HLA-DPB1 mismatch alleles represent powerful leukemia rejection antigens in CD4 T-cell immunotherapy after allogeneic stem-cell transplantation
Herr W, Eichinger Y, Beshay J, Bloetz A, Vatter S, Mirbeth C, Distler E, Hartwig UF, Thomas S (2017)
Publication Type: Journal article
Publication year: 2017
Journal
Book Volume: 31
Pages Range: 434-445
Journal Issue: 2
DOI: 10.1038/leu.2016.210
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.
Involved external institutions
Universitätsklinikum Regensburg
Germany (DE)
Johannes Gutenberg-Universität Mainz (JGU)
Germany (DE)
Germany (DE)
Johannes Gutenberg-Universität Mainz (JGU)
Germany (DE)
How to cite
APA:
Herr, W., Eichinger, Y., Beshay, J., Bloetz, A., Vatter, S., Mirbeth, C.,... Thomas, S. (2017). HLA-DPB1 mismatch alleles represent powerful leukemia rejection antigens in CD4 T-cell immunotherapy after allogeneic stem-cell transplantation. Leukemia, 31(2), 434-445. https://doi.org/10.1038/leu.2016.210
MLA:
Herr, W., et al. "HLA-DPB1 mismatch alleles represent powerful leukemia rejection antigens in CD4 T-cell immunotherapy after allogeneic stem-cell transplantation." Leukemia 31.2 (2017): 434-445.
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