title: In situ dissection of the graft-versus-host activities of cytotoxic T cells specific for minor histocompatibility antigens.
abstract: Minor histocompatibility antigens (mHags) are immunogenic peptides from polymorphic cellular proteins that induce strong T-cell responses after human leukocyte antigen (HLA)-matched, mHag-mismatched stem-cell transplantation. mHags with broad or limited tissue expression are target antigens for graft-versus-host (GvH) and graft-versus-leukemia (GvL) reactivities. Separation of these activities is crucial for adoptive immunotherapy of leukemia without GvH disease. Therefore, using a skin-explant assay we investigated the in situ activities of cytotoxic T lymphocytes (CTLs) specific for the ubiquitously expressed mHag H-Y and for the hematopoietic-restricted mHags HA-1 and HA-2. H-Y-specific CTLs, visualized by tetrameric HLA-mHag peptide complexes, infiltrated male skin sections within 24 hours, induced severe GvH reactions of grade III-IV and produced high levels of IFN-gamma. In contrast, CTLs specific for the hematopoietic system-specific mHags HA-1 and HA-2 induced no or low GvH reactions above background and produced little or no interferon-gamma, unless the skin sections were preincubated with HA-1/HA-2 synthetic peptides. These results provide the first in situ dissection of GvH effects by mHag-specific CTLs and show that ubiquitously expressed mHags are the prime targets of GvH disease.
authors.affiliation: University Department of Haematology, Royal Victoria Infirmary, University of Newcastle, Newcastle upon Tyne, UK.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Dickinson
authors.forename: Xiao-Nong
authors.initials: XN
authors.lastname: Wang
authors.forename: Lisbet
authors.initials: L
authors.lastname: Sviland
authors.forename: Florry A
authors.initials: FA
authors.lastname: Vyth-Dreese
authors.forename: Graham H
authors.initials: GH
authors.lastname: Jackson
authors.forename: Ton N M
authors.initials: TN
authors.lastname: Schumacher
authors.forename: John B A G
authors.initials: JB
authors.lastname: Haanen
authors.forename: Tuna
authors.initials: T
authors.lastname: Mutis
authors.forename: Els
authors.initials: E
authors.lastname: Goulmy
mesh_terms: D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology / Q000473:pathology; D006087:Graft vs Host Reaction / Q000276:immunology*; D006182:H-Y Antigen / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D066298:In Vitro Techniques; D015778:Minor Histocompatibility Antigens / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism; D012867:Skin / Q000276:immunology / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology
chemical_list: D006182:H-Y Antigen; C110615:HA-1 antigen; C080145:HA-2 antigen; D015778:Minor Histocompatibility Antigens; D009363:Neoplasm Proteins; D009842:Oligopeptides