A frameshift polymorphism in P2X5 elicits an allogeneic cytotoxic T lymphocyte response associated with remission of chronic myeloid leukemia
Björn de Rijke, … , Elly van de Wiel-van Kemenade, Harry Dolstra
Björn de Rijke, … , Elly van de Wiel-van Kemenade, Harry Dolstra
Published December 1, 2005
Citation Information: J Clin Invest. 2005;115(12):3506-3516. https://doi.org/10.1172/JCI24832.
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Research Article Immunology

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

Björn de Rijke, Agnes van Horssen-Zoetbrood, Jeffrey M. Beekman, Britt Otterud, Frans Maas, Rob Woestenenk, Michel Kester, Mark Leppert, Anton V. Schattenberg, Theo de Witte, Elly van de Wiel-van Kemenade, Harry Dolstra

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P2X5 gene expression is restricted to leukemic and normal CD34+ progenit...
P2X5 gene expression is restricted to leukemic and normal CD34+ progenitor cells as well as lymphoid cells. (A) P2X5 expression determined by real-time quantitative PCR in CD34+ subpopulations isolated from leukemia patients (CML blast crises, n = 4 and acute myeloid leukemia, n = 10) and healthy stem cell donors (normal BM, n = 4 and G-CSF–mobilized peripheral blood, n = 5). Leukemic CD34+ subsets isolated from CML patient UPN389 at first relapse are indicated by the arrows. (B) P2X5 expression determined by real-time quantitative RT-PCR in freshly isolated cells or primary cell cultures of hematopoietic and nonhematopoietic origin. Expression is shown relative to the P2X5 expression measured in the reference cell line JVM-2, which is susceptible to lysis by the LRH-1–specific CTL RP1. The housekeeping Pbgd gene was used for normalization. Cell types with P2X5 expression less than 0.4 were not recognized by CTL RP1, indicating that these cell types can be considered as LRH-1 negative. This arbitrary threshold is indicated with a dashed line. The mean expression level for each cell population is shown by the thick line.