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Tetrameric HLA class I–minor histocompatibility antigen peptide complexes demonstrate minor histocompatibility antigen-specific cytotoxic T lymphocytes in patients with graft-versus-host disease

Nature Medicine volume 5, pages 839–842 (1999)Cite this article

Abstract

Graft-versus-host disease (GvHD) is a chief complication of allogeneic bone marrow transplantation1. In HLA-identical bone marrow transplantation, GvHD may be induced by disparities in minor histocompatibility antigens (mHags) between the donor and the recipient, with the antigen being present in the recipient and not in the donor2. Cytotoxic T lymphocytes (CTLs) specific for mHags of the recipients can be isolated from the blood of recipients with severe GvHD (ref. 3). A retrospective study demonstrated an association between mismatch for mHags HA-1, -2, -4 and -5 and the occurrence of GvHD in adult recipients of bone marrow from HLA genotypically identical donors4. Tetrameric HLA-peptide complexes have been used to visualize and quantitate antigen-specific CTLs in HIV-infected individuals and during Epstein-Barr virus and lymphocytic choriomeningitis virus infections5,6,7,8. Here we show the direct ex vivo visualization of mHag-specific CTLs during GvHD using tetrameric HLA-class and I-mHag HA-1 and HY peptide complexes. In the peripheral blood of 17 HA-1 or HY mismatched marrow recipients, HA-1- and HY-specific CTLs were detected as early as 14 days after bone marrow transplantation. The tetrameric complexes demonstrated a significant increase in HA-1- and HY-specific CTLs during acute and chronic GvHD, which decreased after successful GvHD treatment. HLA class I–mHag peptide tetramers may serve as clinical tools for the diagnosis and monitoring of GvHD patients.

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Figure 1: Specificity of tetrameric complexes.
Figure 2: Monitoring and functional analysis of mHag-specific CTLs.
Figure 3: The correlation between the frequency of circulating HA-1- and HY-specific CTLs and GvHD.

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Acknowledgements

We thank A. Brand, and M. Oudshoorn for critical reading of the manuscript. This work was supported by grants from the Leiden University Medical Center (LUMC), the J.A. Cohen Institute for Radiopathology and Radiation Protection (IRS), the Dutch Cancer Society (KWF), the Leukemia Research Fund, and the Kay Kendall Leukemia Research Fund.

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Authors and Affiliations

  1. The Department of Immunohematology and Blood Bank, Leiden University Medical Center, binusdreef 2, PO Box 9600, 2300 RC Leiden, The Netherlands

    Tuna Mutis, Ellen Schrama & Els Goulmy

  2. The Department of Hematology, Leiden University Medical Center, binusdreef 2, PO Box 9600, 2300 RC Leiden, The Netherlands

    J.H. Frederik Falkenburg

  3. Molecular Immunology Group, John Radcliffe Hospital, Oxford, UK

    Geraldine Gillespie

  4. Department of Hematology, University Hospital, Birmingham, UK

    Paul Moss

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  1. Tuna Mutis
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  2. Geraldine Gillespie
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Correspondence to Tuna Mutis.

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Mutis, T., Gillespie, G., Schrama, E. et al. Tetrameric HLA class I–minor histocompatibility antigen peptide complexes demonstrate minor histocompatibility antigen-specific cytotoxic T lymphocytes in patients with graft-versus-host disease. Nat Med 5, 839–842 (1999). https://doi.org/10.1038/10563

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