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Immunobiology

In vitro generation of cytotoxic effectors activated by interleukin 2 (IL-2): comparison of autologous peripheral blood stem cells (PBSC) from adults and children

Bone Marrow Transplantation volume 27, pages 869–875 (2001)Cite this article

Abstract

Previous studies demonstrated that ex vivo IL-2- activated PBSC could generate cytotoxic effectors without impairing haematopoietic reconstitution. Clinical experience and previous studies indicated that children with solid tumours could benefit from high-dose chemotherapy with immune modulation. We studied the generation of cytotoxic effectors from growth-factor ± chemotherapy-mobilised PBSC from 10 patients (five adults and five children) with different solid tumours. Cells were placed in culture in serum-free culture medium supplemented with IL-2 1000 U/ml ± IL-12 for 1, 2, 4 or 7 days. Anti-tumour cytotoxicity was tested against K562, Daudi and two neuroblastoma cell lines (Gau, NB91). Cultured adult PBSC in the presence of IL-2 (1000 U/ml) showed marked cytotoxicity against all the cell lines tested from day 1. At day 2, with an E:T ratio of 25:1, cytotoxicity was 53% ± 10.4, 63.2% ± 23.8, 38% ± 9.1, and 39% ± 15.7 against K562, Daudi, Gau and NB91, respectively. Cytotoxic activity of child PBSC was significantly lower (P < 0.05) and was displayed after longer culture times (day 4). No difference was found in the phenotype analysis of lymphoid subsets before and after IL-2 activation between adult and child PBSC. Haematological properties of the graft were not significantly impaired by IL-2 activation. Bone Marrow Transplantation (2001) 27, 869–875.

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References

  1. Hartmann O, Valteau-Couanet D, Vassal G et al. Prognostic factors in metastatic neuroblastoma in patients over 1 year of age treated with high-dose chemotherapy and stem cell transplantation: a multivariate analysis in 218 patients treated in a single institution Bone Marrow Transplant 1999 23: 789–795

    Article  CAS  PubMed  Google Scholar 

  2. Matthay KK, Villablanca JG, Seeger RC et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group New Engl J Med 1999 341: 1165–1173

    Article  CAS  PubMed  Google Scholar 

  3. Rill DR, Santana VM, Roberts WM et al. Direct demonstration that autologous bone marrow transplantation for solid tumors can return a multiplicity of tumorigenic cells Blood 1994 84: 380–383

    CAS  PubMed  Google Scholar 

  4. Jones RJ, Ambinder RF, Piantadosi S, Santos GW . Evidence of a graft-versus-lymphoma effect associated with allogeneic bone marrow transplantation Blood 1991 77: 649–653

    CAS  PubMed  Google Scholar 

  5. Charak BS, Brynes RK, Groshen S et al. Bone marrow transplantation with interleukin-2-activated bone marrow followed by interleukin-2 therapy for acute myeloid leukemia in mice Blood 1990 76: 2187–2190

    CAS  PubMed  Google Scholar 

  6. Areman EM, Rhodes PL, Mazumder A, Meehan KR . Differential effects of IL-2 incubation on hematopoietic potential of autologous bone marrow and mobilized PBSC from patients with hematologic malignancies J Hematother 1999 8: 39–44

    Article  CAS  PubMed  Google Scholar 

  7. Meehan KR, Verma UN, Cahill R et al. Interleukin-2-activated hematopoietic stem cell transplantation for breast cancer: investigation of dose level with clinical correlates Bone Marrow Transplant 1997 20: 643–651

    Article  CAS  PubMed  Google Scholar 

  8. Meehan KR, Arun B, Gehan EA et al. Immunotherapy with interleukin-2 and alpha-interferon after IL-2-activated hematopoietic stem cell transplantation for breast cancer Bone Marrow Transplant 1999 23: 667–673

    Article  CAS  PubMed  Google Scholar 

  9. Toh HC, McAfee SL, Sackstein R et al. High-dose cyclophosphamide + carboplatin and interleukin-2 (IL-2) activated autologous stem cell transplantation followed by maintenance IL-2 therapy in metastatic breast carcinoma Bone Marrow Transplant 2000 25: 19–24

    Article  CAS  PubMed  Google Scholar 

  10. Evans AE, D'Angio GJ, Randolph J . A proposed staging for children with neuroblastoma. Children's cancer study group A Cancer 1971 27: 374–378

    Article  CAS  PubMed  Google Scholar 

  11. Valteau D, Scott V, Carcelain G et al. T-cell receptor repertoire in neuroblastoma patients Cancer Res 1996 56: 362–369

    CAS  PubMed  Google Scholar 

  12. Valteau-Couanet D, Rubie H, Meresse V et al. Phase I–II study of interleukin-2 after high-dose chemotherapy and autologous bone marrow transplantation in poorly responding neuroblastoma Bone Marrow Transplant 1995 16: 515–520

    CAS  PubMed  Google Scholar 

  13. Main EK, Monos DS, Lampson LA . IFN-treated neuroblastoma cell lines remain resistant to T cell-mediated allo-killing, and susceptible to non-MHC-restricted cytotoxicity J Immunol 1988 141: 2943–2950

    CAS  PubMed  Google Scholar 

  14. Foreman NK, Rill DR, Coustan-Smith E et al. Mechanisms of selective killing of neuroblastoma cells by natural killer cells and lymphokine activated killer cells. Potential for residual disease eradication Br J Cancer 1993 67: 933–938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rossi AR, Pericle F, Rashleigh S et al. Lysis of neuroblastoma cell lines by human natural killer cells activated by interleukin-2 and interleukin-12 Blood 1994 83: 1323–1328

    CAS  PubMed  Google Scholar 

  16. Charak BS, Brynes RK, Katsuda S et al. Induction of graft versus leukemia effect in bone marrow transplantation: dosage and time schedule dependency of interleukin 2 therapy Cancer Res 1991 51: 2015–2020

    CAS  PubMed  Google Scholar 

  17. Blaise D, Olive D, Michallet M et al. Impairment of leukaemia-free survival by addition of interleukin-2-receptor antibody to standard graft-versus-host prophylaxis Lancet 1995 345: 1144–1146

    Article  CAS  PubMed  Google Scholar 

  18. Verma UN, Areman E, Dickerson SA et al. Interleukin-2 activation of chemotherapy and growth factor-mobilized peripheral blood stem cells for generation of cytotoxic effectors Bone Marrow Transplant 1995 15: 199–206

    CAS  PubMed  Google Scholar 

  19. Philip T, Bernard JL, Zucker JM et al. High-dose chemoradiotherapy with bone marrow transplantation as consolidation treatment in neuroblastoma: an unselected group of stage IV patients over 1 year of age J Clin Oncol 1987 5: 266–271

    Article  CAS  PubMed  Google Scholar 

  20. Dini G, Garaventa A, Lanino E et al. Total body irradiation, vincristine in continuous infusion and high-dose melphalan with transplant of autologous bone marrow in the treatment of neuroblastoma Pediatr Med Chir 1987 9: 1–7

    CAS  PubMed  Google Scholar 

  21. Ladenstein R, Lasset C, Hartmann O et al. Comparison of auto vs allografting as consolidation of primary treatments in advanced neuroblastoma over one year of age at diagnosis: report from the European Group for Bone Marrow Transplantation Bone Marrow Transplant 1994 14: 37–46

    CAS  PubMed  Google Scholar 

  22. Matthay KK, Seeger RC, Reynolds CP et al. Allogeneic versus autologous purged bone marrow transplantation for neuroblastoma: a report from the Childrens Cancer Group J Clin Oncol 1994 12: 2382–2389

    Article  CAS  PubMed  Google Scholar 

  23. Foreman NK, Rill DR, Coustan-Smith E et al. Mechanisms of selective killing of neuroblastoma cells by natural killer cells and lymphokine activated killer cells. Potential for residual disease eradication Br J Cancer 1993 67: 933–938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Verma UN, Mazumder A . Interleukin-12 (IL-12) alone or in synergistic combination with IL-2 for in vitro activation of human bone marrow: differential effects at different time points Bone Marrow Transplant 1995 16: 365–372

    CAS  PubMed  Google Scholar 

  25. 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 

  26. Miller JS, Prosper F, McCullar V . Natural killer (NK) cells are functionally abnormal and NK cell progenitors are diminished in granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cell collections Blood 1997 90: 3098–3105

    CAS  PubMed  Google Scholar 

  27. Verma UN, Yankelevich B, Hodgson J, Mazumder A . Effect of the in vivo priming regimen for peripheral blood stem cells (PBSC) mobilization on in vitro generation of cytotoxic effectors by IL–2 activation of PBSC in a murine model Bone Marrow Transplant 1997 19: 265–273

    Article  CAS  PubMed  Google Scholar 

  28. Areman EM, Mazumder A, Kotula PL et al. Hematopoietic potential of IL-2-cultured peripheral blood stem cells from breast cancer patients Bone Marrow Transplant 1996 18: 521–525.

    CAS  PubMed  Google Scholar 

  29. Lopez-Jimenez J, Quiroga R, Ramos P et al. IL-2 effects on allogeneic and autologous transplant haemopoietic progenitors in long-term cultures Bone Marrow Transplant 1996 18: 899–905

    CAS  PubMed  Google Scholar 

  30. Cuturi MC, Anegon I, Sherman F, Loudon R et al. Production of hematopoietic colony-stimulating factors by human natural killer cells J Exp Med 1989 169: 569–583

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Pediatrics Department, Department of Clinical Biology, Institut Gustave Roussy, Villejuif, France

    D Valteau-Couanet, PS Beaussier & O Hartmann

  2. Department of Clinical Biology, Immunology Unit, Institut Gustave Roussy, Villejuif, France

    E Angevin & C Leboulaire

  3. Department of Clinical Biology, Hematology Unit, Institut Gustave Roussy, Villejuif, France

    C Bayle

  4. Etablissement Français du Sang, Ile de France, France

    F Beaujean

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  1. D Valteau-Couanet
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Valteau-Couanet, D., Angevin, E., Leboulaire, C. et al. In vitro generation of cytotoxic effectors activated by interleukin 2 (IL-2): comparison of autologous peripheral blood stem cells (PBSC) from adults and children. Bone Marrow Transplant 27, 869–875 (2001). https://doi.org/10.1038/sj.bmt.1702870

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