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 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-γ. 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-γ, 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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Acknowledgements
We thank the medical BMT team at the Royal Victoria Infirmary, Newcastle for taking patient skin biopsies; L.C.J.M. Oomen for assistance in the preparation of CLSM photomicrographs; and A. Thompson for his support. This work was supported by grants from the J.A. Cohen Institute for Radiopathology and Radiation Protection; the Dutch Cancer Society; the Leiden University Medical Center; European Commission (BIO4-CT98-0236 and QLRT-2000-00010); Wellcome Trust; and Tyneside Leukemia Research Association.
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Dickinson, A., Wang, XN., Sviland, L. et al. In situ dissection of the graft-versus-host activities of cytotoxic T cells specific for minor histocompatibility antigens. Nat Med 8, 410–414 (2002). https://doi.org/10.1038/nm0402-410
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DOI: https://doi.org/10.1038/nm0402-410
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