Effect of vascular endothelial growth factor and FLT3 ligand on dendritic cell generation in vivo

The cytokine FLT3 ligand (FL) enhances dendritic cell (DC) generation and h as therefore been proposed as a means to boost antitumor immunity, Vascular endothelial growth factor (VEGF) is produced by a large percentage of tumo rs and is required for development of tumor neovasculature, We previously s howed that VEGF decreases DC production and function in vivo. In this study , we tested the hypothesis that VEGF regulates FL effects on DC generation. In seven experiments, four groups of mice were treated with PBS, VEGF alon e (100 ng/h), FL alone (10 mu g/day), or with the combination of FL and VEG F, VEGF and PBS were administered continuously for 14 days via s.c. pumps. FL was given s.c. daily for 9 days, beginning on day 4. Tissues were collec ted and the number, phenotype, and function of lymph node, splenic, and thy mic DCs were analyzed on day 14, As expected, treatment with FL resulted in a marked Increase in the number of lymph node and spleen DCs and a smaller increase in thymic DC; Pretreatment of mice with VEGF inhibited these FL e ffects in lymph nodes and thymus by about 50%, whereas spleen DG numbers we re undiminished by VEGF, VEGF treatment in vivo also inhibited the ability of FL to increase the number of hemopoietic precursor cells and the level o f maturity exhibited by DC derived from these hemopoietic precursor cells i n vitro, VEGF inhibited FL-inducibIe activation of transcription factor NF- kappa B, These data suggest that VEGF interferes with the ability of FL to promote dendritic cell differentiation from bone marrow progenitor cells in mice and therefore may decrease the therapeutic efficacy of FL in settings where increased numbers of DCs might provide clinical benefits.