Vaccination with syngeneic, lymphoma-derived immunoglobulin idiotype combined with granulocyte/macrophage colony-stimulating factor primes mice for a protective T-cell response.
The idiotype of the Ig expressed by a B-cell malignancy (Id) can serve as a unique tumor-specific antigen and as a model for cancer vaccine development. In murine models of Id vaccination, formulation of syngeneic Id with carrier proteins or adjuvants induces an anti-idiotypic antibody response. However, inducing a potent cell-mediated response to this weak antigen instead would be highly desirable. In the 38C13 lymphoma model, we observed that low doses of free granulocyte/macrophage colony-stimulating factor (GM-CSF) 10,000 units i.p. or locally s.c. daily for 4 days significantly enhanced protective antitumor immunity induced by s.c. Id-keyhole limpet hemocyanin (KLH) immunization. This effect was critically dependent upon effector CD4+ and CD8+ T cells and was not associated with any increased anti-idiotypic antibody production. Lymphocytes from spleens and draining lymph nodes of mice primed with Id-KLH plus GM-CSF, but not with Id-KLH alone, demonstrated significant proliferation to Id in vitro without any biased production of interferon gamma or interleukin 4 protein or mRNA. As a further demonstration of potency, 50% of mice immunized with Id-KLH plus GM-CSF on the same day as challenge with a large s.c. tumor inoculum remained tumor-free at day 80, compared with 17% for Id-KLH alone, when immunization was combined with cyclophosphamide. Taken together, these results demonstrate that GM-CSF can significantly enhance the immunogenicity of a defined self-antigen and that this effect is mediated exclusively by activating the T-cell arm of the immune response.
Kwak
L W
LW
Division of Clinical Sciences, National Cancer Institute, Frederick, MD, USA.
Young
H A
HA
Pennington
R W
RW
Weeks
S D
SD
D000276:Adjuvants, Immunologic; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis; D000917:Antibody Formation / Q000187:drug effects; D019496:Cancer Vaccines / Q000276:immunology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D007111:Immunity, Cellular / Q000187:drug effects*; D007130:Immunoglobulin Idiotypes / Q000276:immunology*; D007167:Immunotherapy; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008809:Mice, Inbred C3H; D011994:Recombinant Proteins; D013601:T-Lymphocytes / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000888:Antibodies, Anti-Idiotypic; D019496:Cancer Vaccines; D007130:Immunoglobulin Idiotypes; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor