title: Granulocyte/macrophage-colony stimulating factor and interleukin-4 expand and activate type-1 dendritic cells (DC1) when administered in vivo to cancer patients.
abstract: Two rare populations of cells with the features of dendritic cell precursors (preDC) can be identified in human peripheral blood. PreDC1 are HLA-DR+/CD11c+ cells which mature into DC1 capable of stimulating Th1 responses. In contrast, preDC2 are HLA-DR+/CD11c-/CD123+ cells that promote Th2 responses when matured into DC2. We hypothesized that administration of GM-CSF and IL-4, growth factors for DC1, would specifically augment the number and function of circulating DC1 in vivo. Patients with advanced metastatic cancer were treated with GM-CSF (2.5 microg/kg/day) and IL-4 (4 or 6 microg/kg/day) for 7 days. Cytokine administration at the highest IL-4 dose produced an average 2.3-fold increase in preDC2 number, but a 6.5-fold increase in preDC1, resulting in an increased ratio of circulating preDC1:preDC2 from 1.4:1 pre-treatment to 4.3:1 after cytokine therapy. DC1 precursors identified after in vivo therapy were larger, more complex and expressed higher levels of HLA-DR, CD11c and CD80 than pre-treatment cells. DC1 isolated from the peripheral blood of patients receiving GM-CSF/IL-4 therapy demonstrated MLR activity comparable to that of monocyte-derived DC generated in vitro from the patients' pre-treatment blood using GM-CSF and IL-4. We conclude that systemic administration of GM-CSF and IL-4 preferentially expands and matures the preDC1 population in vivo. These effects correlate with antigen-presenting activity, providing a mechanism by which systemic GM-CSF and IL-4 might stimulate anti-tumor immunity in vivo.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, UCLA School of Medicine, Los Angeles, CA 90095-1690, USA. skiertscher@mednet.ucla.edu
authors.forename: Sylvia M
authors.initials: SM
authors.lastname: Kiertscher
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Gitlitz
authors.forename: Robert A
authors.initials: RA
authors.lastname: Figlin
authors.forename: Michael D
authors.initials: MD
authors.lastname: Roth
mesh_terms: D015703:Antigens, CD / Q000097:blood; D016022:Case-Control Studies; D003713:Dendritic Cells / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage*; D006684:HLA-DR Antigens / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D015847:Interleukin-4 / Q000008:administration & dosage*; D008214:Lymphocytes / Q000276:immunology; D009000:Monocytes / Q000276:immunology; D009369:Neoplasms / Q000097:blood / Q000276:immunology* / Q000628:therapy*; D009360:Neoplastic Cells, Circulating; D010641:Phenotype; D011994:Recombinant Proteins; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D006684:HLA-DR Antigens; D011994:Recombinant Proteins; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor