Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified

doi:10.1084/jem.184.5.1953

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Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified

E Maraskovsky, K Brasel, M Teepe, ER Roux, SD Lyman, K Shortman and HJ McKenna
Department of Immunobiology, Immunex Corporation, Seattle, Washington 98101, USA.

Dendritic cells (DC) are the most efficient APC for T cells. The clinical use of DC as vectors for anti-tumor and infectious disease immunotherapy has been limited by their trace levels and accessibility in normal tissue and terminal state of differentiation. In the present study, daily injection of human Flt3 ligand (Flt3L) into mice results in a dramatic numerical increase in cells co-expressing the characteristic DC markers-class II MHC, CD11c, DEC205, and CD86. In contrast, in mice treated with either GM-CSF, GM-CSF plus IL-4, c-kit ligand (c-kitL), or G-CSF, class II+ CD11c+ cells were not significantly increased. Five distinct DC subpopulations were identified in the spleen of Flt3L-treated mice using CD8 alpha and CD11b expression. These cells exhibited veiled and dendritic processes and were as efficient as rare, mature DC isolated from the spleens of untreated mice at presenting allo-Ag or soluble Ag to T cells, or in priming an Ag-specific T cell response in vivo. Dramatic numerical increases in DC were detected in the bone marrow, gastro-intestinal lymphoid tissue (GALT), liver, lymph nodes, lung, peripheral blood, peritoneal cavity, spleen, and thymus. These results suggest that Flt3L could be used to expand the numbers of functionally mature DC in vivo for use in clinical immunotherapy.
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Kataoka, K., McGhee, J. R., Kobayashi, R., Fujihashi, K., Shizukuishi, S., Fujihashi, K. (2004). Nasal Flt3 Ligand cDNA Elicits CD11c+CD8+ Dendritic Cells for Enhanced Mucosal Immunity. J. Immunol. 172: 3612-3619 [Abstract] [Full Text]
Higano, C. S., Vogelzang, N. J., Sosman, J. A., Feng, A., Caron, D., Small, E. J (2004). Safety and Biological Activity of Repeated Doses of Recombinant Human Flt3 Ligand in Patients with Bone Scan-Negative Hormone-Refractory Prostate Cancer. Clin. Cancer Res. 10: 1219-1225 [Abstract] [Full Text]
Colvin, B. L., Morelli, A. E., Logar, A. J., Lau, A. H., Thomson, A. W. (2004). Comparative evaluation of CC chemokine-induced migration of murine CD8{alpha}+ and CD8{alpha}- dendritic cells and their in vivo trafficking. J. Leukoc. Biol. 75: 275-285 [Abstract] [Full Text]
Appel, S., Boehmler, A. M., Grunebach, F., Muller, M. R., Rupf, A., Weck, M. M., Hartmann, U., Reichardt, V. L., Kanz, L., Brummendorf, T. H., Brossart, P. (2004). Imatinib mesylate affects the development and function of dendritic cells generated from CD34+ peripheral blood progenitor cells. Blood 103: 538-544 [Abstract] [Full Text]
Klein, J. R., Wang, H.-C. (2004). Characterization of a novel set of resident intrathyroidal bone marrow-derived hematopoietic cells: potential for immune-endocrine interactions in thyroid homeostasis. J. Exp. Biol. 207: 55-65 [Abstract] [Full Text]
Zheng, R., Levis, M., Piloto, O., Brown, P., Baldwin, B. R., Gorin, N. C., Beran, M., Zhu, Z., Ludwig, D., Hicklin, D., Witte, L., Li, Y., Small, D. (2004). FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells. Blood 103: 267-274 [Abstract] [Full Text]
Coates, P. T. H., Barratt-Boyes, S. M., Zhang, L., Donnenberg, V. S., O'Connell, P. J., Logar, A. J., Duncan, F. J., Murphey-Corb, M., Donnenberg, A. D., Morelli, A. E., Maliszewski, C. R., Thomson, A. W. (2003). Dendritic cell subsets in blood and lymphoid tissue of rhesus monkeys and their mobilization with Flt3 ligand. Blood 102: 2513-2521 [Abstract] [Full Text]
Kumamoto, T., Shalhevet, D., Matsue, H., Mummert, M. E., Ward, B. R., Jester, J. V., Takashima, A. (2003). Hair follicles serve as local reservoirs of skin mast cell precursors. Blood 102: 1654-1660 [Abstract] [Full Text]
Hamrah, P., Liu, Y., Zhang, Q., Dana, M. R. (2003). Alterations in Corneal Stromal Dendritic Cell Phenotype and Distribution in Inflammation. Arch Ophthalmol 121: 1132-1140 [Abstract] [Full Text]
Doxsee, C. L., Riter, T. R., Reiter, M. J., Gibson, S. J., Vasilakos, J. P., Kedl, R. M. (2003). The Immune Response Modifier and Toll-Like Receptor 7 Agonist S-27609 Selectively Induces IL-12 and TNF-{alpha} Production in CD11c+CD11b+CD8- Dendritic Cells. J. Immunol. 171: 1156-1163 [Abstract] [Full Text]