Alternative roles for interferon-gamma in the immune response to DNA vaccines encoding related melanosomal antigens.
Tyrosinase-related proteins-1 and -2 (gp75/TRP-1 and TRP-2) are melanosomal membrane glycoproteins recognized by antibodies and T-cells from patients with melanoma. Xenogeneic DNA immunization against gp75/TRP-1 generates antibody-dependent tumor immunity and autoimmune depigmentation. In contrast xenogeneic TRP-2 DNA immunization induces immunity mediated by CD8+ T-cells. The role of IFN-gamma in the generation of tumor immunity and autoimmune depigmentation in these two models was investigated. No tumor protection and minimal depigmentation was observed after immunization with human TRP-2 DNA in mice deficient in IFN-gamma ligand. Repletion with recombinant murine IFN-gamma restored tumor immunity. Experiments using IL4 deficient mice demonstrated that tumor immunity was unaffected but that autoimmune depigmentation was potentially accelerated, consistent with down-modulation of autoimmunity against TRP-2 by IL4. In contrast, IFN-gamma was not required for the generation of immunity to gp75/TRP-1. In fact, exogenous IFN-gamma ablated autoantibody responses against gp75/TRP-1 after xenogeneic DNA immunization, consistent with a down-regulatory effect of IFN-gamma. These results show that immunity to TRP-2 following DNA immunization uses an IFN-gamma-dependent Th1 pathway, but immunity to gp75/TRP-1 is down-regulated by IFN-gamma.
The Swim Across America Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. wolchokj@mskcc.org
J D
JD
Wolchok
R
R
Srinivasan
M A
MA
Perales
A N
AN
Houghton
W B
WB
Bowne
N E
NE
Blachere
D000818:Animals; D000912:Antibodies, Neoplasm / Q000096:biosynthesis; D000951:Antigens, Neoplasm / Q000276:immunology / Q000627:therapeutic use; D001323:Autoantibodies / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use; D002478:Cells, Cultured; D004273:DNA, Neoplasm / Q000276:immunology / Q000627:therapeutic use; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D007371:Interferon-gamma / Q000378:metabolism / Q000502:physiology*; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D008545:Melanoma / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D011257:Pregnancy Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D019444:Vaccines, DNA / Q000276:immunology* / Q000627:therapeutic use
D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D001323:Autoantibodies; D019496:Cancer Vaccines; D004273:DNA, Neoplasm; D007370:Interferon Type I; D011257:Pregnancy Proteins; D019444:Vaccines, DNA; C020947:interferon tau; D007371:Interferon-gamma; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase