Cancer Immunology, Immunotherapy

, Volume 58, Issue 9, pp 1481–1488 | Cite as

The prevention and treatment of cytomegalovirus infection in haematopoietic stem cell transplantation

  • Mark Tuthill
  • Frederick Chen
  • Samantha Paston
  • Hugo De La Peña
  • Sylvie Rusakiewicz
  • Alejandro Madrigal
Focussed Research Review

Abstract

Allogeneic haematopoietic stem cell transplantation (HSCT) is an intensive medical treatment involving myeloablative chemo-radiotherapy followed by stem cell rescue using allogeneic haematopoietic stem cells harvested from HLA-matched donors, which is primarily used for the treatment of haematological malignancies. Cytomegalovirus (CMV) infection is one of the major causes of morbidity and death after HSCT. This focused research review highlights the advances made with research into CMV in the HSCT setting. It provides the reader with an overview of current CMV research into the prevention and management of CMV infection.

Keywords

CMV Vaccine Adoptive cellular therapy Artificial antigen presenting cells 

References

  1. 1.
    Kolb HJ, Schattenberg A, Goldman JM et al (1995) Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 86:2041–2050PubMedGoogle Scholar
  2. 2.
    Gratwohl A, Brand R, Frassoni F et al (2005) Cause of death after allogeneic haematopoietic stem cell transplantation (HSCT) in early leukaemias: an EBMT analysis of lethal infectious complications and changes over calendar time. Bone Marrow Transplant 36:757–769PubMedCrossRefGoogle Scholar
  3. 3.
    Fischer SA (2008) Emerging viruses in transplantation: there is more to infection after transplant than CMV and EBV. Transplantation 86:1327–1339PubMedCrossRefGoogle Scholar
  4. 4.
    Alford CA, Stagno S, Pass RF, Britt WJ (1990) Congenital and perinatal cytomegalovirus infections. Rev Infect Dis 12:S745–S753PubMedGoogle Scholar
  5. 5.
    Paston SJ, Dodi IA, Madrigal JA (2004) Progress made towards the development of a CMV peptide vaccine. Hum Immunol 65:544–549PubMedCrossRefGoogle Scholar
  6. 6.
    Gamadia LE, Remmerswaal EB, Weel JF et al (2003) Primary immune responses to human CMV: a critical role for IFN-gamma-producing CD4+ T cells in protection against CMV disease. Blood 101:2686–2692PubMedCrossRefGoogle Scholar
  7. 7.
    Casazza JP, Betts MR, Price DA et al (2006) Acquisition of direct antiviral effector functions by CMV-specific CD4+ T lymphocytes with cellular maturation. J Exp Med 203:2865–2877PubMedCrossRefGoogle Scholar
  8. 8.
    Pourgheysari B, Piper KP, McLarnon A et al (2008) Early reconstitution of effector memory CD4+ CMV-specific T cells protects against CMV reactivation following allogeneic SCT. Bone Marrow Transplant [Epub ahead of print]Google Scholar
  9. 9.
    Wills MR, Carmichael AJ, Mynard K et al (1996) 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 70:7569–7579PubMedGoogle Scholar
  10. 10.
    Riddell SR, Rabin M, Geballe AP et al (1991) Class I MHC-restricted cytotoxic T lymphocyte recognition of cells infected with human cytomegalovirus does not require endogenous viral gene expression. J Immunol 146:2795–2804PubMedGoogle Scholar
  11. 11.
    Solache A, Morgan CL, Dodi AI et al (1999) Identification of three HLA-A*0201-restricted cytotoxic T cell epitopes in the cytomegalovirus protein pp65 that are conserved between eight strains of the virus. J Immunol 163:5512–5518PubMedGoogle Scholar
  12. 12.
    Kern F, Surel IP, Faulhaber N et al (1999) Target structures of the CD8(+)-T-cell response to human cytomegalovirus: the 72-kilodalton major immediate-early protein revisited. J Virol 73:8179–8184PubMedGoogle Scholar
  13. 13.
    Gyulai Z, Endresz V, Burian K et al (2000) Cytotoxic T lymphocyte (CTL) responses to human cytomegalovirus pp65, IE1-Exon4, gB, pp150, and pp28 in healthy individuals: reevaluation of prevalence of IE1-specific CTLs. J Infect Dis 181:1537–1546PubMedCrossRefGoogle Scholar
  14. 14.
