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Stem cell transplantation

HLA-DPB1 mismatch alleles represent powerful leukemia rejection antigens in CD4 T-cell immunotherapy after allogeneic stem-cell transplantation

Leukemia volume 31, pages 434–445 (2017)Cite this article

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Abstract

Refractory or relapsed acute myeloid leukemia (AML) represents a frequent complication after allogeneic hematopoietic stem-cell transplantation (HSCT). We show herein that primary in vitro stimulation of CD45RA-selected CD4 T cells of stem-cell donors with 10/10 HLA-matched AML blasts results in expansion of cytolytic T-lymphocytes (CTL) that almost all recognize HLA-DPB1 mismatch alleles, which clinically occur in up to 80% of donor-patient pairs. Primary AML blasts were found to strongly express HLA-DPB1, whereas fibroblasts and keratinocytes used as surrogate target cells for graft-versus-host disease did express HLA-DPB1 only upon IFN-γ pre-treatment. Since patients’ AML blasts are rarely available in clinical routine, we developed a protocol based on stimulation of donor-derived CD45RA-selected CD4 T cells with autologous dendritic cells electroporated with RNA encoding patients’ HLA-DPB1 mismatch alleles. Short-term stimulated T cell-lines specifically lysed HLA-DPB1 mismatch-expressing AML blasts, but not fibroblasts and keratinocytes without IFN-γ pre-treatment. Notably, these CD4 CTL efficiently eliminated AML blasts upon adoptive transfer into leukemia-engrafted NSG mice. In conclusion, we show strong immunogenicity of HLA-DPB1 mismatch alleles in CD45RA-selected CD4 T cells of stem-cell donors and introduce a novel strategy to reliably generate HLA-DPB1-specific CD4 CTL that might be powerful cellular therapeutics in relapsed or refractory AML after HSCT.

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Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (DFG), Clinical Research Group KFO183, projects no. 5 (ED, WH) and no. 6 (UH), by DFG Graduiertenkolleg GRK1043, project A3 (WH), by the Regensburg Center for Interventional Immunology (RCI) (ST), by project DJCLS R12/02 and the RCI FACS Core Facility both funded by German José Carreras Leukemia Foundation, and by the DFG Major Research Instrumentation Program (INST 89/341-1 FUGG).

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  1. W Herr, Y Eichinger, J Beshay and A Bloetz: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany

    W Herr, S Vatter, C Mirbeth & S Thomas

  2. Regensburg Center for Interventional Immunology, University of Regensburg, Regensburg, Germany

    W Herr, C Mirbeth & S Thomas

  3. Department of Internal Medicine III, Hematology, Oncology and Pneumology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

    W Herr, Y Eichinger, J Beshay, A Bloetz, E Distler, U F Hartwig & S Thomas

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Herr, W., Eichinger, Y., Beshay, J. et al. HLA-DPB1 mismatch alleles represent powerful leukemia rejection antigens in CD4 T-cell immunotherapy after allogeneic stem-cell transplantation. Leukemia 31, 434–445 (2017). https://doi.org/10.1038/leu.2016.210

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