title: Myeloid leukemic progenitor cells can be specifically targeted by minor histocompatibility antigen LRH-1-reactive cytotoxic T cells.
abstract: CD8(+) T cells recognizing minor histocompatibility antigens (MiHAs) on leukemic stem and progenitor cells play a pivotal role in effective graft-versus-leukemia reactivity after allogeneic stem cell transplantation (SCT). Previously, we identified a hematopoiesis-restricted MiHA, designated LRH-1, which is presented by HLA-B7 and encoded by the P2X5 purinergic receptor gene. We found that P2X5 is significantly expressed in CD34(+) leukemic subpopulations from chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) patients. Here, we demonstrate that LRH-1-specific CD8(+) T-cell responses are frequently induced in myeloid leukemia patients following donor lymphocyte infusions. Patients with high percentages of circulating LRH-1-specific CD8(+) T cells had no or only mild graft-versus-host disease. Functional analysis showed that LRH-1-specific cytotoxic T lymphocytes (CTLs) isolated from 2 different patients efficiently target LRH-1-positive leukemic CD34(+) progenitor cells from both CML and AML patients, whereas mature CML cells are only marginally lysed due to down-regulation of P2X5. Furthermore, we observed that relative resistance to LRH-1 CTL-mediated cell death due to elevated levels of antiapoptotic XIAP could be overcome by IFN-gamma prestimulation and increased CTL-target ratios. These findings provide a rationale for use of LRH-1 as immunotherapeutic target antigen to treat residual or persisting myeloid malignancies after allogeneic SCT.
authors.affiliation: Central Hematology Laboratory, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen.
authors.forename: Wieger J
authors.initials: WJ
authors.lastname: Norde
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Overes
authors.forename: Frans
authors.initials: F
authors.lastname: Maas
authors.forename: Hanny
authors.initials: H
authors.lastname: Fredrix
authors.forename: Johanna C M
authors.initials: JC
authors.lastname: Vos
authors.forename: Michel G D
authors.initials: MG
authors.lastname: Kester
authors.forename: Robbert
authors.initials: R
authors.lastname: van der Voort
authors.forename: Inge
authors.initials: I
authors.lastname: Jedema
authors.forename: J H Frederik
authors.initials: JH
authors.lastname: Falkenburg
authors.forename: Anton V
authors.initials: AV
authors.lastname: Schattenberg
authors.forename: Theo M
authors.initials: TM
authors.lastname: de Witte
authors.forename: Harry
authors.initials: H
authors.lastname: Dolstra
mesh_terms: D000328:Adult; D018952:Antigens, CD34 / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000276:immunology*; D012333:RNA, Messenger / Q000032:analysis; D018048:Receptors, Purinergic P2 / Q000235:genetics; D058485:Receptors, Purinergic P2X5; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: D018952:Antigens, CD34; D004268:DNA-Binding Proteins; C546465:P2RX5 protein, human; D012333:RNA, Messenger; D018048:Receptors, Purinergic P2; D058485:Receptors, Purinergic P2X5; D014157:Transcription Factors; D051636:X-Linked Inhibitor of Apoptosis Protein