Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Cellular immunotherapy for viral infection after HSC transplantation

Nature Reviews Immunology volume 5, pages 9–20 (2005)Cite this article

Key Points

  • Allogeneic haematopoietic stem cell (HSC) transplantation (HSCT) involves complete replacement of the blood and immune systems of the patient with those of the donor.

  • HSCT is associated with marked immunosuppression, which extends for several months after transplantation until donor T cells can be generated de novo from donor HSCs in vivo. This leads to significant morbidity and mortality from bacterial and viral infections during the post-transplant period.

  • Donor T cells can be transferred with the donor HSC graft at the time of transplantation, and these provide some protection against infection. However, these T cells can mediate graft-versus-host disease, so the number of T cells that is transferred is often reduced during HSC processing.

  • Reactivation of latent herpesviruses, such as cytomegalovirus and Epstein–Barr virus, is a problem, and current antiviral agents do not provide complete protection against this. Reconstitution of a virus-specific immune response is required for sustained control of viral replication.

  • If the transplant donor has immunity to a specific virus, antigen-specific T cells can be cultured from the donor and subsequently infused into the patient. This has been successfully carried out in a series of studies to control the replication of cytomegalovirus and Epstein–Barr virus.

  • Techniques such as cytokine-secretion assays and the use of peptide–HLA tetramers allow the possibility of selecting antigen-specific T cells from the donor followed by direct infusion into the patient. These techniques have now been developed to clinical scale.

  • Several regulatory issues need to be overcome if cellular immunotherapy is to fulfil its potential for the control of infectious disease.

Abstract

Medical advances such as allogeneic transplantation can expose patients to periods of marked immunosuppression, during which viral infections are an important cause of morbidity and mortality. Control of infection will depend ultimately on the restoration of adequate antiviral immunity, and cellular immunotherapy is an attractive approach to improving immune protection. Developments in basic immunology have led to a greater understanding of the nature of protective immunity in immunocompetent donors, and this knowledge is now being used to direct immunotherapeutic protocols. Moreover, immunological techniques that have recently been developed as research tools, such as peptide–HLA tetramers and cytokine-secretion assays, have potential application for clinical use in this setting.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: T-cell immune reconstitution after allogeneic haematopoietic stem-cell transplantation.
Figure 2: The pattern of infectious disease after allogeneic haematopoietic stem-cell transplantation.
Figure 3: The evolution of adoptive T-cell therapy for viral infection after allogeneic haematopoietic stem-cell transplantation.

Similar content being viewed by others

References

  1. Thomas, E. D. The Nobel Lectures in Immunology. The Nobel Prize for Physiology or Medicine, 1990. Bone marrow transplantation — past, present and future. Scand. J. Immunol. 39, 339–345 (1994). A review of HSCT by the physician who won a Nobel Prize for its development.

    Article  CAS  PubMed  Google Scholar 

  2. Dumont-Girard, F. et al. Reconstitution of the T-cell compartment after bone marrow transplantation: restoration of the repertoire by thymic emigrants. Blood 92, 4464–4471 (1998).

    CAS  PubMed  Google Scholar 

  3. Douek, D. C. et al. Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution. Lancet 355, 1875–1881 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Roux, E. et al. Recovery of immune reactivity after T-cell-depleted bone marrow transplantation depends on thymic activity. Blood 96, 2299–2303 (2000).

    CAS  PubMed  Google Scholar 

  5. Dey, B., Sykes, M. & Spitzer, T. R. Outcomes of recipients of both bone marrow and solid organ transplants. A review. Medicine (Baltimore) 77, 355–369 (1998).

    Article  CAS  Google Scholar 

  6. Lewin, S. R. et al. Direct evidence for new T-cell generation by patients after either T-cell-depleted or unmodified allogeneic hematopoietic stem cell transplantations. Blood 100, 2235–2242 (2002).

    CAS  PubMed  Google Scholar 

  7. Bahceci, E. et al. Early reconstitution of the T-cell repertoire after non-myeloablative peripheral blood stem cell transplantation is from post-thymic T-cell expansion and is unaffected by graft-versus-host disease or mixed chimaerism. Br. J. Haematol. 122, 934–943 (2003).

    Article  PubMed  Google Scholar 

  8. Lewis, V. A. et al. Respiratory disease due to parainfluenza virus in adult bone marrow transplant recipients. Clin. Infect. Dis. 23, 1033–1037 (1996).

    Article  CAS  PubMed  Google Scholar 

  9. Whimbey, E., Englund, J. A. & Couch, R. B. Community respiratory virus infections in immunocompromised patients with cancer. Am. J. Med. 102, 10–18; discussion 25–26 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Sissons, J. G., Bain, M. & Wills, M. R. Latency and reactivation of human cytomegalovirus. J. Infect 44, 73–77 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Wills, M. R. et al. The human cytotoxic T-lymphocyte (CTL) response to cytomegalovirus is dominated by structural protein pp65: frequency, specificity, and T-cell receptor usage of pp65-specific CTL. J. Virol. 70, 7569–7579 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Weekes, M. P. et al. Large clonal expansions of human virus-specific memory cytotoxic T lymphocytes within the CD57+ CD28− CD8+ T-cell population. Immunology 98, 443–449 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gillespie, G. M. et al. Functional heterogeneity and high frequencies of cytomegalovirus-specific CD8+ T lymphocytes in healthy seropositive donors. J. Virol. 74, 8140–8150 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Waldrop, S. L., Davis, K. A., Maino, V. C. & Picker, L. J. Normal human CD4+ memory T cells display broad heterogeneity in their activation threshold for cytokine synthesis. J. Immunol. 161, 5284–5295 (1998).

    CAS  PubMed  Google Scholar 

  15. Khan, N. et al. Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J. Immunol. 169, 1984–1992 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Karrer, U. et al. Memory inflation: continuous accumulation of antiviral CD8+ T cells over time. J. Immunol. 170, 2022–2029 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Han, C. S., Miller, W., Haake, R. & Weisdorf, D. Varicella zoster infection after bone marrow transplantation: incidence, risk factors and complications. Bone Marrow Transplant. 13, 277–283 (1994).

    CAS  PubMed  Google Scholar 

  18. Soderberg-Naucler, C., Fish, K. N. & Nelson, J. A. Reactivation of latent human cytomegalovirus by allogeneic stimulation of blood cells from healthy donors. Cell 91, 119–126 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Broers, A. E. et al. Increased transplant-related morbidity and mortality in CMV-seropositive patients despite highly effective prevention of CMV disease after allogeneic T-cell-depleted stem cell transplantation. Blood 95, 2240–2245 (2000).

    CAS  PubMed  Google Scholar 

  20. Craddock, C. et al. Cytomegalovirus seropositivity adversely influences outcome after T-depleted unrelated donor transplant in patients with chronic myeloid leukaemia: the case for tailored graft-versus-host disease prophylaxis. Br. J. Haematol. 112, 228–236 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Quinnan, G. V. et al. HLA-restricted cytotoxic T lymphocytes are an early immune response and important defense mechanism in cytomegalovirus infections. Rev. Infect. Dis. 6, 156–163 (1984).

    Article  PubMed  Google Scholar 

  22. Reusser, P., Riddell, S. R., Meyers, J. D. & Greenberg, P. D. Cytotoxic T-lymphocyte response to cytomegalovirus after human allogeneic bone marrow transplantation: pattern of recovery and correlation with cytomegalovirus infection and disease. Blood 78, 1373–1380 (1991). An early study of antigen-specific immune reconstitution after HSCT, which indicates that patients who fail to develop cellular immunity to CMV are at increased risk of CMV disease.

