International Journal of Hematology

, Volume 80, Issue 5, pp 441–448 | Cite as

Reconstitution of HLA-A*2402-Restricted Cytomegalovirus-Specific T-Cells Following Stem Cell Transplantation

  • Hisashi Gondo
  • Daisuke Himeji
  • Kenjiro Kamezaki
  • Akihiko Numata
  • Tetsuya Tanimoto
  • Ken Takase
  • Kenichi Aoki
  • Hideho Henzan
  • Koji Nagafuji
  • Toshihiro Miyamoto
  • Fumihiko Ishikawa
  • Kazuya Shimoda
  • Shuichi Inaba
  • Hiroshi Tsukamoto
  • Takahiko Horiuchi
  • Hitoshi Nakashima
  • Takeshi Otsuka
  • Koji Kato
  • Mika Kuroiwa
  • Masakazu Higuchi
  • Tsunefumi Shibuya
  • Tomohiko Kamimura
  • Kiyotaka Kuzushima
  • Tatsuya Tsurumi
  • Yoshinobu Kanda
  • Mine Harada
Article

Abstract

Cytomegalovirus (CMV)-specific immune reconstitution early after stem cell transplantation (SCT) was evaluated prospectively by detecting CD8+ T-cells, which recognize the peptide QYDPVAALF in the context of HLA-A*2402. Fifteen allogeneic SCT recipients were included in the study. All recipients and donors were seropositive for CMV and had the HLA-A*2402 allele. CMV-specific T-cells were detected as early as 1 month after transplantation, and their numbers increased to peak levels 2 to 5 months after transplantation. The numbers of CMV-specific T-cells in patients who developed grade II to IV acute graft-versus-host disease (GVHD) and received corticosteroids for acute GVHD were low in the early period after allogeneic SCT. There was a trend toward earlier reconstitution of CMV-specific CD8+ T-cells in allogeneic peripheral blood SCT (PBSCT) patients than in allogeneic bone marrow transplantation patients. The contribution of T-cells in the graft to the recovery of CMV-specific immune responses was also suggested by the finding that the reconstitution of CMV-specific CD8+ T-cells was delayed in CD34-selected autologous PBSCT compared with unpurged autologous PBSCT. The reconstitution of CMV-specific CD8+ T-cells was delayed in patients with CMV disease or recurrent CMV reactivation. These observations suggest that the detection of CMV-specific T-cells with an HLA-peptide tetramer is useful to assess immune reconstitution against CMV and to identify patients at risk for CMV disease or recurrent CMV reactivation after SCT.

