Self-Tolerance to the Murine Homologue of a Tyrosinase-derived Melanoma Antigen: Implications for Tumor Immunotherapy

doi:10.1084/jem.191.7.1221

Published online 3 April 2000.

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© The Rockefeller University Press, 0022-1007/2000/4/1221/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 7, April 3, 2000 1221-1232

Original Article

Self-Tolerance to the Murine Homologue of a Tyrosinase-derived Melanoma Antigen: Implications for Tumor Immunotherapy

Teresa A. Colella^a, Timothy N.J. Bullock^a, Liane B. Russell^b, David W. Mullins^a, Willem W. Overwijk^c, Chance John Luckey^a, Richard A. Pierce^a, Nicholas P. Restifo^c, and Victor H. Engelhard^a
^a Department of Microbiology and the Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908
^b Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831
^c Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

Correspondence to: Victor H. Engelhard, Department of Microbiology and the Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908. Tel:804-924-2423 Fax:804-924-1221 E-mail:vhe{at}virginia.edu.

The human tyrosinase-derived peptide YMDGTMSQV is presentedon the surface of human histocompatibility leukocyte antigen(HLA)-A*0201⁺ melanomas and has been suggested to be a tumorantigen despite the fact that tyrosinase is also expressed inmelanocytes. To gain information about immunoreactivity andself-tolerance to this antigen, we established a model usingthe murine tyrosinase-derived homologue of this peptide FMDGTMSQV,together with transgenic mice expressing the HLA-A*0201 recombinantmolecule AAD. The murine peptide was processed and presentedby AAD similarly to its human counterpart. After immunizationwith recombinant vaccinia virus encoding murine tyrosinase,we detected a robust AAD-restricted cytotoxic T lymphocyte (CTL)response to FMDGTMSQV in AAD transgenic mice in which the entiretyrosinase gene had been deleted by a radiation-induced mutation.A residual response was observed in the AAD⁺tyrosinase⁺ miceafter activation under certain conditions. At least some ofthese residual CTLs in AAD⁺tyrosinase⁺ mice were of high avidityand induced vitiligo upon adoptive transfer into AAD⁺tyrosinase⁺hosts. Collectively, these data suggest that FMDGTMSQV is naturallyprocessed and presented in vivo, and that this presentationleads to substantial but incomplete self-tolerance. The relevanceof this model to an understanding of the human immune responseto tyrosinase is discussed.

Key Words: tyrosinase, self-tolerance, MHC class I, cytotoxic T lymphocytes,immunotherapy

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