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Immune Reconstitution

Cytomegalovirus-specific immune recovery following allogeneic HLA-identical sibling transplantation with reduced-intensity preparative regimen

Bone Marrow Transplantation volume 33, pages 839–846 (2004)Cite this article

Summary:

Cytomegalovirus (CMV) represents a major cause of morbidity after allogeneic stem cell transplantation (allo-SCT). Using interferon-gamma-enzyme-linked immunospot (ELISPOT) assay and HLA-peptide tetramers, we analysed 54 patients who received a reduced-intensity conditioning regimen, including fludarabine, busulphan and antithymocyte globulin (ATG), with the aim of defining essential elements of protective immunity to CMV. The cumulative incidence of CMV positive antigenaemia was 37% occurring at a median of 43 days (range, 7–104) after allo-SCT. In univariate analysis, conditioning regimen (ATG dose) and graft characteristics (graft source and CD3+ T-cell dose) significantly influenced CMV-specific immune recovery. A significant correlation (P=0.000002) was found between CMV-specific T cells detected by IFN-gamma ELISPOT assay and pp65-specific CD8+ T-cell frequency quantified by tetramers. CMV-specific CD8+ T cells presented a phenotype of effector cells (perforin and 2B4 positive). In multivariate analysis, bone marrow (BM) as a graft source was the only variable associated with an increased risk of CMV positive antigenaemia (P=0.0001) in line with the ELISPOT assay showing a higher frequency of functional CMV-specific effectors within peripheral blood stem cell grafts as compared to BM. Thus, early monitoring of CMV-specific immune recovery using sensitive new tools might prove useful for patient management after allo-SCT.

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References

  1. Einsele H, Ehninger G, Hebart H et al. Polymerase chain reaction monitoring reduces the incidence of cytomegalovirus disease and the duration and side effects of antiviral therapy after bone marrow transplantation. Blood 1995; 86: 2815–2820.

    CAS  PubMed  Google Scholar 

  2. Boeckh M, Bowden RA, Gooley T et al. Successful modification of a pp65 antigenemia-based early treatment strategy for prevention of cytomegalovirus disease in allogeneic marrow transplant recipients. Blood 1999; 93: 1781–1782.

    CAS  PubMed  Google Scholar 

  3. Slavin S, Nagler A, Naparstek E et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998; 91: 756–763.

    CAS  PubMed  Google Scholar 

  4. Khouri IF, Keating M, Korbling M et al. Transplant-lite: induction of graft-versus-malignancy using fludarabine- based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 1998; 16: 2817–2824.

    Article  CAS  PubMed  Google Scholar 

  5. McSweeney PA, Niederwieser D, Shizuru JA et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001; 97: 3390–3400.

    Article  CAS  PubMed  Google Scholar 

  6. Mohty M, Faucher C, Vey N et al. Rate of secondary viral and bacterial infections in patients undergoing allogeneic bone marrow mini-transplantation. Bone Marrow Transplant 2000; 26: 251–255.

    Article  CAS  PubMed  Google Scholar 

  7. Chakrabarti S, Mackinnon S, Chopra R et al. High incidence of cytomegalovirus infection after nonmyeloablative stem cell transplantation: potential role of Campath-1H in delaying immune reconstitution. Blood 2002; 99: 4357–4363.

    Article  CAS  PubMed  Google Scholar 

  8. Hebart H, Daginik S, Stevanovic S et al. Sensitive detection of human cytomegalovirus peptide-specific cytotoxic T-lymphocyte responses by interferon-gamma-enzyme-linked immunospot assay and flow cytometry in healthy individuals and in patients after allogeneic stem cell transplantation. Blood 2002; 99: 3830–3837.

    Article  CAS  PubMed  Google Scholar 

  9. Ozdemir E, St John LS, Gillespie G et al. Cytomegalovirus reactivation following allogeneic stem cell transplantation is associated with the presence of dysfunctional antigen-specific CD8+ T cells. Blood 2002; 100: 3690–3697.

    Article  CAS  PubMed  Google Scholar 

  10. Molldrem JJ, Lee PP, Wang C et al. Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia. Nat Med 2000; 6: 1018–1023.

    Article  CAS  PubMed  Google Scholar 

  11. Reusser P, Riddell SR, Meyers JD et al. Cytotoxic T-lymphocyte response to cytomegalovirus after human allogeneic bone marrow transplantation: pattern of recovery and correlation with cytomegalovirus infection and disease. Blood 1991; 78: 1373–1380.

    CAS  PubMed  Google Scholar 

  12. Mohty M, Bay JO, Faucher C et al. Graft-versus-host disease following allogeneic transplantation from HLA-identical sibling with antithymocyte globulin-based reduced-intensity preparative regimen. Blood 2003; 102: 470–476.

    Article  CAS  PubMed  Google Scholar 

  13. Mohty M, Kuentz M, Michallet M et al. Chronic graft-versus-host disease after allogeneic blood stem cell transplantation: long-term results of a randomized study. Blood 2002; 100: 3128–3134.

    Article  CAS  PubMed  Google Scholar 

  14. Mohty M, Jarrossay D, Lafage-Pochitaloff M et al. Circulating blood dendritic cells from myeloid leukemia patients display quantitative and cytogenetic abnormalities as well as functional impairment. Blood 2001; 98: 3750–3756.

    Article  CAS  PubMed  Google Scholar 

  15. Mohty M, Isnardon D, Blaise D et al. Identification of precursors of leukemic dendritic cells differentiated from patients with acute myeloid leukemia. Leukemia 2002; 16: 2267–2274.

    Article  CAS  PubMed  Google Scholar 

  16. Mohty M, Stoppa AM, Blaise D et al. Differential regulation of dendritic cell function by the immunomodulatory drug thalidomide. J Leukocyte Biol 2002; 72: 939–945.

    CAS  PubMed  Google Scholar 

  17. Gooley TA, Leisenring W, Crowley J et al. 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 

  18. Cox DR . Regression models and life-tables (with discussions), Series B. J Roy Stat Soc 1972; 34: 187–220.

    Google Scholar 

  19. Boeckh M . Current antiviral strategies for controlling cytomegalovirus in hematopoietic stem cell transplant recipients: prevention and therapy. Transpl Infect Dis 1999; 1: 165–178.

    Article  CAS  PubMed  Google Scholar 

  20. Speiser DE, Colonna M, Ayyoub M et al. The activatory receptor 2B4 is expressed in vivo by human CD8+ effector alpha beta T cells. J Immunol 2001; 167: 6165–6170.

    Article  CAS  PubMed  Google Scholar 

  21. Gamadia LE, Rentenaar RJ, Baars PA et al. Differentiation of cytomegalovirus-specific CD8(+) T cells in healthy and immunosuppressed virus carriers. Blood 2001; 98: 754–761.

    Article  CAS  PubMed  Google Scholar 

  22. Gamadia LE, Remmerswaal EB, Weel JF et al. Primary immune responses to human CMV: a critical role for IFN-gamma-producing CD4+ T cells in protection against CMV disease. Blood 2003; 101: 2686–2692.

    Article  CAS  PubMed  Google Scholar 

  23. Chen G, Shankar P, Lange C et al. CD8T cells specific for human immunodeficiency virus, Epstein–Barr virus, and cytomegalovirus lack molecules for homing to lymphoid sites of infection. Blood 2001; 98: 156–164.

    Article  CAS  PubMed  Google Scholar 

  24. Cwynarski K, Ainsworth J, Cobbold M et al. Direct visualization of cytomegalovirus-specific T-cell reconstitution after allogeneic stem cell transplantation. Blood 2001; 97: 1232–1240.

    Article  CAS  PubMed  Google Scholar 

  25. Gratama JW, van Esser JW, Lamers CH et al. Tetramer-based quantification of cytomegalovirus (CMV)-specific CD8+ T lymphocytes in T-cell-depleted stem cell grafts and after transplantation may identify patients at risk for progressive CMV infection. Blood 2001; 98: 1358–1364.

    Article  CAS  PubMed  Google Scholar 

  26. Einsele H, Ehninger G, Steidle M et al. Lymphocytopenia as an unfavorable prognostic factor in patients with cytomegalovirus infection after bone marrow transplantation. Blood 1993; 82: 1672–1678.

    CAS  PubMed  Google Scholar 

  27. Hertenstein B, Hampl W, Bunjes D et al. In vivo/ex vivo T cell depletion for GVHD prophylaxis influences onset and course of active cytomegalovirus infection and disease after BMT. Bone Marrow Transplant 1995; 15: 387–393.

