title: Self-tolerance to the murine homologue of a tyrosinase-derived melanoma antigen: implications for tumor immunotherapy.
abstract: The human tyrosinase-derived peptide YMDGTMSQV is presented on the surface of human histocompatibility leukocyte antigen (HLA)-A*0201(+) melanomas and has been suggested to be a tumor antigen despite the fact that tyrosinase is also expressed in melanocytes. To gain information about immunoreactivity and self-tolerance to this antigen, we established a model using the murine tyrosinase-derived homologue of this peptide FMDGTMSQV, together with transgenic mice expressing the HLA-A*0201 recombinant molecule AAD. The murine peptide was processed and presented by AAD similarly to its human counterpart. After immunization with 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 entire tyrosinase gene had been deleted by a radiation-induced mutation. A residual response was observed in the AAD(+)tyrosinase(+) mice after activation under certain conditions. At least some of these residual CTLs in AAD(+)tyrosinase(+) mice were of high avidity and induced vitiligo upon adoptive transfer into AAD(+)tyrosinase(+) hosts. Collectively, these data suggest that FMDGTMSQV is naturally processed and presented in vivo, and that this presentation leads to substantial but incomplete self-tolerance. The relevance of this model to an understanding of the human immune response to tyrosinase is discussed.
authors.affiliation: Department of Microbiology and the Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Colella
authors.forename: T N
authors.initials: TN
authors.lastname: Bullock
authors.forename: L B
authors.initials: LB
authors.lastname: Russell
authors.forename: D W
authors.initials: DW
authors.lastname: Mullins
authors.forename: W W
authors.initials: WW
authors.lastname: Overwijk
authors.forename: C J
authors.initials: CJ
authors.lastname: Luckey
authors.forename: R A
authors.initials: RA
authors.lastname: Pierce
authors.forename: N P
authors.initials: NP
authors.lastname: Restifo
authors.forename: V H
authors.initials: VH
authors.lastname: Engelhard
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology*; D003429:Cross Reactions; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D008544:Melanocytes / Q000276:immunology; D008545:Melanoma / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000276:immunology*; D010455:Peptides / Q000276:immunology; D017634:Self Tolerance / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D015789:HLA-A2 Antigen; D010455:Peptides; D014442:Monophenol Monooxygenase