Increased dendritic cell number and function following continuous in vivo infusion of granulocyte macrophage-colony-stimulating factor and interleukin-4.
Dendritic cells (DCs) are rare antigen-presenting cells that play a central role in stimulating immune responses. The combination of recombinant granulocyte macrophage-colony-stimulating factor (rGM-CSF) and recombinant interleukin-4 (rIL-4) provides an important stimulus for generating DCs from murine bone marrow precursors in vitro. Using miniature osmotic pumps, we now demonstrate that continuous infusion of these cytokines for 7 days had a similar effect in vivo, increasing the number and function of splenic DCs. Administration of rGM-CSF/rIL-4 (10 microg/d each) increased the concentration of CD11(+) DCs by 2.7-fold and the absolute number of splenic DCs by an average of 5.7-fold. DC number also increased in peripheral blood and lymph nodes. The resultant DCs exhibited a different phenotype and function than those in control mice or mice treated with rGM-CSF alone. rGM-CSF/IL-4 increased both the myeloid (CD11c(+)/CD11b(+)) and the lymphoid (CD11c(+)/CD8alpha(+)) subpopulations, whereas rGM-CSF increased only myeloid DCs. DCs were highly concentrated in the T-cell areas of white pulp after rGM-CSF/IL-4 administration, whereas they were diffusely distributed throughout white pulp, marginal zones, and red pulp in mice treated with rGM-CSF alone. rGM-CSF/rIL-4 also significantly increased the expression of major histocompatibility complex (MHC) class I and MHC class II on CD11c(+) cells and increased their capacity to take up antigens by macropinocytosis and receptor-mediated endocytosis. Splenic DCs generated in response to rGM-CSF/rIL-4 were functionally immature in terms of allostimulatory activity, but this activity increased after short-term in vitro culture. Systemic treatment with rGM-CSF/rIL-4 enhanced the response to an adenoviral-based vaccine and led to antigen-specific retardation in the growth of established tumor. We conclude that systemic therapy with the combination of rGM-CSF/rIL-4 provides a new approach for generating DCs in vivo.
Basak
Saroj K
SK
Division of Pulmonary and Critical Care, Department of Medicine, UCLA School of Medicine, Los Angeles 90095-1690, USA. sbasak@mednet.ucla.edu
Harui
Airi
A
Stolina
Marina
M
Sharma
Sherven
S
Mitani
Kohnosuke
K
Dubinett
Steven M
SM
Roth
Michael D
MD
D000818:Animals; D019496:Cancer Vaccines; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D004347:Drug Interactions; D004705:Endocytosis / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology*; D006649:Histocompatibility Antigens / Q000187:drug effects / Q000378:metabolism; D007167:Immunotherapy; D007263:Infusions, Parenteral; D015847:Interleukin-4 / Q000008:administration & dosage / Q000494:pharmacology*; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000628:therapy; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D016896:Treatment Outcome
D019496:Cancer Vaccines; D006649:Histocompatibility Antigens; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor