Abstract
Dendritic cells (DC) are the most potent professional antigen-presenting cells with exquisite capacity to interact with T cells to initiate strong primary cellular immune responses. The antigen-presenting capability of DC makes them attractive vehicles for the delivery of therapeutic cancer vaccines. Recently, we have demonstrated that the introduction of a recombinant gene encoding the human Flt3L gene into mice could result in the expansion of the DC population in vivo. In this report, we have introduced the human Flt-3L gene via naked DNA-based immunization in combination with the muc-1 tumor peptide to immunize mice. We demonstrated that the population of DC expanded following stimulation with the human Flt-3L gene in vivo is functional and they are able to elicit potent muc-1 peptide-specific cellular responses. The strategy described here allows the efficient generation of antigen-specific CTL immunity in vivo and has the potential to be applied in developing efficient protocols for antigen-specific immunotherapy of human malignancies.
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References
Steinman RM, Pack M, Inaba K . Dendritic cells in the T-cell areas of lymphoid organs Immunol Rev 1997 156: 25–37
Pagila P, Chiodoni C, Rodolfo M, Colombo MP . Murine dendritic cells loaded in vitro with soluble protein prime cytotoxic T lymphocytes against tumor antigen in vivo J Exp Med 1996 183: 317–322
Celluzzi CM et al. Peptide-pulsed dendritic cells induce antigen-specific CTL-mediated protective tumor immunity J Exp Med 1996 183: 283–287
Nestle FO et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells Nat Med 1998 21: 328–332
Yang S et al. Murine dendritic cells transfected with human GP100 elicit both antigen-specific CD8(+) and CD4(+) T-cell responses and are more effective than DNA vaccines at generating anti-tumor immunity Int J Cancer 1999 83: 532–540
Fong L et al. Dendritic cells injected via different routes induce immunity in cancer patients J Immunol 2001 166: 4254–4259
Austyn JM, Kupiec-Weglinski JW, Hankins DF, Morris PJ . Migration patterns of dendritic cells in the mouse. Homing to T cell-dependent areas of spleen, and binding within marginal zone J Exp Med 1988 167: 646–651
Maraskovsky E et al. Dramatic increases in the numbers of functionally mature dendritic cells in Flt-3 ligand-treated mice: multiple dendritic cell subpopulations identified J Exp Med 1996 184: 1953–1962
Lynch DH et al. Flt-3 ligand induces tumor regression and antitumor immune responses in vivo Nat Med 1997 3: 625–631
Esche C et al. Flt-3 ligand administration inhibits tumor growth in murine melanoma and lymphoma Cancer Res 1998 58: 380–383
Ardavin C, Wu L, Li CL, Shortman K . Thymic dendritic cells and T cells develop simultaneously in the thymus from a common precursor population Nature 1993 362: 761–763
Wu L, Li CL, Shortman K . Thymic dendritic cell precursors: relationship to the T lymphocyte lineage and phenotype of the dendritic cell progeny J Exp Med 1996 184: 903–911
Gary A, Travis M, Cen D, Chen B . Human T, B, natural killer and dendritic cells arise from a common bone marrow progenitor cell subset Immunity 1995 3: 459–473
Xiaofeng W et al. Regression of human mammary adenocarcinoma by systemic administration of a recombinant gene encoding the hFlex-trail fusion protein Mol Ther 2001 3: 368–374
Inaba KM et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor J Exp Med 1992 176: 1693–1702
Liu F, Song YK, Liu D . Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA Gene Therapy 1999 6: 1258–1266
Apostolopoulos V, McKenzie IFC . Cellular mucins: targets for immunotherapy Crit Rev Immunol 1996 14: 930–938
O'Garra A . Cytokines induce the development of functionally heterogeneous T helper cell subsets Immunity 1998 8: 275–283
Heufler C et al. Interleukin-12 is produced by dendritic cells and mediates T helper 1 development as well as interferon-(production by T helper cells Eur J Immunol 1996 26: 659–668
