title: HLA-DPB1 mismatch alleles represent powerful leukemia rejection antigens in CD4 T-cell immunotherapy after allogeneic stem-cell transplantation.
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.
authors.affiliation: Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany.|Regensburg Center for Interventional Immunology, University of Regensburg, Regensburg, Germany.|Department of Internal Medicine III, Hematology, Oncology and Pneumology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Herr
authors.affiliation: Department of Internal Medicine III, Hematology, Oncology and Pneumology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Y
authors.initials: Y
authors.lastname: Eichinger
authors.affiliation: Department of Internal Medicine III, Hematology, Oncology and Pneumology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Beshay
authors.affiliation: Department of Internal Medicine III, Hematology, Oncology and Pneumology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Bloetz
authors.affiliation: Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Vatter
authors.affiliation: Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany.|Regensburg Center for Interventional Immunology, University of Regensburg, Regensburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Mirbeth
authors.affiliation: Department of Internal Medicine III, Hematology, Oncology and Pneumology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Distler
authors.affiliation: Department of Internal Medicine III, Hematology, Oncology and Pneumology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
authors.forename: U F
authors.initials: UF
authors.lastname: Hartwig
authors.affiliation: Department of Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany.|Regensburg Center for Interventional Immunology, University of Regensburg, Regensburg, Germany.|Department of Internal Medicine III, Hematology, Oncology and Pneumology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Thomas
mesh_terms: D000483:Alleles; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology; D005260:Female; D005838:Genotype; D059868:HLA-DP beta-Chains / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007167:Immunotherapy; D016219:Immunotherapy, Adoptive; D007938:Leukemia / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D014019:Tissue Donors; D014184:Transplantation, Homologous
chemical_list: D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen