Abstract
Recipients of hematopoietic SCT undergo a period of profound immunosuppression due to the chemotherapy and/or radiotherapy used for the conditioning and to the graft versus host reaction. SCT patients are highly susceptible to the development of viral infections such as CMV or EBV. The achievement of a competent immunological response, such as viral-specific T cells, is associated with a lower incidence of viral infections. Methods for direct identification of antigen-specific T cells have been based on the functional characteristics of these T cells. Techniques such as proliferation and ELISPOT assays, intracellular cytokine staining and IFN-γ capture have been used to quantitate and obtain viral-specific T cells. Multimers are composed of several MHC molecules loaded with immunodominant peptides joined to a fluorescent molecule, which signal can be quantified by a flow cytometer. Multimer technology together with recent advances in flow cytometry, have facilitated the monitoring and selection of antigen-specific T cells without the need for in vitro cultures and manipulation. This has resulted in a better characterization of the function and phenotype of the different subpopulations of T cells involved in the immune recovery post allogeneic SCT. It is becoming a distinct possibility to isolate individual antigen-specific T cells, without long-term culture techniques, and potentially use them as adoptive immunotherapy in the SCT setting.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Zaia J, Baden L, Boeckh MJ, Chakrabarti S, Einsele H, Ljungman P et al. Viral disease prevention after hematopoietic cell transplantation. Bone Marrow Transplant 2009; 44: 471–482.
Winston DJ, Ho WG, Bartoni K, Du Mond C, Ebeling DF, Buhles WC et al. Ganciclovir prophylaxis of cytomegalovirus infection and disease in allogeneic bone marrow transplant recipients. Results of a placebo-controlled, double-blind trial. Ann Intern Med 1993; 118: 179–184.
Goodrich JM, Bowden RA, Fisher L, Keller C, Schoch G, Meyers JD . Ganciclovir prophylaxis to prevent cytomegalovirus disease after allogeneic marrow transplant. Ann Intern Med 1993; 118: 173–178.
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.
Riddell SR, Rabin M, Geballe AP, Britt WJ, Greenberg PD, Class I . MHC-restricted cytotoxic T lymphocyte recognition of cells infected with human cytomegalovirus does not require endogenous viral gene expression. J Immunol 1991; 146: 2795–2804.
Walter EA, Greenberg PD, Gilbert MJ, Finch RJ, Watanabe KS, Thomas ED 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.
Sili U, Huls MH, Davis AR, Gottschalk S, Brenner MK, Heslop HE et al. Large-scale expansion of dendritic cell-primed polyclonal human cytotoxic T-lymphocyte lines using lymphoblastoid cell lines for adoptive immunotherapy. J Immunother 2003; 26: 241–256.
Szmania S, Galloway A, Bruorton M, Musk P, Aubert G, Arthur A 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.
Einsele H, Roosnek E, Rufer N, Sinzger C, Riegler S, Loffler J 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.
Schub A, Schuster IG, Hammerschmidt W, Moosmann A . CMV-specific TCR-transgenic T cells for immunotherapy. J Immunol 2009; 183: 6819–6830.
Lanzavecchia A, Sallusto F . Progressive differentiation and selection of the fittest in the immune response. Nat Rev Immunol 2002; 2: 982–987.
Kaech SM, Wherry EJ, Ahmed R . Effector and memory T-cell differentiation: implications for vaccine development. Nat Rev Immunol 2002; 2: 251–262.
Wherry EJ, Teichgraber V, Becker TC, Masopust D, Kaech SM, Antia R et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat Immunol 2003; 4: 225–234.
Lanzavecchia A, Sallusto F . Dynamics of T lymphocyte responses: intermediates, effectors, and memory cells. Science 2000; 290: 92–97.
Gett AV, Hodgkin PD . Cell division regulates the T cell cytokine repertoire, revealing a mechanism underlying immune class regulation. Proc Natl Acad Sci USA 1998; 95: 9488–9493.
Pihlgren M, Dubois PM, Tomkowiak M, Sjogren T, Marvel J . Resting memory CD8+ T cells are hyperreactive to antigenic challenge in vitro. J Exp Med 1996; 184: 2141–2151.
