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In situ dissection of the graft-versus-host activities of cytotoxic T cells specific for minor histocompatibility antigens

Nature Medicine volume 8, pages 410–414 (2002)Cite this article

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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Figure 1: GvH reactions induced by mHag-specific CTLs specific for H-Y and HA-1 in the skin-explant assay.
Figure 2: Differential induction of GvH reactions by mHag-specific CTLs.
Figure 3: In situ localization of mHag-specific CTLs in the skin-explant assay.

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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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Authors and Affiliations

  1. University Department of Haematology, Royal Victoria Infirmary, University of Newcastle, Newcastle upon Tyne, UK

    Anne M. Dickinson, Xiao-Nong Wang & Graham H. Jackson

  2. Department of Pathology, Haukeland Sykehus, Bergen, Norway

    Lisbet Sviland

  3. Department of Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands

    Florry A. Vyth-Dreese, Ton N.M. Schumacher & John B.A.G. Haanen

  4. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands

    Tuna Mutis & Els Goulmy

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  1. Anne M. Dickinson
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Correspondence to Els Goulmy.

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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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