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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

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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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Figure 2

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The LRH-1 locus is closely linked to a cluster of markers on chromosome ...
The LRH-1 locus is closely linked to a cluster of markers on chromosome 17p13.2. (A) LRH-1 segregation pattern for individuals of the CEPH pedigrees 1331, 1332, 1347, 1413, 1362, and 102. EBV-LCLs of all available family members were transduced with HLA-B*0702 and tested for recognition by CTL RP1. Filled circles (females) or squares (males) represent individuals scored as positive for the LRH-1 phenotype, and open circles (females) or squares (males) represent individuals scored as negative. Shaded symbols represent individuals from whom no EBV-LCLs was available. (B) Genetic map of chromosome 17p13.2 showing relative marker loci oriented with the centromere at the bottom of the figure. lod scores summed for all available families used in the linkage analysis are shown to the right of each genomic marker. CEPH families that are not genotyped for a particular marker and therefore not included in the linkage analysis are indicated in parentheses.
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