Biology of Blood and Marrow Transplantation
Volume 16, Issue 7 , Pages 994-1004 , July 2010

Protective Immunity Transferred by Infusion of Cytomegalovirus-Specific CD8+ T Cells within Donor Grafts: Its Associations with Cytomegalovirus Reactivation Following Unmanipulated Allogeneic Hematopoietic Stem Cell Transplantation

  • Xiao-Hua Luo

      Affiliations

    • Department of Onco-Haematology, Children's Hospital of Chongqing Medical University, Chongqing, China
    • ,
  • Xiao-Jun Huang

      Affiliations

    • Peking University Institute of Hematology, People's Hospital, Beijing 100044, China
    • Corresponding Author InformationCorrespondence and reprint requests: Xiao-Jun Huang, Peking University, People's Hospital, Institute of Hematology, 11 Xizhimen South Street, Beijing 100044, China.
    • ,
  • Kai-Yan Liu

      Affiliations

    • Peking University Institute of Hematology, People's Hospital, Beijing 100044, China
    • ,
  • Lan-Ping Xu

      Affiliations

    • Peking University Institute of Hematology, People's Hospital, Beijing 100044, China
    • ,
  • Dai-Hong Liu

      Affiliations

    • Peking University Institute of Hematology, People's Hospital, Beijing 100044, China

Received 25 November 2009 ,Accepted 5 February 2010.

References 

  1. Nichols WG, Corey L, Gooley T, et al. High risk of death due to bacterial and fungal infection among cytomegalovirus (CMV)-seronegative recipients of stem cell transplants from seropositive donors: evidence for indirect effects of primary CMV infection. J Infect Dis. 2002;185:273–282
  2. Boeckh M, Nichols WG. The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy. Blood. 2004;103:2003–2008
  3. Reusser P, Einsele H, Lee J, et al. Randomized multicenter trial of foscarnet versus ganciclovir for preemptive therapy of cytomegalovirus infection after allogeneic stem cell transplantation. Blood. 2002;99:1159–1164
  4. Goodrich JM, Mori M, Gleaves CA, et al. Early treatment with ganciclovir to prevent cytomegalovirus disease after allogeneic bone marrow transplantation. N Engl J Med. 1991;325:1601–1607
  5. Boeckh M, Gooley TA, Bowden RA. Effect of high-dose acyclovir on survival in allogeneic marrow transplant recipients who received ganciclovir at engraftment or for cytomegalovirus pp65 antigenemia. J Infect Dis. 1998;178:1153–1157
  6. 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
  7. Gandhi MK, Wills MR, Okecha G, et al. Late diversification in the clonal composition of human cytomegalovirus–specific CD8+ T cells following allogeneic hemopoietic stem cell transplantation. Blood. 2003;102:3427–3438
  8. 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
  9. 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
  10. 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
  11. Lilleri D, Fornara C, Chiesa A, et al. Human cytomegalovirus–specific CD4+ and CD8+ T-cell reconstitution in adult allogeneic hematopoietic stem cell transplant recipients and immune control of viral infection. Haematologica. 2008;93:248–256
  12. Lilleri D, Gerna G, Fornara C, et al. Prospective simultaneous quantification of human cytomegalovirus–specific CD4+ and CD8+ T-cell reconstitution in young recipients of allogeneic hematopoietic stem cell transplants. Blood. 2006;108:1406–1412
  13. 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
  14. Cobbold M, Khan N, Pourgheysari B, et al. Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA-peptide tetramers. J Exp Med. 2005;202:379–386
  15. Micklethwaite KP, Clancy L, Sandher U, et al. Prophylactic infusion of cytomegalovirus-specific cytotoxic T lymphocytes stimulated with Ad5f35pp65 gene–modified dendritic cells after allogeneic hemopoietic stem cell transplantation. Blood. 2008;112:3974–3981
  16. Micklethwaite K, Hansen A, Foster A, et al. Ex vivo expansion and prophylactic infusion of CMV-pp65 peptide–specific cytotoxic T-lymphocytes following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2007;13:707–714
  17. Northfield JW, Loo CP, Barbour JD, et al. Human immunodeficiency virus type 1 (HIV-1)-specific CD8+ TEMRA cells in early infection are linked to control of HIV-1 viremia and predict the subsequent viral load set point. J Virol. 2007;81:5759–5765
  18. Lanzavecchia A, Sallusto F. Understanding the generation and function of memory T cell subsets. Curr Opin Immunol. 2005;17:326–332
  19. Gamadia LE, Remmerswaal EBM, 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
  20. Sallusto F, Lenig D, Forster R, et al. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999;401:708–712
  21. Ferrari V, Cacere CR, Machado CM, et al. Distinct patterns of regeneration of central memory, effector memory and effector TCD8+ cell subsets after different hematopoietic cell transplant types: possible influence in the recovery of anti-cytomegalovirus immune response and risk for its reactivation. Clin Immunol. 2006;119:261–271
  22. Date Y, Kimura A, Kato H, et al. DNA typing of the HLA-A gene: population study and identification of four new alleles in Japanese. Tissue Antigens. 1996;47:93–101
  23. Imanishi, T., T. Akaza, A. Kimura, K. Tokunaga, and T. Gojobori. 1992. Allele and haplotype frequencies for HLA and complement loci in various ethnic groups. HLA 1991, Proceedings of the Eleventh International Histocompatibility Workshop and Conference. K. Tjuji, M. Aizawa, and T. Sasazuki, editors. Oxford University Press, Oxford/New York/Tokyo. 1065 -1220.
  24. Lu D-P, Dong L, Wu T, et al. Conditioning including antithymocyte globulin followed by unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation can achieve comparable outcomes with HLA-identical sibling transplantation. Blood. 2006;107:3065–3073
  25. Huang XJ, Liu DH, Liu KY, et al. Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transplant. 2006;38:291–297
  26. Huang XJ, Jiang Q, Chen H, et al. Low-dose methotrexate for the treatment of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2005;36:343–348
  27. Huang XJ, Liu DH, Liu KY, et al. Treatment of acute leukemia with unmanipulated HLA-mismatched/haploidentical blood and bone marrow transplantation. Biol Blood Marrow Transplant. 2009;15:257–265
  28. Luo XH, Chang YJ, Xu LP, et al. The impact of graft composition on clinical outcomes in unmanipulated HLA-mismatched//haploidentical hematopoietic SCT. Bone Marrow Transplant. 2008;43:29–36
  29. Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis. 2002;34:1094–1097
  30. Zhou W, Longmate J, Lacey SF, et al. Impact of donor CMV status on viral infection and reconstitution of multifunction CMV-specific T cells in CMV-positive transplant recipients. Blood. 2009;113:6465–6476
  31. Khan N, Shariff N, Cobbold M, et al. Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J Immunol. 2002;169:1984–1992
  32. Ouyang Q, Wagner WM, Voehringer D, et al. Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1). Exp Gerontol. 2003;38:911–920
  33. Khan N, Hislop A, Gudgeon N, et al. Herpesvirus-specific CD8 T cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection. J Immunol. 2004;173:7481–7489
  34. Einsele H, Kapp M, Grigoleit GU. CMV-specific T cell therapy. Blood Cells Mol Dis. 2008;40:71–75
  35. Dunne PJ, Faint JM, Gudgeon NH, et al. Epstein-Barr virus–specific CD8+ T cells that re-express CD45RA are apoptosis-resistant memory cells that retain replicative potential. Blood. 2002;100:933–940
  36. Wills MR, Carmichael AJ, Weekes MP, et al. Human virus–specific CD8+ CTL clones revert from CD45ROhigh to CD45RAhigh in vivo: CD45RAhighCD8+ T cells comprise both naive and memory cells. J Immunol. 1999;162:7080–7087
  37. Hinrichs CS, Borman ZA, Cassard L, et al. Adoptively transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity. Proc Natl Acad Sci USA. 2009;106:17469–17474
  38. Klebanoff CA, Gattinoni L, Torabi-Parizi P, et al. Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc Natl Acad Sci USA. 2005;102:9571–9576
  39. Kim TK, St. John LS, Wieder ED, et al. Human late memory CD8+ T cells have a distinct cytokine signature characterized by CC chemokine production without IL-2 production. J Immunol. 2009;183:6167–6174
  40. Harari A, Dutoit V, Cellerai C, et al. Functional signatures of protective antiviral T-cell immunity in human virus infections. Immunol Rev. 2006;211:236–254
  41. Michie CA, McLean A, Alcock C, et al. Lifespan of human lymphocyte subsets defined by CD45 isoforms. Nature. 1992;360:264–265
  42. Monteiro M, Evaristo C, Legrand A, et al. Cartography of gene expression in CD8 single cells: novel CCR7- subsets suggest differentiation independent of CD45RA expression. Blood. 2007;109:2863–2870
  43. van Leeuwen EM, Gamadia LE, Baars PA, et al. Proliferation requirements of cytomegalovirus-specific, effector-type human CD8+ T cells. J Immunol. 2002;169:5838–5843
  44. Plunkett FJ, Franzese O, Finney HM, et al. The loss of telomerase activity in highly differentiated CD8+CD28-CD27- T cells is associated with decreased Akt (Ser473) phosphorylation. J Immunol. 2007;178:7710–7719
  45. Wrzesinski C, Paulos CM, Gattinoni L, et al. Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8+ T cells. J Clin Invest. 2007;117:492–501
  46. The transfer of adaptive immunity to CMV during hematopoietic stem cell transplantation is dependent on the specificity and phenotype of CMV-specific T cells in the donor. Scheinberg et al. Blood. 2009;114:5071–5080
  47. Franzke A, Piao W, Lauber J, et al. G-CSF as immune regulator in T cells expressing the G-CSF receptor: implications for transplantation and autoimmune diseases. Blood. 2003;102:734–739
  48. Jun HX, Jun CY, Yu ZX. In vivo induction of T-cell hyporesponsiveness and alteration of immunological cells of bone marrow grafts using granulocyte colony-stimulating factor. Haematologica. 2004;89:1517–1524
  49. Champagne P, Ogg GS, King AS, et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature. 2001;410:106–111
  50. Mackall CL, Gress RE. Pathways of T-cell regeneration in mice and humans: implications for bone marrow transplantation and immunotherapy. Immunol Rev. 1997;157:61–72
  51. Rezvani K, Yong ASM, Savani BN, et al. Graft-versus-leukemia effects associated with detectable Wilms tumor 1–specific T lymphocytes after allogeneic stem-cell transplantation for acute lymphoblastic leukemia. Blood. 2007;110:1924–1932
  52. Chalandon Y, Degermann S, Villard J, et al. Pretransplantation CMV-specific T cells protect recipients of T-cell–depleted grafts against CMV-related complications. Blood. 2006;107:389–396
  53. Carrasco J, Godelaine D, Van Pel A, et al. CD45RA on human CD8 T cells is sensitive to the time elapsed since the last antigenic stimulation. Blood. 2006;108:2897–2905
  54. Szmania S, Galloway A, Bruorton M, et al. Isolation and expansion of cytomegalovirus-specific cytotoxic T lymphocytes to clinical scale from a single blood draw using dendritic cells and HLA-tetramers. Blood. 2001;98:505–512
  55. Hobeika A, Osada T, Serra D, et al. Detailed analysis of cytomegalovirus (CMV)-specific T cells expanded for adoptive immunotherapy of CMV infection following allogeneic stem cell transplantation for malignant disease. Cytotherapy. 2008;10:289–302
  56. Bunde T, Kirchner A, Hoffmeister B, et al. Protection from cytomegalovirus after transplantation is correlated with immediate early 1–specific CD8 T cells. J Exp Med. 2005;201:1031–1036
  57. Sacre K, Nguyen S, Deback C, et al. Expansion of human cytomegalovirus (HCMV) immediate-early 1–specific CD8+ T cells and control of HCMV replication after allogeneic stem cell transplantation. J Virol. 2008;82:10143–10152
  58. Waller EC, Day E, Sissons JG, et al. Dynamics of T cell memory in human cytomegalovirus infection. Med Microbiol Immunol. 2008;197:83–96

 Financial disclosure: See Acknowledgments, page 1002.

PII: S1083-8791(10)00063-7

doi: 10.1016/j.bbmt.2010.02.007

Biology of Blood and Marrow Transplantation
Volume 16, Issue 7 , Pages 994-1004 , July 2010

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