Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibodies, Neoplasm / biosynthesis
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Antigens, Neoplasm / immunology
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Antigens, Neoplasm / therapeutic use
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Autoantibodies / biosynthesis
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CD4-Positive T-Lymphocytes / chemistry
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / immunology
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Cancer Vaccines / immunology
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Cancer Vaccines / therapeutic use
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Cells, Cultured
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DNA, Neoplasm / immunology
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DNA, Neoplasm / therapeutic use
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Humans
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Interferon Type I / genetics
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Interferon Type I / immunology
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Interferon Type I / therapeutic use
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Interferon-gamma / metabolism
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Interferon-gamma / physiology*
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Intramolecular Oxidoreductases / genetics
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Intramolecular Oxidoreductases / immunology
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Intramolecular Oxidoreductases / therapeutic use
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Melanoma / genetics
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Melanoma / immunology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Mutant Strains
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Pregnancy Proteins / genetics
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Pregnancy Proteins / immunology
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Pregnancy Proteins / therapeutic use
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Tumor Cells, Cultured
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Vaccines, DNA / immunology*
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Vaccines, DNA / therapeutic use
Substances
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Antibodies, Neoplasm
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Antigens, Neoplasm
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Autoantibodies
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Cancer Vaccines
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DNA, Neoplasm
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Interferon Type I
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Pregnancy Proteins
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Vaccines, DNA
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interferon tau
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Interferon-gamma
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Intramolecular Oxidoreductases
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dopachrome isomerase