Sato M, Iwakabe K, Kimura S, Nishimura T . Functional skewing of bone marrow-derived dendritic cells by Th1- or Th2-inducing cytokines Immunol Lett 1999 67: 63–68
Denton G, Sekowski M, Price MR . Induction of antibody responses to breast carcinoma associated mucins using synthetic peptide constructs as immunogens Cancer Lett 1993 70: 143–150
Avichezer D, Taylor-Papadimitriou J, Arnon R . A short synthetic peptide (DTRPAP) induces anti-mucin (MUC-1) antibody, which is reactive with human ovarian and breast cancer cells Cancer Biochem Biophys 1998 16: 113–128
Braun SE et al. Flt3 ligand antitumor activity in a murine breast cancer model: a comparison with granulocyte–macrophage colony-stimulating factor and a potential mechanism of action Hum Gene Ther 1999 10: 2141–2151
Liu YJ . Dendritic cell subsets and lineages, and their functions in innate and adaptive immunity Cell 2001 106: 259–262
Ardavin C, Wu L, Li C-L, Shortman K . Thymic dendritic cells and T cells develop simultaneously in the thymus from a common precursor population Nature 1993 362: 761–763
Sauders D et al. Dendritic cell development in culture from thymic precursor cells in the absence of granulocyte/macrophage colony-stimulating factor J Exp Med 1996 184: 2185–2196
Henderson RA et al. Human dendritic cells genetically engineered to express high levels of the human epithelial tumor antigen mucin (MUC-1) Cancer Res 1996 56: 3763–3770
Pecher G, Finn OJ . Induction of cellular immunity in chimpanzees to human tumor-associated antigen mucin by vaccination with MUC-1 cDNA-transfected Epstein–Barr virus-immortalized autologous B cells Proc Natl Acad Sci USA 1996 93: 1699–1704
Apostolopoulos V, Pietersz GA, McKenzie FC . Cell-mediated immune responses to MUC1 fusion protein coupled to mannan Vaccine 1996 14: 930–938
Goydos JS et al. A phase I trial of a synthetic mucin peptide vaccine J Surg Res 1996 63: 298–304
Karanikas V et al. Antibody and T cell responses of patients with adenocarcinoma immunized with mannan-Muc-1 fusion protein J Clin Invest 1997 100: 2783–2792
Banchereau J, Steinman RM . Dendritic cells and the control of immunity Nature 1998 392: 245–252
Savary CA et al. Characteristics of human dendritic cells generated in a microgravity analog culture system In Vitro Cell Dev Biol Anim 2001 37: 216–222
Kotera Y et al. Humoral immunity against a tandem repeat epitope of human mucin MUC-1 in sera from breast, pancreatic, and colon cancer patients Cancer Res 1994 54: 2856–2860
Andersson E et al. A tandem repeat of MUC1 core protein induces a weak in vitro immune response in human B cells Cancer Immunol Immunother 1999 47: 249–256
Carbone FR, Moore MW, Sheil JM, Bevan MJ . Induction of cytotoxic T lymphocytes by primary in vitro stimulation with peptides J Exp Med 1998 167: 1767–1779
Lyman SD et al. Cloning of the human homologue of the murine flt-3 ligand: a growth factor for early hematopoietic progenitor cells Blood 1994 83: 2795–2801
Felgner JH et al. Enhanced gene delivery and mechanism studies with a novel series of cationic lipid formulations J Biol Chem 1994 269: 2550–2561
Taswell C . Limiting dilution assays for the determination of immunocompetent cell frequencies J Immunol 1981 126: 1614–1619
Fazekas DE, Groth ST . The evaluation of limiting dilution assays - review article J Immunol Meth 1984 49: 11–23
Lefkovis I, Waldmann H . Limiting dilution analysis of the cells of the immune system Immunol Today 1984 5: 265–272
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This work was supported by grants from the National Medical Research Council of Singapore and the National Science and Technology Board, Singapore.
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Fong, C., Hui, K. Generation of potent and specific cellular immune responses via in vivo stimulation of dendritic cells by pNGVL3-hFLex plasmid DNA and immunogenic peptides. Gene Ther 9, 1127–1138 (2002). https://doi.org/10.1038/sj.gt.3301783
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DOI: https://doi.org/10.1038/sj.gt.3301783
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