype of lymphocyte subsets after autologous peripheral blood stem cell transplantation Bone Marrow Transplant 1997 19: 149–156

    Article  CAS  Google Scholar 

  43. Lotzova E, Savary CA, Champlin RE . Genesis of human oncolytic natural killer cells from primitive CD34+CD33− bone marrow progenitors J Immunol 1993 150: 5263–5269

    CAS  PubMed  Google Scholar 

  44. Miller JS, Verfaillie C, McGlave P . The generation of human natural killer cells from CD34+/DR-primitive progenitors in long-term bone marrow culture Blood 1992 80: 2182–2187

    CAS  PubMed  Google Scholar 

  45. Talmadge JE, Phillips H, Schindler J et al. Systematic preclinical study on the therapeutic properties of recombinant human interleukin 2 for the treatment of metastatic disease Cancer Res 1987 47: 5725–5732

    CAS  PubMed  Google Scholar 

  46. Kuribayashi K, Gillis S, Kern DE, Henney CS . Murine NK cell cultures: effects of interleukin-2 and interferon on cell growth and cytotoxic reactivity J Immunol 1981 126: 2321–2327

    CAS  PubMed  Google Scholar 

  47. Shaw AR, Bleackley RC, Merryweather JP, Barr PJ . Modulation of human natural killer cell activity by recombinant human interleukin 2 Cell Immunol 1985 91: 193–200

    Article  CAS  Google Scholar 

  48. Thompson JA, Lee DJ, Cox WW et al. Recombinant interleukin 2 toxicity, pharmacokinetics, and immunomodulatory effects in a phase I trial Cancer Res 1987 47: 4202–4207

    CAS  PubMed  Google Scholar 

  49. Higuchi CM, Thompson JA, Petersen FB et al. Toxicity and immunomodulatory effects of interleukin-2 after autologous bone marrow transplantation for hematologic malignancies Blood 1991 77: 2561–2568

    CAS  PubMed  Google Scholar 

  50. Gonzalez-Barca E, Granena A, Fernandez-Sevilla A et al. Low-dose subcutaneous interleukin-2 in patients with minimal residual lymphoid neoplasm disease Eur J Haematol 1999 62: 231–238

    Article  CAS  Google Scholar 

  51. Lopez-Jimenez J, Perez-Oteyza J, Munoz A et al. Subcutaneous versus intravenous low-dose IL-2 therapy after autologous transplantation: results of a prospective, non-randomized study Bone Marrow Transplant 1997 19: 429–434

    Article  CAS  Google Scholar 

  52. Miller JS, Tessmer-Tuck J, Pierson BA et al. Low dose subcutaneous interleukin-2 after autologous transplantation generates sustained in vivo natural killer cell activity Biol Blood Marrow Transplant 1997 3: 34–44

    CAS  Google Scholar 

  53. Lauria F, Raspadori D, Ventura MA et al. Immunologic and clinical modifications following low-dose subcutaneous administration of rIL-2 in non-Hodgkin's lymphoma patients after autologous bone marrow transplantation Bone Marrow Transplant 1996 18: 79–85

    CAS  PubMed  Google Scholar 

  54. Soiffer RJ, Murray C, Gonin R, Ritz J . Effect of low-dose interleukin-2 on disease relapse after T-cell-depleted allogeneic bone marrow transplantation Blood 1994 84: 964–971

    CAS  Google Scholar 

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Acknowledgements

Portions of this study were published as an abstract in Proceedings of ASCO 2000; 19: 61a.

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  1. Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA

    LF Porrata, DJ Inwards, MQ Lacy & SN Markovic

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  1. LF Porrata
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Porrata, L., Inwards, D., Lacy, M. et al. Immunomodulation of early engrafted natural killer cells with interleukin-2 and interferon-α in autologous stem cell transplantation. Bone Marrow Transplant 28, 673–680 (2001). https://doi.org/10.1038/sj.bmt.1703203

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