    CAS  PubMed  Google Scholar 

  28. Junghanss C, Boeckh M, Carter RA et al. Incidence and outcome of cytomegalovirus infections following nonmyeloablative compared with myeloablative allogeneic stem cell transplantation, a matched control study. Blood 2002; 99: 1978–1985.

    Article  CAS  PubMed  Google Scholar 

  29. Yu C, Seidel K, Nash RA et al. Synergism between mycophenolate mofetil and cyclosporine in preventing graft-versus-host disease among lethally irradiated dogs given DLA-nonidentical unrelated marrow grafts. Blood 1998; 91: 2581–2587.

    CAS  PubMed  Google Scholar 

  30. Allison AC, Eugui EM . Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF). Clin Transplant 1996; 10: 77–84.

    CAS  PubMed  Google Scholar 

  31. Mohty M, Gaugler B, Faucher C et al. Recovery of lymphocyte and dendritic cell subsets following reduced intensity allogeneic bone marrow transplantation. Hematology 2002; 7: 157–164.

    Article  CAS  PubMed  Google Scholar 

  32. Faucher C, Mohty M, Vey N et al. Bone marrow as stem cell source for allogeneic HLA-identical sibling transplantation following reduced-intensity preparative regimen. Exp Hematol 2003; 31: 873–880.

    Article  PubMed  Google Scholar 

  33. Li CR, Greenberg PD, Gilbert MJ et al. Recovery of HLA-restricted cytomegalovirus (CMV)-specific T-cell responses after allogeneic bone marrow transplant: correlation with CMV disease and effect of ganciclovir prophylaxis. Blood 1994; 83: 1971–1979.

    CAS  PubMed  Google Scholar 

  34. Einsele H, Roosnek E, Rufer N et al. Infusion of cytomegalovirus (CMV)-specific T cells for the treatment of CMV infection not responding to antiviral chemotherapy. Blood 2002; 99: 3916–3922.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by the ‘Action Thématique Concertée (ATC) biothérapie’ (INSERM; coordinator: D Olive) and the ARECA project of the Association pour la Recherche sur le Cancer (ARC; coordinator: D Blaise) and by grants from the ‘Association Sang pour Cent la Vie’ (Paris, France) and from the ‘Ligue Departementale contre le Cancer du Gard’ (Nimes, France) (to MM). MM was also supported by the ‘Association Mediterraneenne pour le Developpement de la Transplantation’ (Marseille, France). We thank the ‘Association pour la Recherche sur le Cancer (ARC)’, the ‘Ligue Nationale contre le Cancer’ and the GEFLUC for their generous and continued support for our ongoing work. We thank the nursing staff for providing excellent care for our patients and S Jut-Landi and N Baratier for excellent technical assistance. We also thank the following physicians at the Institut Paoli-Calmettes for their dedicated patient care: A Gonçalves, F Viret, AC Braud, N Vey, GL Damaj, V Ivanov, AM Stoppa, RT Costello, JM Schiano de Collela, A Charbonnier, R Bouabdallah, D Coso, C Chabannon, G Novakovitch and P Ladaique.

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Author notes

  1. A M Mohty: MM and AMM contributed equally to this study.

Authors and Affiliations

  1. Unité de Transplantation et de Thérapie Cellulaire (UTTC), Institut Paoli-Calmettes, Marseille, France

    M Mohty, D Blaise, C Faucher & K Bilger

  2. Laboratoire d'Immunologie des Tumeurs, Institut Paoli-Calmettes, Marseille, France

    M Mohty, A M Mohty, D Isnardon, D Olive & B Gaugler

  3. Département d'Hématologie, Institut Paoli-Calmettes and Université de la Méditerranée, Marseille, France

    D Blaise & J A Gastaut

  4. Département de Biologie, Institut Paoli-Calmettes and Université de la Méditerranée, Marseille, France

    D Sainty

  5. Département d'Oncologie Médicale, Institut Paoli-Calmettes and Université de la Méditerranée, Marseille, France

    P Viens

  6. Institut National de la Santé et de la Recherche Médicale (INSERM), U119, Marseille, France

    D Olive & B Gaugler

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  1. M Mohty
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Correspondence to M Mohty.

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Mohty, M., Mohty, A., Blaise, D. et al. Cytomegalovirus-specific immune recovery following allogeneic HLA-identical sibling transplantation with reduced-intensity preparative regimen. Bone Marrow Transplant 33, 839–846 (2004). https://doi.org/10.1038/sj.bmt.1704442

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