Key words

HLA-A*2402 Cytomegalovirus CMV-specific T-cells Stem cell transplantation Tetramer 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Zaia JA. Cytomegalovirus infection. In: Thomas ED, Blume KG, Forman SJ, eds. Hematopoietic Cell Transplantation. Malden, Mass: Blackwell Science; 1999;560–583.Google Scholar
  2. 2.
    Boeckh M, Gooley TA, Myerson D, Cunningham T, Schoch G, Bowden RA. Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study. Blood. 1996;88:4063–4071.PubMedGoogle Scholar
  3. 3.
    Li CR, Greenberg PD, Gilbert MJ, Goodrich JM, Riddell SR. 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.PubMedGoogle Scholar
  4. 4.
    Drew WL, Miner RC, Busch DF, et al. Prevalence of resistance in patients receiving ganciclovir for serious cytomegalovirus infection. J Infect Dis. 1991;163:716–719.CrossRefPubMedGoogle Scholar
  5. 5.
    Erice A, Borrell N, Li W, Miller WJ, Balfour HH Jr. Ganciclovir susceptibilities and analysis of UL97 region in cytomegalovirus (CMV) isolates from bone marrow recipients with CMV disease after antiviral prophylaxis. J Infect Dis. 1998;178:531–534.CrossRefGoogle Scholar
  6. 6.
    Nichols WG, Corey L, Gooley T, et al. Rising pp65 antigenemia during preemptive anticytomegalovirus therapy after allogeneic hematopoietic stem cell transplantation: risk factors, correlation with DNA load, and outcomes. Blood. 2001;97:867–874.CrossRefPubMedGoogle Scholar
  7. 7.
    Miller W, Flynn P, McCullough J, et al. Cytomegalovirus infection after bone marrow transplantation: an association with acute graftv-host disease. Blood. 1986;67:1162–1167.PubMedGoogle Scholar
  8. 8.
    Slavin MA, Bindra RR, Gleaves CA, Pettinger MB, Bowden RA. Ganciclovir sensitivity of cytomegalovirus at diagnosis and during treatment of cytomegalovirus pneumonia in marrow transplant recipients. Antimicrob Agents Chemother. 1993;37:1360–1363.CrossRefPubMedGoogle Scholar
  9. 9.
    Riddell SR, Watanabe KS, Goodrich JM, Li CR, Agha ME, Greenberg PD. Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science. 1992;257:238–241.CrossRefPubMedGoogle Scholar
  10. 10.
    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.CrossRefPubMedGoogle Scholar
  11. 11.
    Walter EA, Greenberg PD, Gilbert MJ, et al. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med. 1995;333:1038–1044.CrossRefGoogle Scholar
  12. 12.
    Herr W, Schneider AW, Lohse KH, Meyer zum Büschenfelde KH, Wölfel T. Detection and quantification of blood-derived CD8+ Tlymphocytes secreting tumor necrosis factor α in response to HLA-A2.1-binding melanoma and viral peptide antigens. J Immunol Methods. 1996;191:131–142.CrossRefPubMedGoogle Scholar
  13. 13.
    Waldrop SL, Pitcher CJ, Peterson DM, Maino VC, Picker LJ. Determination of antigen-specific memory/effector CD4+ T cell frequencies by flow cytometry: evidence for a novel, antigen-specific homeostatic mechanism in HIV-associated immunodeficiency. J Clin Invest. 1997;99:1739–1750.CrossRefPubMedGoogle Scholar
  14. 14.
    Kuzushima K, Hayashi N, Kimura H, Tsurumi T. Efficient identification of HLA-A*2402-restricted cytomegalovirus-specific CD8+ T-cell epitopes by a computer algorithm and an enzyme-linked immunospot assay. Blood. 2001;98:1872–1881.CrossRefPubMedGoogle Scholar
  15. 15.
    Hebart H, Daginik S, Stevanovic S, et al. Sensitive detection of human cytomegalovirus peptide-specific cytotoxic T-lymphocyte responses by interferon-γ-enzyme-linked immunospot assay and flow cytometry in healthy individuals and in patients after allogeneic stem cell transplantation. Blood. 2002;99:3830–3837.CrossRefPubMedGoogle Scholar
  16. 16.
    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.CrossRefPubMedGoogle Scholar
  17. 17.
    Gratama JW, van Esser JWJ, Lamers CHJ, 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.CrossRefPubMedGoogle Scholar
  18. 18.
    Gratama JW, Cornelissen JJ. Diagnostic potential of tetramerbased monitoring of cytomegalovirus-specific CD8+ T lymphocytes in allogeneic stem cell transplantation. Clin Immunol. 2003;106:29–35.CrossRefPubMedGoogle Scholar
  19. 19.
    Park MH, Juji T, Tokunaga K. HLA ethnic study of Japanese and Koreans. In: Tsuji K, Aizawa M, Sasazuki T, eds. HLA 1991. Vol 1. Oxford, UK: Oxford University Press; 1992;674–676.Google Scholar
  20. 20.
    Imanishi T, Akaza T, Kimura A, Tokunaga K, Gojoberi T. Allele and haplotype frequencies for HLA and complement loci in various ethnic groups. In: Tsuji K, Aizawa M, Sasazuki T, eds. HLA 1991. Vol 1. Oxford, UK: Oxford University Press; 1992;1065–1220.Google Scholar
  21. 21.
    Tokunaga K, Ishikawa Y, Ogawa A, et al. Sequence-based association analysis of HLA class I and II alleles in Japanese supports conservation of common haplotypes. Immunogenetics. 1997;46:199–205.CrossRefPubMedGoogle Scholar
  22. 22.
    Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15:825–828.PubMedGoogle Scholar
  23. 23.
    Gondo H, Harada M, Miyamoto T, et al. Autologous peripheral blood stem cell transplantation for acute myelogenous leukemia. Bone Marrow Transplant. 1997;20:821–826.CrossRefPubMedGoogle Scholar
  24. 24.
    Gondo H, Minematsu T, Harada M, et al. Cytomegalovirus (CMV) antigenaemia for rapid diagnosis and monitoring of CMV-associated disease after bone marrow transplantation. Br J Haematol. 1994;86:130–137.CrossRefPubMedGoogle Scholar
  25. 25.
    Machida U, Kami M, Fukui T, et al. Real-time automated PCR for early diagnosis and monitoring of cytomegalovirus infection after bone marrow transplantation. J Clin Microbiol. 2000;38:2536–2542. 26. Ljungman P, Griffiths P. Definitions of cytomegalovirus infection and disease. In: Michelson S, Plotkin SA, eds. Multidisciplinary Approach to Understanding Cytomegalovirus Disease. Amsterdam, the Netherlands: Elsevier Science; 1993;233-237.PubMedGoogle Scholar
  26. 27.
    Kondo E, Akatsuka Y, Kuzushima K, et al. Identification of novel CTL epitopes of CMV-pp65 presented by a variety of HLA alleles. Blood. 2004;103:630–638.CrossRefPubMedGoogle Scholar
  27. 28.
    Boeckh M, Leisenring W, Riddell SR, et al. Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and T-cell immunity. Blood. 2003;101:407–414.CrossRefPubMedGoogle Scholar
  28. 29.
    Hakki M, Riddell SR, Storek J, et al. Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy, and subclinical reactivation. Blood. 2003;102:3060–3067.CrossRefPubMedGoogle Scholar
  29. 30.
    Lacey SF, Gallez-Hawkins G, Crooks M, et al. Characterization of cytotoxic function of CMV-pp65-specific CD8+ T-lymphocytes identified by HLA tetramers in recipients and donors of stem-cell transplants. Transplantation. 2002;74:722–732.CrossRefPubMedGoogle Scholar
  30. 31.
    Hazenberg MD, Otto SA, de Pauw ES, et al. T-cell receptor excision circle and T-cell dynamics after allogeneic stem cell transplantation are related to clinical events. Blood. 2002;99:3449–3453.CrossRefPubMedGoogle Scholar
  31. 32.
    Gillespie GM, Wills MR, Appay V, et al. Functional heterogeneity and high frequencies of cytomegalovirus-specific CD8+ T lymphocytes in healthy seropositive donors. J Virol. 2000;74:8140–8150. 33.Noga SJ, Civin CI. Positive stem-cell selection for hematopoietic transplantation. In: Ferrara JLM, Deeg HJ, Burakoff SJ, eds. Graftversus-Host Disease. New York, NY: Marcel Dekker; 1997;717-732.CrossRefPubMedGoogle Scholar
  32. 34.
    Crippa F, Holmberg L, Carter RA, et al. Infectious complications after autologous CD34-selected peripheral blood stem cell transplantation. Biol Blood Marrow Transplant. 2002;8:281–289.CrossRefPubMedGoogle Scholar
  33. 35.
    Rutella S, Pierelli L, Sica S, Rumi C, Leone G. Transplantation of autologous peripheral blood progenitor cells: impact of CD34-cell selection on immunological reconstitution. Leuk Lymphoma. 2001; 42:1207–1220.CrossRefPubMedGoogle Scholar
  34. 36.
    Miyamoto T, Gondo H, Miyoshi Y, et al. Early viral complications following CD34-selected autologous peripheral blood stem cell transplantation for non-Hodgkin’s lymphoma. Br J Haematol. 1998;100:348–350.CrossRefPubMedGoogle Scholar
  35. 37.
    Holmberg LA, Boeckh M, Hooper H, et al. Increased incidence of cytomegalovirus disease after autologous CD34-selected peripheral blood stem cell transplantation. Blood. 1999;94:4029–4035.PubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2004

