In situ dissection of the graft-versus-host activities of cytotoxic T cells specific for minor histocompatibility antigens
Anne M. Dickinson1, Xiao-Nong Wang1, Lisbet Sviland2, Florry A. Vyth-Dreese3, Graham H. Jackson1, Ton N.M. Schumacher3, John B.A.G. Haanen3, Tuna Mutis4
& Els Goulmy4
1
University Department of Haematology, Royal Victoria Infirmary, University of Newcastle, Newcastle upon Tyne, UK
2
Department of Pathology, Haukeland Sykehus, Bergen, Norway
3
Department of Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands
4
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands
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 transplantation1,
2. mHags with broad or limited tissue expression are target antigens for graft-versus-host (GvH) and graft-versus-leukemia (GvL) reactivities1. 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 complexes3, infiltrated male skin sections within 24 hours, induced severe GvH reactions of grade III−IV and produced high levels of IFN-. 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-, 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.
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