In situ dissection of the graft-versus-host activities of cytotoxic T cells specific for minor histocompatibility antigens.
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.
Dickinson
Anne M
AM
University Department of Haematology, Royal Victoria Infirmary, University of Newcastle, Newcastle upon Tyne, UK.
Wang
Xiao-Nong
XN
Sviland
Lisbet
L
Vyth-Dreese
Florry A
FA
Jackson
Graham H
GH
Schumacher
Ton N M
TN
Haanen
John B A G
JB
Mutis
Tuna
T
Goulmy
Els
E
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
D006182:H-Y Antigen; C110615:HA-1 antigen; C080145:HA-2 antigen; D015778:Minor Histocompatibility Antigens; D009363:Neoplasm Proteins; D009842:Oligopeptides