    CAS  PubMed  Google Scholar 

  23. Li, C. R., Greenberg, P. D., Gilbert, M. J., Goodrich, J. M. & Riddell, S. R. 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 83, 1971–1979 (1994).

    CAS  PubMed  Google Scholar 

  24. Wursch, A. M. et al. The effect of cytomegalovirus infection on T lymphocytes after allogeneic bone marrow transplantation. Clin. Exp. Immunol. 62, 278–287 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Cwynarski, K. et al. Direct visualization of cytomegalovirus-specific T-cell reconstitution after allogeneic stem cell transplantation. Blood 97, 1232–1240 (2001). The first application of peptide–HLA tetramers to monitor antigen-specific immune reconstitution after HSCT. It indicates that several variables influence the generation of CMV-specific CD8+ T cells in this setting.

    Article  CAS  PubMed  Google Scholar 

  26. Aubert, G. et al. Cytomegalovirus-specific cellular immune responses and viremia in recipients of allogeneic stem cell transplants. J. Infect. Dis. 184, 955–963 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Hebart, H. 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 99, 3830–3837 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Gratama, J. W. 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 98, 1358–1364 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Einsele, H. et al. Lymphocytopenia as an unfavorable prognostic factor in patients with cytomegalovirus infection after bone marrow transplantation. Blood 82, 1672–1678 (1993).

    CAS  PubMed  Google Scholar 

  30. Reusser, P. et al. Cytomegalovirus-specific T-cell immunity in recipients of autologous peripheral blood stem cell or bone marrow transplants. Blood 89, 3873–3879 (1997).

    CAS  PubMed  Google Scholar 

  31. Walter, E. A. 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. 333, 1038–1044 (1995).

    Article  CAS  PubMed  Google Scholar 

  32. Gratama, J. W. et al. The influence of cytomegalovirus carrier status on lymphocyte subsets and natural immunity. Clin. Exp. Immunol. 69, 16–24 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Ljungman, P. et al. Cytomegalovirus viraemia and specific T-helper cell responses as predictors of disease after allogeneic marrow transplantation. Br. J. Haematol. 83, 118–124 (1993).

    Article  CAS  PubMed  Google Scholar 

  34. Ozdemir, E. et al. Cytomegalovirus reactivation following allogeneic stem cell transplantation is associated with the presence of dysfunctional antigen-specific CD8+ T cells. Blood 100, 3690–3697 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Engstrand, M. et al. Cellular responses to cytomegalovirus in immunosuppressed patients: circulating CD8+ T cells recognizing CMVpp65 are present but display functional impairment. Clin. Exp. Immunol. 132, 96–104 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rickinson, A. B. & Moss, D. J. Human cytotoxic T lymphocyte responses to Epstein–Barr virus infection. Annu. Rev. Immunol. 15, 405–431 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. Rickinson, A. B. & Kieff, E. in Fields Virology (eds Fields, B. N., Knipe, D. M. & Howley, P. M.) 296 (Lippincott Williams & Wilkins, Philadelphia, 2001).

    Google Scholar 

  38. Greenspan, J. S. et al. Replication of Epstein–Barr virus within the epithelial cells of oral 'hairy' leukoplakia, an AIDS-associated lesion. N. Engl. J. Med. 313, 1564–1571 (1985).

    Article  CAS  PubMed  Google Scholar 

  39. Paya, C. V. et al. Epstein–Barr virus-induced posttransplant lymphoproliferative disorders. ASTS/ASTP EBV-PTLD Task Force and The Mayo Clinic Organized International Consensus Development Meeting. Transplantation 68, 1517–1525 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. Starzl, T. E. et al. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet 1, 583–587 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Dotti, G. et al. Epstein–Barr virus-negative lymphoproliferate disorders in long-term survivors after heart, kidney, and liver transplant. Transplantation 69, 827–833 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Milpied, N. et al. Humanized anti-CD20 monoclonal antibody (Rituximab) in post transplant B-lymphoproliferative disorder: a retrospective analysis on 32 patients. Ann. Oncol. 11 (Suppl. 1), 113–116 (2000).

    Article  PubMed  Google Scholar 

  43. Grob, J. P. et al. Immune donors can protect marrow-transplant recipients from severe cytomegalovirus infections. Lancet 1, 774–776 (1987).

    Article  CAS  PubMed  Google Scholar 

  44. Boland, G. J., Vlieger, A. M., Ververs, C. & De Gast, G. C. Evidence for transfer of cellular and humoral immunity to cytomegalovirus from donor to recipient in allogeneic bone marrow transplantation. Clin. Exp. Immunol. 88, 506–511 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Storek, J. et al. Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation. Blood 97, 3380–3389 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Holmberg, L. A. et al. Increased incidence of cytomegalovirus disease after autologous CD34-selected peripheral blood stem cell transplantation. Blood 94, 4029–4035 (1999).

    CAS  PubMed  Google Scholar 

  47. Davison, G. M. et al. Immune reconstitution after allogeneic bone marrow transplantation depleted of T cells. Transplantation 69, 1341–1347 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Hromas, R. et al. Failure of ribavirin to clear adenovirus infections in T cell-depleted allogeneic bone marrow transplantation. Bone Marrow Transplant. 14, 663–664 (1994).

    CAS  PubMed  Google Scholar 

  49. Small, T. N. et al. Comparison of immune reconstitution after unrelated and related T-cell-depleted bone marrow transplantation: effect of patient age and donor leukocyte infusions. Blood 93, 467–480 (1999).

    CAS  PubMed  Google Scholar 

  50. Sullivan, K. M. et al. Graft-versus-host disease as adoptive immunotherapy in patients with advanced hematologic neoplasms. N. Engl. J. Med. 320, 828–834 (1989).

    Article  CAS  PubMed  Google Scholar 

  51. Kolb, H. J. et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 76, 2462–2465 (1990). Classic description of DLI for the treatment of leukaemia relapse after HSCT.

    CAS  PubMed  Google Scholar 

  52. Shlomchik, W. D. et al. Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science 285, 412–415 (1999). Important paper showing that 'direct' antigen presentation by host APCs initiates the T-cell immune response that causes GVHD.

    Article  CAS  PubMed  Google Scholar 

  53. Papadopoulos, E. B. et al. Infusions of donor leukocytes to treat Epstein–Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation. N. Engl. J. Med. 330, 1185–1191 (1994). Description of the use of unmanipulated DLI to treat EBV-associated PTLD.

    Article  CAS  PubMed  Google Scholar 

  54. Chakrabarti, S., Collingham, K. E., Fegan, C. D., Pillay, D. & Milligan, D. W. Adenovirus infections following haematopoietic cell transplantation: is there a role for adoptive immunotherapy? Bone Marrow Transplant. 26, 305–307 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Riddell, S. R. et al. Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science 257, 238–241 (1992). Landmark description of adoptive therapy with CMV-specific CD8+ T-cell lines for patients who have received an HSC transplant.

    Article  CAS  PubMed  Google Scholar 

  56. Einsele, H. et al. Infusion of cytomegalovirus (CMV)-specific T cells for the treatment of CMV infection not responding to antiviral chemotherapy. Blood 99, 3916–3922 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. Peggs, K., Verfuerth, S. & Mackinnon, S. Induction of cytomegalovirus (CMV)-specific T-cell responses using dendritic cells pulsed with CMV antigen: a novel culture system free of live CMV virions. Blood 97, 994–1000 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Maecker, H. T. et al. Factors affecting the efficiency of CD8+ T cell cross-priming with exogenous antigens. J. Immunol. 166, 7268–7275 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Peggs, K. S. et al. Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines. Lancet 362, 1375–1377 (2003).

