Granulocyte/macrophage-colony stimulating factor and interleukin-4 expand and activate type-1 dendritic cells (DC1) when administered in vivo to cancer patients.
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.
Kiertscher
Sylvia M
SM
Division of Pulmonary and Critical Care Medicine, UCLA School of Medicine, Los Angeles, CA 90095-1690, USA. skiertscher@mednet.ucla.edu
Gitlitz
Barbara J
BJ
Figlin
Robert A
RA
Roth
Michael D
MD
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
D015703:Antigens, CD; D006684:HLA-DR Antigens; D011994:Recombinant Proteins; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor