title: DNA fusion vaccines induce targeted epitope-specific CTLs against minor histocompatibility antigens from a normal or tolerized repertoire.
abstract: We have designed DNA fusion vaccines able to induce high levels of epitope-specific CD8(+) T cells, using linked CD4(+) T cell help. Such vaccines can activate effective immunity against tumor Ags. To model performance against minor histocompatibility (H) Ags important in allogeneic hemopoietic stem cell transplantation, responses against the H2D(b)-restricted Uty and Smcy male HY epitopes have been investigated. Vaccination of females induced high levels of tetramer-specific, IFN-gamma-producing CD8(+) T cells against each epitope. Vaccines incorporating a single epitope primed effector CTL able to kill male splenocytes in vitro and in vivo, and HY(Db)Uty-specific vaccination accelerated rejection of syngeneic male skin grafts. Priming against either epitope established long-term memory, expandable by injection of male cells. Expanded CD8(+) T cells remained specific for the priming HY epitope, with responses to the second suppressed. To investigate vaccine performance in a tolerized repertoire, male mice were vaccinated with the fusion constructs. Strikingly, this also generated epitope-specific IFN-gamma-producing CD8(+) T cells with cytotoxic function. However, numbers and avidity were lower than in vaccinated females, and vaccinated males failed to reject CFSE-labeled male splenocytes in vivo. Nevertheless, these findings indicate that DNA fusion vaccines can mobilize CD8(+) T cells against endogenous minor H Ags, even from a profoundly tolerized repertoire. In the transplantation setting, vaccination of donors could prime and expand specific T cells for in vivo transfer. For patients, vaccination could activate a potentially less tolerized repertoire against similar Ags that may be overexpressed by tumor cells, for focused immune attack.
authors.affiliation: Molecular Immunology Group, Southampton University Hospitals Trust, Southampton, Hampshire, United Kingdom. j.rice@soton.ac.uk
authors.forename: Jason
authors.initials: J
authors.lastname: Rice
authors.forename: Sarah
authors.initials: S
authors.lastname: Buchan
authors.forename: Hamlata
authors.initials: H
authors.lastname: Dewchand
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Simpson
authors.forename: Freda K
authors.initials: FK
authors.lastname: Stevenson
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D005260:Female; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006182:H-Y Antigen / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D012737:Sex Factors; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D013744:Tetanus Toxin / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; D006182:H-Y Antigen; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D013744:Tetanus Toxin; D019444:Vaccines, DNA; D014614:Vaccines, Synthetic; D007371:Interferon-gamma