Expression of P2X5 in lymphoid malignancies results in LRH-1-specific cytotoxic T-cell-mediated lysis.
Minor histocompatibility antigens (MiHA) selectively expressed by haematopoietic cells are attractive targets for specific immunotherapy after allogeneic stem cell transplantation (SCT). Previously, we described LRH-1 as a haematopoietic-lineage restricted MiHA that is capable of eliciting an allogeneic cytotoxic T-lymphocyte (CTL) response after SCT and donor lymphocyte infusion. Importantly, the gene encoding LRH-1, P2X5, is not expressed in prominent graft-versus-host-disease target tissues such as skin, liver and gut. Here, we investigate whether LRH-1-specific immunotherapy may be exploited for the treatment of lymphoid malignancies. We examined P2X5 mRNA expression in a large panel of patient samples and cell lines from different types of lymphoid malignancies by real-time quantitative reverse transcription polymerase chain reaction. P2X5 mRNA was highly expressed in malignant cells from all stages of lymphoid development. Furthermore, all LRH-1-positive lymphoid tumour cell lines were susceptible to LRH-1 CTL-mediated lysis in flow cytometry-based cytotoxicity assays. However, interferon-gamma production was low or absent after stimulation with some cell lines, possibly due to differences in activation thresholds for CTL effector functions. Importantly, primary cells from patients with lymphoid malignancies were effectively lysed by LRH-1-specific CTL. These findings indicate that MiHA LRH-1 is a potential therapeutic target for cellular immunotherapy of lymphoid malignancies.
Overes
Ingrid M
IM
Central Haematology Laboratory, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
de Rijke
Björn
B
van Horssen-Zoetbrood
Agnes
A
Fredrix
Hanny
H
de Graaf
Aniek O
AO
Jansen
Joop H
JH
van Krieken
J Han J M
JH
Raymakers
Reinier A P
RA
van der Voort
Robbert
R
de Witte
Theo M
TM
Dolstra
Harry
H
D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004268:DNA-Binding Proteins / Q000276:immunology*; D006801:Humans; D007945:Leukemia, Lymphoid / Q000276:immunology* / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology* / Q000473:pathology; D009101:Multiple Myeloma / Q000276:immunology / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D018048:Receptors, Purinergic P2 / Q000096:biosynthesis* / Q000235:genetics; D058485:Receptors, Purinergic P2X5; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; C546465:P2RX5 protein, human; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018048:Receptors, Purinergic P2; D058485:Receptors, Purinergic P2X5; D014157:Transcription Factors