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Many human and mouse tumor antigens are normal, nonmutated tissue differentiation antigens. Consequently, immunization with these "self" antigens could induce autoimmunity. When we tried to induce immune responses to five mouse melanocyte differentiation antigens, gp100, MART-1, tyrosinase, and tyrosinase-related proteins (TRP) 1 and TRP-2, we observed striking depigmentation and melanocyte destruction only in the skin of mice inoculated with a vaccinia virus encoding mouse TRP-1. These mice rejected a lethal challenge of B16 melanoma, indicating the immune response against TRP-1 could destroy both normal and malignant melanocytes. Cytotoxic T lymphocytes specific for TRP-1 could not be detected in depigmented mice, but high titers of IgG anti-TRP-1 antibodies were present. Experiments with knockout mice revealed an absolute dependence on major histocompatibility complex class II, but not major histocompatibility complex class I, for the induction of both vitiligo and tumor protection. Together, these results suggest that the deliberate induction of self-reactivity using a recombinant viral vector can lead to tumor destruction, and that in this model, CD4(+) T lymphocytes are an integral part of this process. Vaccine strategies targeting tissue differentiation antigens may be valuable in cancers arising from nonessential cells and organs such as melanocytes, prostate, testis, breast, and ovary.

Original publication

DOI

10.1073/pnas.96.6.2982

Type

Journal article

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Date

03/1999

Volume

96

Pages

2982 - 2987

Addresses

Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Keywords

CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Melanocytes, Animals, Mice, Knockout, Humans, Mice, Vaccinia virus, Melanoma, Experimental, Vitiligo, Oxidoreductases, Proteins, Membrane Glycoproteins, DNA, Recombinant, Cancer Vaccines, Antigens, Neoplasm, Autoantigens, Vaccination, Autoimmunity, Cytotoxicity, Immunologic, Genetic Vectors, Female, Male