Injection of DNA encoding granulocyte-macrophage colony-stimulating factor recruits dendritic cells for immune adjuvant effects.
An important issue for effective vaccines is the development of potent adjuvants that can facilitate induction or augmentation of immunity. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a growth factor for myeloid progenitors of monocytes and dendritic cells (DC), which upon maturation are antigen-presenting cells (APC). The adjuvant effects of inoculation of DNA encoding GM-CSF into skin were studied. Initial experiments examined whether the GM-CSF gene injected into the skin of mice could affect the density of epidermal DC (Langerhans cells). DNA encoding GM-CSF delivered by particle bombardment into skin resulted in a significant increase of epidermal DC at the inoculation site. Kinetic analysis of epidermal recruitment after GM-CSF inoculation showed an increase in DC that peaked at seven days. This increase was accompanied by recruitment of DC into draining lymph nodes. The adjuvant effects of DNA encoding GM-CSF inoculated into skin were measured by the ability to augment antibody and T-cell responses against poorly immunogenic tumor antigens. Peptide immunization at skin sites containing epidermal DC newly recruited by GM-CSF DNA elicited T-cell responses against mutant p53, whereas peptide immunization of control skin sites did not elicit any detectable T-cell responses. Likewise, generation of antibodies following immunization with DNA encoding human gp75TRP1, a tyrosinase family member expressed by melanomas, was accelerated and protection from tumor challenge augmented by GM-CSF DNA.
Bowne
W B
WB
Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Wolchok
J D
JD
Hawkins
W G
WG
Srinivasan
R
R
Gregor
P
P
Blachere
N E
NE
Moroi
Y
Y
Engelhorn
M E
ME
Houghton
A N
AN
Lewis
J J
JJ
D000276:Adjuvants, Immunologic / Q000235:genetics*; D000818:Animals; D000917:Antibody Formation; D019470:Biolistics; D015153:Blotting, Western; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D004817:Epidermis / Q000276:immunology / Q000473:pathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D006801:Humans; D007271:Injections, Intradermal; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011233:Precipitin Tests; D013601:T-Lymphocytes / Q000276:immunology; D019444:Vaccines, DNA / Q000235:genetics / Q000494:pharmacology*
D000276:Adjuvants, Immunologic; D019444:Vaccines, DNA; D016178:Granulocyte-Macrophage Colony-Stimulating Factor