    Stanley SM, Dodi IA, Evans CR et al (2006) Layer guided-acoustic plate mode biosensors for monitoring MHC-peptide interactions. Analyst 131:892–894PubMedCrossRefGoogle Scholar
  15. 15.
    Lacey SF, Villacres MC, La Rosa C et al (2003) Relative dominance of HLA-B*07 restricted CD8+ T-lymphocyte immune responses to human cytomegalovirus pp65 in persons sharing HLA-A*02 and HLA-B*07 alleles. Hum Immunol 64:440–452PubMedCrossRefGoogle Scholar
  16. 16.
    Höllsberg P (2002) Contribution of HLA class I allele expression to CD8+ T-cell responses against Epstein-Barr virus. Scand J Immunol 55:189–195PubMedCrossRefGoogle Scholar
  17. 17.
    Altman JD, Moss PA, Goulder PJ et al (1996) Phenotypic analysis of antigen-specific T lymphocytes. Science 274:94–96PubMedCrossRefGoogle Scholar
  18. 18.
    Callan MF, Tan L, Annels N et al (1998) Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr virus in vivo. J Exp Med 187:1395–1402PubMedCrossRefGoogle Scholar
  19. 19.
    Chen FE, Aubert G, Travers P et al (2002) HLA tetramers and anti-CMV immune responses: from epitope to immunotherapy. Cytotherapy 4:41–48PubMedCrossRefGoogle Scholar
  20. 20.
    Aubert G, Hassan-Walker AF, Madrigal JA et al (2001) Cytomegalovirus-specific cellular immune responses and viremia in recipients of allogeneic stem cell transplants. J Infect Dis 184:955–963PubMedCrossRefGoogle Scholar
  21. 21.
    Cwynarski K, Ainsworth J, Cobbold M et al (2001) Direct visualization of cytomegalovirus-specific T-cell reconstitution after allogeneic stem cell transplantation. Blood 97:1232–1240PubMedCrossRefGoogle Scholar
  22. 22.
    Ganepola S, Gentilini C, Hilbers U et al (2007) Patients at high risk for CMV infection and disease show delayed CD8+ T-cell immune recovery after allogeneic stem cell transplantation. Bone Marrow Transplant 39:293–299PubMedCrossRefGoogle Scholar
  23. 23.
    Boeckh M, Leisenring W, Riddell SR et al (2003) Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and T-cell immunity. Blood 101:407–414PubMedCrossRefGoogle Scholar
  24. 24.
    Ozdemir E, Saliba RM, Champlin RE et al (2007) Risk factors associated with late cytomegalovirus reactivation after allogeneic stem cell transplantation for hematological malignancies. Bone Marrow Transplant 40:125–136PubMedCrossRefGoogle Scholar
  25. 25.
    Andrei G, De Clercq E, Snoeck R (2008) Novel inhibitors of human CMV. Curr Opin Investig Drugs 9:32–45Google Scholar
  26. 26.
    Mercorelli B, Sinigalia E, Loregian A, Palù G (2008) Human cytomegalovirus DNA replication: antiviral targets and drugs. Rev Med Virol 18:177–210PubMedCrossRefGoogle Scholar
  27. 27.
    Goodrich JM, Bowden RA, Fisher L et al (1993) Ganciclovir prophylaxis to prevent cytomegalovirus disease after allogeneic marrow transplant. Ann Intern Med 118:173–178PubMedGoogle Scholar
  28. 28.
    Li CR, Greenberg PD, Gilbert MJ et al (1994) 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 83:1971–1979PubMedGoogle Scholar
  29. 29.
    Schmidt-Hieber M, Schwarck S, Stroux A et al (2009) Prophylactic i.v. Igs in patients with a high risk for CMV after allo-SCT. Bone Marrow Transplant [Epub ahead of print]Google Scholar
  30. 30.
    Bale JF Jr, Petheram SJ, Souza IE, Murph JR (1996) Cytomegalovirus reinfection in young children. J Pediatr 128:347–352PubMedCrossRefGoogle Scholar
  31. 31.
    Chandler SH, Handsfield HH, McDougall JK (1987) Isolation of multiple strains of cytomegalovirus from women attending a clinic for sexually transmitted disease. J Infect Dis 155:655–660PubMedGoogle Scholar
  32. 32.
    Plotkin SA, Smiley ML, Friedman HM et al (1984) Towne-vaccine-induced prevention of cytomegalovirus disease after renal transplants. Lancet 10:528–530CrossRefGoogle Scholar
  33. 33.
    Pass RF, Zhang C, Evans A et al (2009) Vaccine prevention of maternal cytomegalovirus infection. NEJM 360:1191–1199PubMedCrossRefGoogle Scholar
  34. 34.
    Wloch MK, Smith LR, Boutsaboualoy S et al (2008) Safety and immunogenicity of a bivalent cytomegalovirus DNA vaccine in healthy adult subjects. J Infect Dis 197:1634–1642PubMedCrossRefGoogle Scholar
  35. 35.
    Heslop HE, Brenner MK, Rooney C et al (1994) Administration of neomycin-resistance-gene-marked EBV-specific cytotoxic T lymphocytes to recipients of mismatched-related or phenotypically similar unrelated donor marrow grafts. Hum Gene Ther 5:381–397PubMedCrossRefGoogle Scholar
  36. 36.
    Rooney CM, Smith CA, Ng C et al (1995) Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lymphoproliferation. Lancet 345:9–13PubMedCrossRefGoogle Scholar
  37. 37.
    Madrigal JA, Travers PJ, Dodi IA (2005) Immunotherapeutic aspects of stem cell transplantation. Hematology 10(Suppl 1):289–292PubMedCrossRefGoogle Scholar
  38. 38.
    Dolstra H, Preijers F, Van de Wiel-van Kemenade E et al (1995) Expansion of CD8+ CD57+ T cells after allogeneic BMT is related with a low incidence of relapse and with cytomegalovirus infection. Br J Haematol 90:300–307PubMedCrossRefGoogle Scholar
  39. 39.
    Fallen PR, Duarte RF, McGreavey L et al (2003) Identification of non-naïve CD4+CD45RA+ T cell subsets in adult allogeneic haematopoietic cell transplant recipients. Bone Marrow Transplant 32:609–616PubMedCrossRefGoogle Scholar
  40. 40.
    Cobbold M, Khan N, Pourgheysari B et al (2005) Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA-peptide tetramers. J Exp Med 202:379–386PubMedCrossRefGoogle Scholar
  41. 41.
    Micklethwaite KP, Clancy L, Sandher U et al (2008) Prophylactic infusion of cytomegalovirus-specific cytotoxic T lymphocytes stimulated with Ad5f35pp65 gene-modified dendritic cells after allogeneic hemopoietic stem cell transplantation. Blood 112:3974–3981PubMedCrossRefGoogle Scholar
  42. 42.
    Myers GD, Krance RA, Weiss H et al (2005) Adenovirus infection rates in pediatric recipients of alternate donor allogeneic bone marrow transplants receiving either antithymocyte globulin (ATG) or alemtuzumab (Campath). Bone Marrow Transplant 36:1001–1008PubMedCrossRefGoogle Scholar
  43. 43.
    Fujita Y, Rooney CM, Heslop HE (2008) Adoptive cellular immunotherapy for viral diseases. Bone Marrow Transplant 41:193–198PubMedCrossRefGoogle Scholar
  44. 44.
    André F, Chaput N, Schartz NE et al (2004) Exosomes as potent cell-free peptide-based vaccine. I. Dendritic cell-derived exosomes transfer functional MHC class I/peptide complexes to dendritic cells. J Immunol 172:2126–2136PubMedGoogle Scholar
  45. 45.
    Segura E, Amigorena S, Thery C (2005) Mature dendritic cells secrete exosomes with strong ability to induce antigen-specific effector immune responses. Blood Cells Mol Dis 35:89–93PubMedCrossRefGoogle Scholar
  46. 46.
    De La Peña H, Madrigal JA, Rusakiewicz S et al (2009) Artificial exosomes as tools for basic and clinical immunology. J Immunol Methods [Epub ahead of print]Google Scholar
  47. 47.
    Babincová M, Altanerová V, Lampert M et al (2000) Site-specific in vivo targeting of magnetoliposomes using externally applied magnetic field. Z Naturforsch [C] 55:278–281Google Scholar
  48. 48.
    Fortin-Ripoche JP, Martina MS, Gazeau F et al (2006) Magnetic targeting of magnetoliposomes to solid tumors with MR imaging monitoring in mice: feasibility. Radiology 239:415–424PubMedCrossRefGoogle Scholar
  49. 49.
    Oelke M, Maus MV, Didiano D et al (2003) Ex vivo induction and expansion of antigen-specific cytotoxic T cells by HLA-Ig-coated artificial antigen-presenting cells. Nat Med 9:619–625PubMedCrossRefGoogle Scholar
  50. 50.
    Papanicolaou GA, Latouche JB, Tan C et al (2003) Rapid expansion of cytomegalovirus-specific cytotoxic T lymphocytes by artificial antigen-presenting cells expressing a single HLA allele. Blood 102:2498–2505PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Mark Tuthill
    • 1
  • Frederick Chen
    • 1
  • Samantha Paston
    • 1
  • Hugo De La Peña
    • 1
  • Sylvie Rusakiewicz
    • 1
  • Alejandro Madrigal
    • 1
  1. 1.The Anthony Nolan Research Institute, Royal Free HospitalLondonUK

Personalised recommendations