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.

  • Original Article
  • Published:

Immunology

In vitro-established alloantigen-specific CD8+ CTLs mediate graft-versus-tumor activity in the absence of graft-versus-host disease

Abstract

Mature donor-derived T cells in allogeneic bone marrow (BM) transplants mediate the graft-versus-tumor (GVT) effect by recognizing alloantigens on leukemic cells. However, alloantigen reactivity towards non-malignant tissues also induces graft-versus-host disease (GVHD). Defining T-cell subpopulations that mediate the GVT effect in the absence of GVHD induction remains a major challenge in allogeneic BM transplantation. In this study, we show that in vitro-generated alloantigen-specific CD8+ cytotoxic T cells (CTLs) established by weekly stimulation with alloantigen-expressing antigen-presenting cells did not induce GVHD in two major histocompatibility complex-mismatched BM transplantation models, where induction of lethal GVHD is dependent on the presence of either CD4+ or CD8+ T cells. Despite their strong alloantigen specificity, transplantation of CTLs did not induce the expression of GVHD-associated cytokines IFN-γ and TNF-α or clinical or histological signs of GVHD, and lead to a survival rate of above 90%. However, transplantation of unstimulated CD8+ T cells, which were not primed by the alloantigen in vitro, induced GVHD in both the transplantation models. Although CTLs were impaired in GVHD induction, they efficiently eradicated Bcr–Abl-transformed B-cell leukemias or mastocytomas. Thus, in vitro-derived CTLs might be useful for optimizing anti-tumor therapy in the absence of GVHD induction.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Welniak LA, Blazar BR, Murphy WJ . Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu Rev Immunol 2007; 25: 139–170.

    Article  CAS  PubMed  Google Scholar 

  2. Ho VT, Soiffer RJ . The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood 2001; 98: 3192–3204.

    Article  CAS  PubMed  Google Scholar 

  3. Kruger K, Mooren FC . T cell homing and exercise. Exerc Immunol Rev 2007; 13: 37–54.

    CAS  PubMed  Google Scholar 

  4. Zheng H, Matte-Martone C, Li H, Anderson BE, Venketesan S, Sheng Tan H et al. Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease. Blood 2008; 111: 2476–2484.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Anderson BE, McNiff J, Yan J, Doyle H, Mamula M, Shlomchik MJ et al. Memory CD4+ T cells do not induce graft-versus-host disease. J Clin Invest 2003; 112: 101–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Beilhack A, Schulz S, Baker J, Beilhack GF, Wieland CB, Herman EI et al. In vivo analyses of early events in acute graft-versus-host disease reveal sequential infiltration of T-cell subsets. Blood 2005; 106: 1113–1122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chen BJ, Deoliveira D, Cui X, Le NT, Son J, Whitesides JF et al. Inability of memory T cells to induce graft-versus-host disease is a result of an abortive alloresponse. Blood 2007; 109: 3115–3123.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Dutt S, Tseng D, Ermann J, George TI, Liu YP, Davis CR et al. Naive and memory T cells induce different types of graft-versus-host disease. J Immunol 2007; 179: 6547–6554.

    Article  CAS  PubMed  Google Scholar 

  9. Zhang Y, Joe G, Hexner E, Zhu J, Emerson SG . Alloreactive memory T cells are responsible for the persistence of graft-versus-host disease. J Immunol 2005; 174: 3051–3058.

    Article  CAS  PubMed  Google Scholar 

  10. Zheng H, Matte-Martone C, Jain D, McNiff J, Shlomchik WD . Central memory CD8+ T cells induce graft-versus-host disease and mediate graft-versus-leukemia. J Immunol 2009; 182: 5938–5948.

    Article  CAS  PubMed  Google Scholar 

  11. Zhang Y, Joe G, Zhu J, Carroll R, Levine B, Hexner E et al. Dendritic cell-activated CD44hiCD8+ T cells are defective in mediating acute graft-versus-host disease but retain graft-versus-leukemia activity. Blood 2004; 103: 3970–3978.

    Article  CAS  PubMed  Google Scholar 

  12. Zhang Y, Joe G, Hexner E, Zhu J, Emerson SG . Host-reactive CD8+ memory stem cells in graft-versus-host disease. Nat Med 2005; 11: 1299–1305.

    Article  CAS  PubMed  Google Scholar 

  13. Panoskaltsis-Mortari A, Price A, Hermanson JR, Taras E, Lees C, Serody JS et al. In vivo imaging of graft-versus-host-disease in mice. Blood 2004; 103: 3590–3598.

    Article  CAS  PubMed  Google Scholar 

  14. Cooke KR, Kobzik L, Martin TR, Brewer J, Delmonte Jr J, Crawford JM et al. An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation: I. The roles of minor H antigens and endotoxin. Blood 1996; 88: 3230–3239.

    CAS  PubMed  Google Scholar 

  15. Miething C, Grundler R, Mugler C, Brero S, Hoepfl J, Geigl J et al. Retroviral insertional mutagenesis identifies RUNX genes involved in chronic myeloid leukemia disease persistence under imatinib treatment. Proc Natl Acad Sci USA 2007; 104: 4594–4599.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chen X, Vodanovic-Jankovic S, Johnson B, Keller M, Komorowski R, Drobyski WR . Absence of regulatory T-cell control of TH1 and TH17 cells is responsible for the autoimmune-mediated pathology in chronic graft-versus-host disease. Blood 2007; 110: 3804–3813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Strauss G, Knape I, Melzner I, Debatin KM . Constitutive caspase activation and impaired death-inducing signaling complex formation in CD95-resistant, long-term activated, antigen-specific T cells. J Immunol 2003; 171: 1172–1182.

    Article  CAS  PubMed  Google Scholar 

  18. Strauss G, Lindquist JA, Arhel N, Felder E, Karl S, Haas TL et al. CD95 co-stimulation blocks activation of naive T cells by inhibiting T cell receptor signaling. J Exp Med 2009; 206: 1379–1393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Teshima T, Hill GR, Pan L, Brinson YS, van den Brink MR, Cooke KR et al. IL-11 separates graft-versus-leukemia effects from graft-versus-host disease after bone marrow transplantation. J Clin Invest 1999; 104: 317–325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sprent J, Schaefer M, Gao EK, Korngold R . Role of T cell subsets in lethal graft-versus-host disease (GVHD) directed to class I versus class II H-2 differences. I. L3T4+ cells can either augment or retard GVHD elicited by Lyt-2+ cells in class I different hosts. J Exp Med 1988; 167: 556–569.

    Article  CAS  PubMed  Google Scholar 

  21. Hattori K, Hirano T, Miyajima H, Yamakawa N, Tateno M, Oshimi K et al. Differential effects of anti-Fas ligand and anti-tumor necrosis factor alpha antibodies on acute graft-versus-host disease pathologies. Blood 1998; 91: 4051–4055.

    CAS  PubMed  Google Scholar 

  22. Tsukada N, Kobata T, Aizawa Y, Yagita H, Okumura K . Graft-versus-leukemia effect and graft-versus-host disease can be differentiated by cytotoxic mechanisms in a murine model of allogeneic bone marrow transplantation. Blood 1999; 93: 2738–2747.

    CAS  PubMed  Google Scholar 

  23. Schmaltz C, Alpdogan O, Horndasch KJ, Muriglan SJ, Kappel BJ, Teshima T et al. Differential use of Fas ligand and perforin cytotoxic pathways by donor T cells in graft-versus-host disease and graft-versus-leukemia effect. Blood 2001; 97: 2886–2895.

    Article  CAS  PubMed  Google Scholar 

  24. Schmaltz C, Alpdogan O, Kappel BJ, Muriglan SJ, Rotolo JA, Ongchin J et al. T cells require TRAIL for optimal graft-versus-tumor activity. Nat Med 2002; 8: 1433–1437.

    Article  CAS  PubMed  Google Scholar 

  25. El-Hayek JM, Rogers TE, Brown GR . The role of TNF in hepatic histopathological manifestations and hepatic CD8+ T cell alloresponses in murine MHC class I disparate GVHD. J Leukoc Biol 2005; 78: 1001–1007.

    Article  CAS  PubMed  Google Scholar 

  26. Chen BJ, Cui X, Sempowski GD, Liu C, Chao NJ . Transfer of allogeneic CD62L- memory T cells without graft-versus-host disease. Blood 2004; 103: 1534–1541.

    Article  CAS  PubMed  Google Scholar 

  27. Beilhack A, Schulz S, Baker J, Beilhack GF, Nishimura R, Baker EM et al. Prevention of acute graft-versus-host disease by blocking T-cell entry to secondary lymphoid organs. Blood 2008; 111: 2919–2928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bono MR, Elgueta R, Sauma D, Pino K, Osorio F, Michea P et al. The essential role of chemokines in the selective regulation of lymphocyte homing. Cytokine Growth Factor Rev 2007; 18: 33–43.

    Article  CAS  PubMed  Google Scholar 

  29. Masopust D, Vezys V, Marzo AL, Lefrancois L . Preferential localization of effector memory cells in nonlymphoid tissue. Science 2001; 291: 2413–2417.

    Article  CAS  PubMed  Google Scholar 

  30. Nakanishi Y, Lu B, Gerard C, Iwasaki A . CD8(+) T lymphocyte mobilization to virus-infected tissue requires CD4(+) T-cell help. Nature 2009; 462: 510–513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Watson D, Hu M, Zhang GY, Wang YM, Alexander SI . Tolerance induction by removal of alloreactive T cells: in-vivo and pruning strategies. Curr Opin Organ Transplant 2009; 14: 357–363.

    Article  PubMed  Google Scholar 

  32. Wirth TC, Xue HH, Rai D, Sabel JT, Bair T, Harty JT et al. Repetitive antigen stimulation induces stepwise transcriptome diversification but preserves a core signature of memory CD8(+) T cell differentiation. Immunity 2010; 33: 128–140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Maxi Weiswange for excellent technical assistance. This research was supported by the Deutsche José Carreras Leukämie-Stiftung e.V. (DJCLS R07/04).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to G Strauss.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hartmann, N., Leithäuser, F., Albers, C. et al. In vitro-established alloantigen-specific CD8+ CTLs mediate graft-versus-tumor activity in the absence of graft-versus-host disease. Leukemia 25, 848–855 (2011). https://doi.org/10.1038/leu.2011.16

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2011.16

Keywords

This article is cited by

Search

Quick links