Authors and Affiliations

  • Hisashi Gondo
    • 1
    • 2
  • Daisuke Himeji
    • 2
  • Kenjiro Kamezaki
    • 2
  • Akihiko Numata
    • 2
  • Tetsuya Tanimoto
    • 2
  • Ken Takase
    • 2
  • Kenichi Aoki
    • 2
  • Hideho Henzan
    • 2
  • Koji Nagafuji
    • 2
  • Toshihiro Miyamoto
    • 2
  • Fumihiko Ishikawa
    • 2
  • Kazuya Shimoda
    • 2
  • Shuichi Inaba
    • 3
  • Hiroshi Tsukamoto
    • 2
  • Takahiko Horiuchi
    • 2
  • Hitoshi Nakashima
    • 2
  • Takeshi Otsuka
    • 2
  • Koji Kato
    • 1
  • Mika Kuroiwa
    • 1
  • Masakazu Higuchi
    • 1
  • Tsunefumi Shibuya
    • 1
  • Tomohiko Kamimura
    • 4
  • Kiyotaka Kuzushima
    • 5
  • Tatsuya Tsurumi
    • 5
  • Yoshinobu Kanda
    • 6
  • Mine Harada
    • 2
  1. 1.Department of HematologyHamanomachi HospitalFukuoka
  2. 2.Medicine and Biosystemic ScienceKyushu University Graduate School of Medical SciencesFukuoka
  3. 3.Blood Transfusion ServiceKyushu University HospitalFukuoka
  4. 4.Department of HematologyHarasanshin General HospitalFukuoka
  5. 5.Divisions of Immunology and VirologyAichi Cancer Center Research InstituteNagoya
  6. 6.Department of Cell Therapy and Transplantation MedicineUniversity of Tokyo HospitalTokyoJapan

Personalised recommendations