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A crucial role for antigen-presenting cells and alloantigen expression in graft-versus-leukemia responses

Nature Medicine volume 11, pages 1244–1249 (2005)Cite this article

Abstract

Graft-versus-leukemia (GVL) response after allogeneic bone marrow transplantation (BMT) represents one of the most potent forms of immunotherapy against malignant diseases1. Antigen-presenting cells (APCs) are crucial for the induction of graft-versus-host disease (GVHD)2,3,4,5,6, the most serious complication of allogeneic BMT, but their role in GVL responses is unclear. Using a series of clinically relevant mouse GVL tumor models, we found that APCs and alloantigen expression on tumors are crucial for GVL. Moreover, APCs of host origin predominated in GVL responses although donor APCs contributed as the acuity of tumor burden decreased.

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Figure 1: APCs are required for GVL.
Figure 2: GVL responses require alloantigen expression.
Figure 3: Host APCs mediate a more robust GVL responses than donor APCs.

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References

  1. Appelbaum, F.R. Haematopoietic cell transplantation as immunotherapy. Nature 411, 385–389 (2001).

    Article  CAS  Google Scholar 

  2. Shlomchik, W.D. et al. Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science 285, 412–415 (1999).

    Article  CAS  Google Scholar 

  3. Teshima, T. et al. Acute graft-versus-host disease does not require alloantigen expression on host epithelium. Nat. Med. 8, 575–581 (2002).

    Article  CAS  Google Scholar 

  4. Ruggeri, L. et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295, 2097–2100 (2002).

    Article  CAS  Google Scholar 

  5. Jones, S.C., Murphy, G.F., Friedman, T.M. & Korngold, R. Importance of minor histocompatibility antigen expression by nonhematopoietic tissues in a CD4+ T cell-mediated graft-versus-host disease model. J. Clin. Invest. 112, 1880–1886 (2003).

    Article  CAS  Google Scholar 

  6. Matte, C.C. et al. Donor APCs are required for maximal GVHD but not for GVL. Nat. Med. 10, 987–992 (2004).

    Article  CAS  Google Scholar 

  7. Pardoll, D. Does the immune system see tumors as foreign or self? Annu. Rev. Immunol. 21, 807–839 (2003).

    Article  CAS  Google Scholar 

  8. Dunn, G.P., Old, L.J. & Schreiber, R.D. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21, 137–148 (2004).

    Article  CAS  Google Scholar 

  9. Bleakley, M. & Riddell, S.R. Molecules and mechanisms of the graft-versus-leukaemia effect. Nat. Rev. Cancer 4, 371–380 (2004).

    Article  CAS  Google Scholar 

  10. Reddy, P. & Ferrara, J.L. Immunobiology of acute graft-versus-host disease. Blood Rev. 17, 187–194 (2003).

    Article  Google Scholar 

  11. Duffner, U.A. et al. Host dendritic cells alone are sufficient to initiate acute graft-versus-host disease. J. Immunol. 172, 7393–7398 (2004).

    Article  CAS  Google Scholar 

  12. Gatza, E. & Okada, C.Y. Tumor cell lysate-pulsed dendritic cells are more effective than TCR Id protein vaccines for active immunotherapy of T cell lymphoma. J. Immunol. 169, 5227–5235 (2002).

    Article  Google Scholar 

  13. Patterson, A.E. & Korngold, R. Infusion of select leukemia-reactive TCR Vbeta+ T cells provides graft-versus-leukemia responses with minimization of graft-versus-host disease following mouse hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant. 7, 187–196 (2001).

    Article  CAS  Google Scholar 

  14. Patterson, A.E. & Korngold, R. Cross-protective mouse graft-versus-leukemia responses to phenotypically distinct myeloid leukemia lines. Biol. Blood Marrow Transplant. 6, 537–547 (2000).

    Article  CAS  Google Scholar 

  15. Zhang, Y., Louboutin, J.P., Zhu, J., Rivera, A.J. & Emerson, S.G. Preterminal host dendritic cells in irradiated mice prime CD8+ T cell-mediated acute graft-versus-host disease. J. Clin. Invest. 109, 1335–1344 (2002).

    Article  CAS  Google Scholar 

  16. Merad, M. et al. Depletion of host Langerhans cells before transplantation of donor alloreactive T cells prevents skin graft-versus-host disease. Nat. Med. 10, 510–517 (2004).

    Article  CAS  Google Scholar 

  17. Mapara, M.Y. & Sykes, M. Tolerance and cancer: mechanisms of tumor evasion and strategies for breaking tolerance. J. Clin. Oncol. 22, 1136–1151 (2004).

    Article  CAS  Google Scholar 

  18. Li, J.M. & Waller, E.K. Donor antigen-presenting cells regulate T-cell expansion and antitumor activity after allogeneic bone marrow transplantation. Biol. Blood Marrow Transplant. 10, 540–551 (2004).

    Article  Google Scholar 

  19. Kolb, H.J., Schmid, C., Barrett, A.J. & Schendel, D.J. Graft-versus-leukemia reactions in allogeneic chimeras. Blood 103, 767–776 (2004).

    Article  CAS  Google Scholar 

  20. Huntly, B.J. & Gilliland, D.G. Cancer biology: summing up cancer stem cells. Nature 435, 1169–1170 (2005).

    Article  CAS  Google Scholar 

  21. Hanahan, D. & Weinberg, R.A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  Google Scholar 

  22. Reddy, P. et al. Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect. Proc. Natl Acad. Sci. USA 101, 3921–3926 (2004).

    Article  CAS  Google Scholar 

  23. Bierman, P.J. et al. Syngeneic hematopoietic stem-cell transplantation for non-Hodgkin's lymphoma: a comparison with allogeneic and autologous transplantation–The Lymphoma Working Committee of the International Bone Marrow Transplant Registry and the European Group for Blood and Marrow Transplantation. J. Clin. Oncol. 21, 3744–3753 (2003).

    Article  Google Scholar 

  24. Wilson, N.S. & Villadangos, J.A. Regulation of antigen presentation and cross-presentation in the dendritic cell network: facts, hypothesis, and immunological implications. Adv. Immunol. 86, 241–305 (2005).

    Article  CAS  Google Scholar 

  25. Eibl, B. et al. Dendritic cells generated from blood precursors of chronic myelogenous leukemia patients carry the Philadelphia translocation and can induce a CML-specific primary cytotoxic T-cell response. Genes Chromosom. Cancer 20, 215–223 (1997).

    Article  CAS  Google Scholar 

  26. Stelljes, M. et al. Graft-versus-host disease after allogeneic hematopoietic stem cell transplantation induces a CD8+ T cell-mediated graft-versus-tumor effect that is independent of the recognition of alloantigenic tumor targets. Blood 104, 1210–1216 (2004).

    Article  CAS  Google Scholar 

  27. Fontaine, P. et al. Adoptive transfer of minor histocompatibility antigen-specific T lymphocytes eradicates leukemia cells without causing graft-versus-host disease. Nat. Med. 7, 789–794 (2001).

    Article  CAS  Google Scholar 

  28. Auffermann-Gretzinger, S. et al. Rapid establishment of dendritic cell chimerism in allogeneic hematopoietic cell transplant recipients. Blood 99, 1442–1448 (2002).

    Article  CAS  Google Scholar 

  29. Kaech, S.M. & Ahmed, R. Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naive cells. Nat. Immunol. 2, 415–422 (2001).

    Article  CAS  Google Scholar 

  30. Mempel, T.R., Henrickson, S.E. & Von Andrian, U.H. T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature 427, 154–159 (2004).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by US National Institutes of Health grants K08 AI052863-01 (to P.R.), PO1 CA 49542 (to J.L.M.F.) and R01 HL55593 (to R.K). P.R. is the recipient of the Alaina J. Enlow Scholar Award from Amy Strelzer Manasevit – National Marrow Donor Program and the New Investigator Award from American Society of Blood and Marrow Transplantation. J.L.M.F. is a recipient of the Doris Duke Distinguished Clinical Scientist Award.

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Author notes

  1. Pavan Reddy and Yoshinobu Maeda: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine, University of Michigan Cancer Center, 1500 East Medical Center Drive, Ann Arbor, Michigan, 48109-0942, USA

    Pavan Reddy, Yoshinobu Maeda, Oleg I Krijanovski & James L M Ferrara

  2. Department of Pathology, University of Florida College of Medicine, P.O. Box 100275, Gainesville, 32610-0275, Florida, USA

    Chen Liu

  3. The Cancer Center, Hackensack University Medical Center, Hackensack University Medical Plaza, 30 Prospect Avenue/Jurist Research Building, Hackensack, 07601, New Jersey, USA

    Robert Korngold

  4. Department of Pediatrics, University of Michigan Cancer Center, 1500 East Medical Center Drive, Ann Arbor, 48109-0942, Michigan, USA

    James L M Ferrara

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  1. Pavan Reddy
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Correspondence to Pavan Reddy.

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Supplementary information

Supplementary Fig. 1

Impaired allostimulatory activity of MMB3.19 cells in an MLR. (PDF 30 kb)

Supplementary Fig. 2

Depletion of CD4+CD25+ regulatory T cells from the donor T cells prior to priming by host APCs does not alter the GVL effect. (PDF 34 kb)

Supplementary Data (PDF 23 kb)

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Reddy, P., Maeda, Y., Liu, C. et al. A crucial role for antigen-presenting cells and alloantigen expression in graft-versus-leukemia responses. Nat Med 11, 1244–1249 (2005). https://doi.org/10.1038/nm1309

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