Berger C, Jensen MC, Lansdorp PM, Gough M, Elliott C, Riddell SR . Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. J Clin Invest 2008; 118: 294–305.
Sallusto F, Geginat J, Lanzavecchia A . Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol 2004; 22: 745–763.
Gattinoni L, Powell DJ, Rosenberg SA, Restifo NP . Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol 2006; 6: 383–393.
Gattinoni L, Klebanoff CA, Palmer DC, Wrzesinski C, Kerstann K, Yu Z et al. Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. J Clin Invest 2005; 115: 1616–1626.
Speiser DE, Romero P . Toward improved immunocompetence of adoptively transferred CD8+ T cells. J Clin Invest 2005; 115: 1467–1469.
Hamann D, Baars PA, Rep MH, Hooibrink B, Kerkhof-Garde SR, Klein MR et al. Phenotypic and functional separation of memory and effector human CD8+ T cells. J Exp Med 1997; 186: 1407–1418.
Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A . Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 1999; 401: 708–712.
Scheinberg P, Melenhorst JJ, Brenchley JM, Hill BJ, Hensel NF, Chattopadhyay PK et al. 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. Blood 2009; 114: 5071–5080.
Luo XH, Huang XJ, Liu KY, Xu LP, Liu DH . Protective immunity transferred by infusion of CMV-specific CD8+ T cells within donor graftsits associations with CMV reactivation following unmanipulated allogeneic hematopoietic stem cell transplantation CMV-specific CD8+ T cells within donor grafts. Biol Blood Marrow Transplant 2010; 16: 994–1004.
Bakker AH, Schumacher TN . MHC multimer technology: current status and future prospects. Curr Opin Immunol 2005; 17: 428–433.
Altman JD, Moss PA, Goulder PJ, Barouch DH, McHeyzer-Williams MG, Bell JI et al. Phenotypic analysis of antigen-specific T lymphocytes. Science 1996; 274: 94–96.
Yao J, Bechter C, Wiesneth M, Harter G, Gotz M, Germeroth L et al. Multimer staining of cytomegalovirus phosphoprotein 65-specific T cells for diagnosis and therapeutic purposes: a comparative study. Clin Infect Dis 2008; 46: e96–105.
Heijnen IA, Barnett D, Arroz MJ, Barry SM, Bonneville M, Brando B et al. Enumeration of antigen-specific CD8+ T lymphocytes by single-platform, HLA tetramer-based flow cytometry: a European multicenter evaluation. Cytometry B Clin Cytom 2004; 62: 1–13.
Maile R, Wang B, Schooler W, Meyer A, Collins EJ, Frelinger JA . Antigen-specific modulation of an immune response by in vivo administration of soluble MHC class I tetramers. J Immunol 2001; 167: 3708–3714.
Neudorfer J, Schmidt B, Huster KM, Anderl F, Schiemann M, Holzapfel G et al. Reversible HLA multimers (Streptamers) for the isolation of human cytotoxic T lymphocytes functionally active against tumor- and virus-derived antigens. J Immunol Methods 2007; 320: 119–131.
Cobbold M, Khan N, Pourgheysari B, Tauro S, McDonald D, Osman H 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.
Uhlin M, Gertow J, Uzunel M, Okas M, Berglund S, Watz E et al. Rapid salvage treatment with virus-specific T cells for therapy-resistant disease. Clin Infect Dis 2012; 55: 1064–1073.
Knabel M, Franz TJ, Schiemann M, Wulf A, Villmow B, Schmidt B et al. Reversible MHC multimer staining for functional isolation of T-cell populations and effective adoptive transfer. Nat Med 2002; 8: 631–637.
Wang X, Simeoni L, Lindquist JA, Saez-Rodriguez J, Ambach A, Gilles ED et al. Dynamics of proximal signaling events after TCR/CD8-mediated induction of proliferation or apoptosis in mature CD8+ T cells. J Immunol 2008; 180: 6703–6712.
Mackall C, Fry T, Gress R, Peggs K, Storek J, Toubert A . Background to hematopoietic cell transplantation, including post transplant immune recovery. Bone Marrow Transplant 2009; 44: 457–462.
Hakki M, Riddell SR, Storek J, Carter RA, Stevens-Ayers T, Sudour P 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.
Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med 2005; 202: 907–912.
Pittet MJ, Grimm J, Berger CR, Tamura T, Wojtkiewicz G, Nahrendorf M et al. In vivo imaging of T cell delivery to tumors after adoptive transfer therapy. Proc Natl Acad Sci USA 2007; 104: 12457–12461.
Brusko TM, Putnam AL, Bluestone JA . Human regulatory T cells: role in autoimmune disease and therapeutic opportunities. Immunol Rev 2008; 223: 371–390.
Rosenberg ES, Billingsley JM, Caliendo AM, Boswell SL, Sax PE, Kalams SA et al. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 1997; 278: 1447–1450.
Brodie SJ, Lewinsohn DA, Patterson BK, Jiyamapa D, Krieger J, Corey L et al. In vivo migration and function of transferred HIV-1-specific cytotoxic T cells. Nat Med 1999; 5: 34–41.
Pourgheysari B, Piper KP, McLarnon A, Arrazi J, Bruton R, Clark F et al. Early reconstitution of effector memory CD4+ CMV-specific T cells protects against CMV reactivation following allogeneic SCT. Bone Marrow Transplant 2009; 43: 853–861.
Ayyoub M, Dojcinovic D, Pignon P, Raimbaud I, Schmidt J, Luescher I et al. Monitoring of NY-ESO-1 specific CD4+ T cells using molecularly defined MHC class II/His-tag-peptide tetramers. Proc Natl Acad Sci USA 107: 7437–7442.
Hackett CJ, Sharma OK . Frontiers in peptide-MHC class II multimer technology. Nat Immunol 2002; 3: 887–889.
Landais E, Romagnoli PA, Corper AL, Shires J, Altman JD, Wilson IA et al. New design of MHC class II tetramers to accommodate fundamental principles of antigen presentation. J Immunol 2009; 183: 7949–7957.
Wang X, Schmitt A, Chen B, Xu X, Mani J, Linnebacher M et al. Streptamer-based selection of WT1-specific CD8(+) T cells for specific donor lymphocyte infusions. Exp Hematol 2010; 38: 1066–1073.
Schmitt A, Tonn T, Busch DH, Grigoleit GU, Einsele H, Odendahl M et al. Adoptive transfer and selective reconstitution of streptamer-selected cytomegalovirus-specific CD8+ T cells leads to virus clearance in patients after allogeneic peripheral blood stem cell transplantation. Transfusion 2011; 51: 591–599.
Andersen RS, Kvistborg P, Frøsig TM, Pedersen NW, Lyngaa R, Bakker AH et al. Parallel detection of antigen-specific T cell responses by combinatorial encoding of MHC multimers. Nat Protoc 2012; 7: 891–902.
Domingo E, Moreno C, Sanchez-Ibarrola A, Panizo C, Paramo JA, Merino J . Enhanced sensitivity of flow cytometry for routine assessment of minimal residual disease. Haematologica 95: 691–692.
Acknowledgements
This work was supported by a research grant (PI10/00136) from the Fondo de Investigaciones Sanitarias del Instituto de Salud Carlos III.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Ramírez, N., Olavarría, E. Viral-specific adoptive immunotherapy after allo-SCT: the role of multimer-based selection strategies. Bone Marrow Transplant 48, 1265–1270 (2013). https://doi.org/10.1038/bmt.2012.262
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/bmt.2012.262
Keywords
This article is cited by
-
GMP-production of purified human B lymphocytes for the adoptive transfer in patients after allogeneic hematopoietic stem cell transplantation
Journal of Translational Medicine (2017)
-
CMV-specific T cell isolation from G-CSF mobilized peripheral blood: depletion of myeloid progenitors eliminates non-specific binding of MHC-multimers
Journal of Translational Medicine (2014)
-
Impact of T cell selection methods in the success of clinical adoptive immunotherapy
Cellular and Molecular Life Sciences (2014)