    Article  PubMed  Google Scholar 

  60. Ribas, A., Butterfield, L. H., Glaspy, J. A. & Economou, J. S. Cancer immunotherapy using gene-modified dendritic cells. Curr. Gene Ther. 2, 57–78 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Ahuja, S. S. et al. Dendritic cell (DC)-based anti-infective strategies: DCs engineered to secrete IL-12 are a potent vaccine in a murine model of an intracellular infection. J. Immunol. 163, 3890–3897 (1999).

    CAS  PubMed  Google Scholar 

  62. Rooney, C. M. et al. Use of gene-modified virus-specific T lymphocytes to control Epstein–Barr-virus-related lymphoproliferation. Lancet 345, 9–13 (1995). Demonstration of the value of EBV-specific CD8+ T-cell infusions to control EBV-associated PTLD after HSCT.

    Article  CAS  PubMed  Google Scholar 

  63. Rooney, C. M. et al. Infusion of cytotoxic T cells for the prevention and treatment of Epstein–Barr virus-induced lymphoma in allogeneic transplant recipients. Blood 92, 1549–1555 (1998).

    CAS  PubMed  Google Scholar 

  64. Savoldo, B. et al. Generation of EBV-specific CD4+ cytotoxic T cells from virus naive individuals. J. Immunol. 168, 909–918 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Gottschalk, S. et al. An Epstein–Barr virus deletion mutant associated with fatal lymphoproliferative disease unresponsive to therapy with virus-specific CTLs. Blood 97, 835–843 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Gustafsson, A. et al. Epstein–Barr virus (EBV) load in bone marrow transplant recipients at risk to develop posttransplant lymphoproliferative disease: prophylactic infusion of EBV-specific cytotoxic T cells. Blood 95, 807–814 (2000).

    CAS  PubMed  Google Scholar 

  67. Khanna, R. et al. Activation and adoptive transfer of Epstein–Barr virus-specific cytotoxic T cells in solid organ transplant patients with posttransplant lymphoproliferative disease. Proc. Natl Acad. Sci. USA 96, 10391–10396 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. Savoldo, B. et al. Generation of autologous Epstein–Barr virus-specific cytotoxic T cells for adoptive immunotherapy in solid organ transplant recipients. Transplantation 72, 1078–1086 (2001).

    Article  CAS  PubMed  Google Scholar 

  69. Comoli, P. et al. Infusion of autologous Epstein–Barr virus (EBV)-specific cytotoxic T cells for prevention of EBV-related lymphoproliferative disorder in solid organ transplant recipients with evidence of active virus replication. Blood 99, 2592–2598 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Haque, T. et al. Complete regression of posttransplant lymphoproliferative disease using partially HLA-matched Epstein Barr virus-specific cytotoxic T cells. Transplantation 72, 1399–1402 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Haque, T. et al. Treatment of Epstein–Barr-virus-positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells. Lancet 360, 436–442 (2002). Demonstration that third-party EBV-specific T cells are useful for controlling EBV-associated PTLD.

    Article  PubMed  Google Scholar 

  72. Heslop, H. E. et al. Long-term restoration of immunity against Epstein–Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes. Nature Med. 2, 551–555 (1996). Demonstration of the use of retroviral gene marking to show that EBV-specific T cells survive for prolonged periods after adoptive transfer.

    Article  CAS  PubMed  Google Scholar 

  73. Rossig, C., Bollard, C. M., Nuchtern, J. G., Rooney, C. M. & Brenner, M. K. Epstein–Barr virus-specific human T lymphocytes expressing antitumor chimeric T-cell receptors: potential for improved immunotherapy. Blood 99, 2009–2016 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. van Esser, J. W. et al. Prevention of Epstein–Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation. Blood 99, 4364–4369 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Meij, P. et al. Impaired recovery of Epstein–Barr virus (EBV)-specific CD8+ T lymphocytes after partially T-depleted allogeneic stem cell transplantation may identify patients at very high risk for progressive EBV reactivation and lymphoproliferative disease. Blood 101, 4290–4297 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Wagner, H. J. et al. Prompt versus pre-emptive intervention for EBV lymphoproliferative disease. Blood 103, 3979–3981 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Kessels, H. W., Wolkers, M. C., van den Boom, M. D., van der Valk, M. A. & Schumacher, T. N. Immunotherapy through TCR gene transfer. Nature Immunol. 2, 957–961 (2001).

    Article  CAS  Google Scholar 

  78. Stanislawski, T. et al. Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer. Nature Immunol. 2, 962–970 (2001).

    Article  CAS  Google Scholar 

  79. Brugger, S. A. et al. Hepatitis B virus clearance by transplantation of bone marrow from hepatitis B immunised donor. Lancet 349, 996–997 (1997).

    Article  CAS  PubMed  Google Scholar 

  80. Wimperis, J. Z. et al. Transfer of a functioning humoral immune system in transplantation of T-lymphocyte-depleted bone marrow. Lancet 1, 339–343 (1986).

    Article  CAS  PubMed  Google Scholar 

  81. Altman, J. D. et al. Phenotypic analysis of antigen-specific T lymphocytes. Science 274, 94–96 (1996). The first report of the development of peptide–HLA tetramers.

    Article  CAS  PubMed  Google Scholar 

  82. Keenan, R. D. et al. Purification of cytomegalovirus-specific CD8 T cells from peripheral blood using HLA–peptide tetramers. Br. J. Haematol. 115, 428–434 (2001).

    Article  CAS  PubMed  Google Scholar 

  83. Tan, R. et al. Rapid death of adoptively transferred T cells in acquired immunodeficiency syndrome. Blood 93, 1506–1510 (1999).

    CAS  PubMed  Google Scholar 

  84. Manz, R., Assenmacher, M., Pfluger, E., Miltenyi, S. & Radbruch, A. Analysis and sorting of live cells according to secreted molecules, relocated to a cell-surface affinity matrix. Proc. Natl Acad. Sci. USA 92, 1921–1925 (1995). Description of the development of the cytokine-secretion assay, which allows the selection of live antigen-specific T cells.

    Article  CAS  PubMed  Google Scholar 

  85. Brosterhus, H. et al. Enrichment and detection of live antigen-specific CD4+ and CD8+ T cells based on cytokine secretion. Eur. J. Immunol. 29, 4053–4059 (1999).

    Article  CAS  PubMed  Google Scholar 

  86. Rauser, G. et al. Rapid generation of combined CMV-specific CD4+ and CD8+ T-cell lines for adoptive transfer into recipients of allogeneic stem cell transplants. Blood 103, 3565–3572 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Feuchtinger, T. et al. Isolation and expansion of human adenovirus-specific CD4+ and CD8+ T cells according to IFN-γ secretion for adjuvant immunotherapy. Exp. Hematol. 32, 282–289 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Boon, A. C. et al. The magnitude and specificity of influenza A virus-specific cytotoxic T-lymphocyte responses in humans is related to HLA-A and -B phenotype. J. Virol. 76, 582–590 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Mann, D., Moreb, J., Smith, S. & Gian, V. Failure of intravenous ribavirin in the treatment of invasive adenovirus infection following allogeneic bone marrow transplantation: a case report. J. Infect. 36, 227–228 (1998).

    Article  CAS  PubMed  Google Scholar 

  90. La Rosa, A. M. et al. Adenovirus infections in adult recipients of blood and marrow transplants. Clin. Infect. Dis. 32, 871–876 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Regn, S. et al. Ex vivo generation of cytotoxic T lymphocytes specific for one or two distinct viruses for the prophylaxis of patients receiving an allogeneic bone marrow transplant. Bone Marrow Transplant. 27, 53–64 (2001).

    Article  CAS  PubMed  Google Scholar 

  92. Leen, A. M. et al. Fiber-modified adenoviruses generate subgroup cross-reactive, adenovirus-specific cytotoxic T lymphocytes for therapeutic applications. Blood 103, 1011–1019 (2004).

