Abstract
It has been proposed that adoptive immunotherapy, for the treatment of relapsed AML, with cytotoxic T lymphocytes which show a relative specificity for the leukemic cells may have the advantage of maximizing the beneficial anti-leukemic effect whilst minimizing the probability of graft-versus-host disease. In this study we differentiated peripheral blood AML cells in vitro into functional dendritic cells (dcs), as demonstrated by cell morphology, immunophenotype and functional activity, in the presence of gm-csf, il-4, tnf-α and flt3 ligand. such dcs could be differentiated from 77% of aml patients, irrespective of their fab classification and clinical status and, in all cases tested, the dcs were shown to derive from the leukemic clone by fish analysis. importantly, from >60% of AML patients, autologous T lymphocytes stimulated with these in vitro generated leukemic DCs displayed specific cytotoxic activity against AML blasts but low reactivity against autologous non-leukemic targets and HLA-matched normal PBMNCs therefore suggesting that the CTLs were AML-specific. The use of FLT3 ligand in our system resulted in a significantly higher number of leukemic DCs as compared to cultures from which FLT3 ligand was omitted which is obviously advantageous if large numbers of specific CTLs are to be generated in the shortest possible time.
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
Loewenberg B, Downing JR, Burnett A . Acute myeloid leukemia New Engl J Med 1999 341: 1051–1062
Antin JH . Graft-versus leukemia: no longer an epiphenomenon Blood 1993 82: 2273–2277
Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, Rimm AA, Ringden O, Rozman C, Speck B, Truitt RC, Zwaan FE, Bortin MM . Graft-versus-leukemia reactions after bone marrow transplantation Blood 1990 75: 555–562
Gale RP, Horowitz MM, Ash RC, Champlin RE, Goldman JM, Rimm AA, Ringden O, Stone JA, Bortin MM . Identical-twin bone marrow transplants for leukemia Ann Intern Med 1994 120: 646–652
Goldman JM, Gale RP, Horowitz MM, Biggs JC, Champlin RE, Gluckman E, Hoffmann RG, Jacobsen SJ, Marmont AM, MCGlave PB . Bone marrow transplantation for chronic mylogenous leukemia in chronic phase. Increased risk for relapse associated with T-cell depletion Ann Intern Med 1995 108: 806–814
Kolb HJ, Mittermueller J, Clemm C, Holler E, Ledderose G, Brehm G, Heim M, Wilmans W . Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients Blood 1990 76: 2462–2465
van Rhee F, Kolb HJ . Donor leukocyte transfusions for leukemic relapse Curr Opin Immunol 1995 2: 423–426
Guinan EC, Gribben JG, Boussiotis VA, Freeman GJ, Nader LM . Pivol role of the B7: CD28 pathway in transplantation tolerance and tumor immunity Blood 1994 84: 3261–3282
Boussiotis VA, Freeman GJ, Gribben JG, Nadler LM . The critical role of CD28 signaling in the prevention of human T-cell anergy Res Immunol 1995 146: 140–149
Boussiotis VA, Freeman GJ, Gray G, Gribben J, Nadler LM . B7 but not intercellular adhesion molecule-1 costimulation prevents the induction of human alloantigen-specific tolerance J Exp Med 1993 178: 1753–1763
Banchereau J, Steinman RM . Dendritic cells and the control of immunity Nature 1998 392: 245–252
Choudhury A, Toubert A, Sutaria S, Charron D, Champlin RE, Claxton DF . Human leukemia-derived dendritic cells-ex-vivo development of specific antileukemic cytotoxicity Crit Rev Immunol 1998 18: 121–131
Choudhury BA, Liang JC, Thomas EK, Flores RL, Xie QS, Agusala K, Sutaria S, Sinha I, Champlin RE, Claxton DF . Dendritic cells derived in vitro from acute myelogenous leukemia cells stimulate autologous, antileukemic T-cell responses Blood 1999 3: 780–786
Charbonnier A, Gaugler B, Sainty D, Lafage-Pochitaloff M, Olive D . Human acute myeloblastic leukemia cells differentiate in vitro in mature dendritic cells and induce the differentiation of cytotoxic T cells against autologous leukemias Eur J Immunol 1999 29: 2567–2578
Stacchini A, Fubini L, Severino A, Sanavio F, Aglietta M, Piacibello W . Expression of type III receptor tyrosine kinases FLT3 and KIT and responses to their ligands by acute myeloid leukemia blasts Leukemia 1996 10: 1584–1591
Birg F, Courcoul MA, Rosnet O, Bardin F, Pébusque MJ, Marchetto S, Tabilio A, Mannoni P, Birnbaum D . Expression of the FMS/KIT-like gene FLT3 in human acute leukemias of the myeloid and lymphoid lineages Blood 1992 80: 2584–2593
Drexler HG . Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells Leukemia 1996 10: 588–599
Szabolcs P, Feller ED, Moore MA, Young JW . Progenitor recruitment and in vitro expansion of immunostimulatory dendritic cells from human CD34+ bone marrow cells by c-kit-ligand, GM-CSF, and TNF alpha Adv Exp Med Biol 1995 378: 17–20
Hirano N, Takahashi T, Ohtake S, Hirashima K, Emi N, Saito K, Hirano M, Shinohara K, Takeuchi M, Taketazu F, Tsunoda S, Ogura M, Omine M, Saito T, Yazaki Y, Ueda R, Hirai H . Expression of costimulatory molecules in human leukemias Leukemia 1996 10: 1168–1176
Costello RT, Mallet F, Sainty D, Maraninchi D, Gastaut JA, Olive D . Regulation of CD80/B7–1 and CD86/B7–2 molecule expression in human primary acute myeloid leukemia and their role in allogenic immune recognition Eur J Immunol 1998 28: 90–103
Law CL, Wormann B, LeBien TW . Analysis of expression and function of CD40 on normal and leukemic human B cell precursors Leukemia 1990 4: 732–738
Gribben JG, Guinan EC, Boussiotis VA, Ke XY, Linsley L, Sieff C, Gray GS, Freeman GJ, Nadler LM . Complete blockade of B7 family-mediated costimulation is necessary to induce human alloantigen-specific anergy: a method to ameliorate graft-versus-host disease and extend the donor pool Blood 1996 87: 4887–4893
Strobl H, Riedl E, Scheinecker C, Bello-Fernandez C, Pickl WF, Rappersberger K, Majdic O, Knapp W . TGF-beta 1 promotes in vitro development of dendritic cells from CD34+ hemopoietic progenitors J Immunol 1996 157: 1499–1507
Molldrem J, Dermime S, Parker K, Jiang YZ, Mavroudis D, Hensel N, Fukushima P, Barrett AJ . Targeted T-cell therapy for human leukemia: cytotoxic T lymphocytes specific for a peptide derived from proteinase 3 preferentially lyse human myeloid leukemia cell Blood 1996 88: 2450–2457
Bocchia M, Wentworth PA, Southwood S, Sidney J, McGraw K, Scheinberg DA, Sette A . Specific binding of leukemia oncogene fusion protein peptides to HLA class I molecules Blood 1995 85: 2680–2684
Gambacorti-Passerini C, Grignani F, Arienti F, Pandolfi PP, Pelicci PG, Parmiani G . Human CD4 lymphocytes specifically recognize a peptide representing the fusion region of the hybrid protein pml/RAR alpha present in acute promyelocytic leukemia cells Blood 1993 81: 1369–1375
Truitt RL, Shih CY, Lefever AV, Tempelis LD, Andreani M, Bortin MM . Characterization of alloimmunization-induced T lymphocytes reactive against AKR leukemia in vitro and correlation with graft-vs-leukemia activity in vivo J Immunol 1983 131: 2050–2058
Gale RP, Champlin RE . How does bone-marrow transplantation cure leukaemia? Lancet 1984 2: 28–30
Poynton CH . T cell depletion in bone marrow transplantation Bone Marrow Transplant 1988 3: 265–279
Marmont AM, Horowitz MM, Gale RP, Sobocinski K, Ash RC, van Bekkum DW, Champlin RE, Dicke KA, Goldman JM, Good RA et al. T-cell depletion of HLA- identical transplants in leukemia Blood 1991 78: 2120–2130
Santiago-Schwarz F, Coppock DL, Hindenburg AA, Kern J . Identification of a malignant counterpart of the monocyte-dendritic cell progenitor in an acute myeloid leukemia Blood 1994 84: 3054–3062
Robinson SP, English N, Jaju R, Kearney L, Knight SC, Reid CD . The in vitro generation of dendritic cells from blast cells in acute myeloid leukaemia Br J Haematol 1998 103: 763–771
Acknowledgements
We thank the doctors and sisters of the BMT unit for helping with sample acquisition, Dr Claudia Schoch for performing the FISH analysis and Professor Dr DJ Schendel for support and helpful discussion.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Woiciechowsky, A., Regn, S., Kolb, HJ. et al. Leukemic dendritic cells generated in the presence of FLT3 ligand have the capacity to stimulate an autologous leukemia-specific cytotoxic T cell response from patients with acute myeloid leukemia. Leukemia 15, 246–255 (2001). https://doi.org/10.1038/sj.leu.2402013
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2402013
Keywords
This article is cited by
-
Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation
Nature Communications (2023)
-
The FLAMSA concept—past and future
Annals of Hematology (2020)
-
Restoration of MYC-repressed targets mediates the negative effects of GM-CSF on RUNX1-ETO leukemogenicity
Leukemia (2017)
-
Augmentation of autologous T cell reactivity with acute myeloid leukemia (AML) blasts by Toll-like receptor (TLR) agonists
Cancer Immunology, Immunotherapy (2015)
-
Acute differentiated dendritic cell leukemia: a variant form of pediatric acute myeloid leukemia with MLL translocation
Leukemia (2007)