title: Effective graft depletion of MiHAg T-cell specificities and consequences for graft-versus-host disease.
abstract: Minor histocompatibility antigen (MiHAg) differences between donor and recipient in MHC-matched allogeneic hematopoietic stem cell transplantation (allo-HSCT) often result in graft-versus-host disease (GVHD). While MiHAg-specific T-cell responses can in theory be directed against a large number of polymorphic differences between donor and recipient, in practice, T-cell responses against only a small set of MiHAgs appear to dominate the immune response, and it has been suggested that immunodominance may predict an important contribution to the development of GVHD. Here, we addressed the feasibility of graft engineering by ex vivo removal of T cells with 1 or more defined antigen specificities in a well-characterized experimental HSCT model (B6 --> BALB.B). We demonstrate that immunodominant H60- and H4-specific CD8(+) T-cell responses can be effectively suppressed through MHC class I tetramer-mediated purging of the naive CD8(+) T cell repertoire. Importantly, the development of GVHD occurs unimpeded upon suppression of the immunodominant MiHAg-specific T-cell response. These data indicate that antigen-specific graft engineering is feasible, but that parameters other than immunodominance may be required to select T-cell specificities that are targeted for removal.
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Moniek A
authors.initials: MA
authors.lastname: de Witte
authors.forename: Mireille
authors.initials: M
authors.lastname: Toebes
authors.forename: Ji-Ying
authors.initials: JY
authors.lastname: Song
authors.forename: Monika C
authors.initials: MC
authors.lastname: Wolkers
authors.forename: Ton N M
authors.initials: TN
authors.lastname: Schumacher
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006082:Graft Enhancement, Immunologic; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000494:pharmacology*; D008212:Lymphocyte Depletion; D051379:Mice; D015778:Minor Histocompatibility Antigens / Q000276:immunology*; D010455:Peptides / Q000276:immunology / Q000494:pharmacology*; D014184:Transplantation, Homologous
chemical_list: D015395:Histocompatibility Antigens Class I; D015778:Minor Histocompatibility Antigens; D010455:Peptides