title: A frameshift polymorphism in P2X5 elicits an allogeneic cytotoxic T lymphocyte response associated with remission of chronic myeloid leukemia.
abstract: Minor histocompatibility antigens (mHAgs) constitute the targets of the graft-versus-leukemia response after HLA-identical allogeneic stem cell transplantation. Here, we have used genetic linkage analysis to identify a novel mHAg, designated lymphoid-restricted histocompatibility antigen-1 (LRH-1), which is encoded by the P2X5 gene and elicited an allogeneic CTL response in a patient with chronic myeloid leukemia after donor lymphocyte infusion. We demonstrate that immunogenicity for LRH-1 is due to differential protein expression in recipient and donor cells as a consequence of a homozygous frameshift polymorphism in the donor. Tetramer analysis showed that emergence of LRH-1-specific CD8+ cytotoxic T cells in peripheral blood and bone marrow correlated with complete remission of chronic myeloid leukemia. Furthermore, the restricted expression of LRH-1 in hematopoietic cells including leukemic CD34+ progenitor cells provides evidence of a role for LRH-1-specific CD8+ cytotoxic T cells in selective graft-versus-leukemia reactivity in the absence of severe graft-versus-host disease. These findings illustrate that the P2X5-encoded mHAg LRH-1 could be an attractive target for specific immunotherapy to treat hematological malignancies recurring after allogeneic stem cell transplantation.
authors.affiliation: Central Hematology Laboratory, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Björn
authors.initials: B
authors.lastname: de Rijke
authors.forename: Agnes
authors.initials: A
authors.lastname: van Horssen-Zoetbrood
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Beekman
authors.forename: Britt
authors.initials: B
authors.lastname: Otterud
authors.forename: Frans
authors.initials: F
authors.lastname: Maas
authors.forename: Rob
authors.initials: R
authors.lastname: Woestenenk
authors.forename: Michel
authors.initials: M
authors.lastname: Kester
authors.forename: Mark
authors.initials: M
authors.lastname: Leppert
authors.forename: Anton V
authors.initials: AV
authors.lastname: Schattenberg
authors.forename: Theo
authors.initials: T
authors.lastname: de Witte
authors.forename: Elly
authors.initials: E
authors.lastname: van de Wiel-van Kemenade
authors.forename: Harry
authors.initials: H
authors.lastname: Dolstra
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D018952:Antigens, CD34 / Q000096:biosynthesis; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D002857:Chromium / Q000378:metabolism; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17; D004268:DNA-Binding Proteins / Q000235:genetics; D000939:Epitopes / Q000737:chemistry; D005260:Female; D016368:Frameshift Mutation; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry; D008040:Genetic Linkage; D005819:Genetic Markers; D005838:Genotype; D020544:Graft vs Leukemia Effect; D015235:HLA-B Antigens / Q000737:chemistry; D015793:HLA-B7 Antigen; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology / Q000628:therapy*; D017493:Leukocyte Common Antigens / Q000737:chemistry; D008126:Lod Score; D008297:Male; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D010375:Pedigree; D010455:Peptides / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D011110:Polymorphism, Genetic; D018048:Receptors, Purinergic P2 / Q000235:genetics* / Q000378:metabolism*; D058485:Receptors, Purinergic P2X5; D012008:Recurrence; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D033581:Stem Cell Transplantation; D013234:Stem Cells; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics; D014184:Transplantation, Homologous
chemical_list: D018952:Antigens, CD34; D004268:DNA-Binding Proteins; D000939:Epitopes; D005819:Genetic Markers; D015235:HLA-B Antigens; C477444:HLA-B*07:02 antigen; D015793:HLA-B7 Antigen; C546465:P2RX5 protein, human; D010455:Peptides; D018048:Receptors, Purinergic P2; D058485:Receptors, Purinergic P2X5; D014157:Transcription Factors; D002857:Chromium; D007371:Interferon-gamma; D016044:Fusion Proteins, bcr-abl; D017493:Leukocyte Common Antigens