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PMID: 10748239 Published · ppublish English Journal Article Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Self-tolerance to the murine homologue of a tyrosinase-derived melanoma antigen: implications for tumor immunotherapy.

The Journal of experimental medicine ·Vol. 191 ·No. 7 ·2000-04-03 ·Pages 1221-32

Colella TA, Bullock TN, Russell LB, Mullins DW, Overwijk WW, Luckey CJ, Pierce RA, Restifo NP, Engelhard VH

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.

MeSH Terms
Amino Acid Sequence Animals Antigen Presentation Antigens, Neoplasm/immunology Cross Reactions HLA-A2 Antigen/genetics,immunology Humans Immunotherapy Melanocytes/immunology Melanoma/immunology Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Molecular Sequence Data Monophenol Monooxygenase/genetics,immunology Peptides/immunology Self Tolerance/immunology T-Lymphocytes, Cytotoxic/immunology
Chemicals
Antigens, Neoplasm HLA-A2 Antigen Peptides Monophenol Monooxygenase
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Colella T A
Department of Microbiology and the Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA.
Bullock T N
Russell L B
Mullins D W
Overwijk W W
Luckey C J
Pierce R A
Restifo N P
Engelhard V H
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.191.7.1221
Published
2000-04-03
Pages
1221-32
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2193167
Subset
IM
Grants
NCI NIH HHS · CA78400 · United States
NCI NIH HHS · CA09109 · United States
Intramural NIH HHS · Z01 BC010763-01 · United States
Intramural NIH HHS · Z99 CA999999 · United States
NIAID NIH HHS · AI21393 · United States
External Links
PubMed source DOI: 10.1084/jem.191.7.1221 PMC Full Text View journal details
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