    Article  CAS  PubMed  Google Scholar 

  93. Leen, A. M. et al. Conserved CTL epitopes on the adenovirus hexon protein expand subgroup cross-reactive and subgroup-specific CD8+ T cells. Blood 104, 2432–2440 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Selby, P. J. et al. The prophylactic role of intravenous and long-term oral acyclovir after allogeneic bone marrow transplantation. Br. J. Cancer 59, 434–438 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cancer Research UK Institute for Cancer Studies, University of Birmingham, B15 2TA, Birmingham, UK

    Paul Moss & Alan Rickinson

Authors
  1. Paul Moss
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alan Rickinson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul Moss.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Infectious Disease Information

CMV

EBV

influenza virus

parainfluenza virus

Pneumocystis jirovecii

respiratory syncytial virus

VZV

Glossary

ALLOGENEIC TRANSPLANTATION

Transplantation of genetically different tissue or cells from another individual of the same species. This can elicit an immune response, which might result in either graft rejection or graft-versus-host disease.

HISTOINCOMPATIBILITY

Genetic difference — between a transplant donor and recipient — that is recognized as 'foreign' by the immune system of the recipient and leads to an immune response to the tissue.

IMMUNODOMINANT EPITOPES

The antigenic components of a complex mixture (such as a whole virus or tumour cell) that are preferentially recognized during an immune response.

GRAFT-VERSUS-HOST DISEASE

(GVHD). Tissue damage in a recipient of allogeneic tissue (usually a bone-marrow transplant) that results from the activity of donor cytotoxic T-lymphocytes recognizing the tissues of the recipient as foreign. GVHD varies markedly in extent, but it can be life threatening in severe cases. Damage to the liver, skin and gut mucosa are common clinical manifestations.

MYELOABLATIVE

Permanently destroys the haematopoietic capacity of the bone marrow.

CENTRAL TOLERANCE

T-cell tolerance generated in the thymus by the deletion of high-avidity autoreactive cells.

NON-PERSISTENT VIRUSES

Viruses, such as influenza virus, that are cleared from the host after acute infection.

PERSISTENT VIRUSES

Viruses that persist in the host after primary infection and are never cleared. The human herpesviruses belong to this category.

PEPTIDE–HLA TETRAMERS

Multivalent complexes of refolded peptide–HLA subunits that are fluorescently tagged and bind T cells specific for the peptide.

CYTOKINE ANALYSIS

Determination of cellular cytokine production using intracellular staining for cytokines or enzyme-linked immunosorbent assays that measure levels of secreted molecules.

STEROID THERAPY

Steroids are lymphocytotoxic and are widely used for the treatment of autoimmune diseases. In the setting of transplantation, they are used to suppress alloreactive immune responses that cause graft-versus-host disease or graft rejection.

GRANULOCYTE COLONY-STIMULATING FACTOR

(G-CSF). A natural molecule, the recombinant form of which is used in clinical situations to boost neutrophil numbers after periods of neutropaenia or to mobilize haematopoietic stem cells (HSCs) from the bone marrow into the bloodstream before leukapheresis to aid the collection of HSCs.

T-CELL RECEPTOR CLONOTYPING

(TCR clonotyping). The use of PCR to determine the TCR usage of a T-cell population. Because the TCR of each T cell is encoded by a uniquely rearranged set of genes, this technique can identify clonal expansions of T cells in a mixed population.

LEUKAPHERESIS

Specific collection of leukocytes from the blood. This is carried out by centrifugation of blood to remove the leukocytes and re-infusion of the erythrocytes into the patient.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moss, P., Rickinson, A. Cellular immunotherapy for viral infection after HSC transplantation. Nat Rev Immunol 5, 9–20 (2005). https://doi.org/10.1038/nri1526

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1526

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing