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Blood, 5 March 2009, Vol. 113, No. 10, pp. 2312-2323. Prepublished online as a Blood First Edition Paper on December 12, 2008; DOI 10.1182/blood-2008-04-153825. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-04-153825v1 113/10/2312    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Norde, W. J. Articles by Dolstra, H. Search for Related Content PubMed PubMed Citation Articles by Norde, W. J. Articles by Dolstra, H. Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA Myeloid leukemic progenitor cells can be specifically targeted by minor histocompatibility antigen LRH-1–reactive cytotoxic T cells Wieger J. Norde1,*, Ingrid M. Overes1,*, Frans Maas1, Hanny Fredrix1, Johanna C. M. Vos1, Michel G. D. Kester2, Robbert van der Voort1, Inge Jedema2, J. H. Frederik Falkenburg2, Anton V. Schattenberg3, Theo M. de Witte1,3, and Harry Dolstra1 1 Central Hematology Laboratory, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen; 2 Department of Hematology, Leiden University Medical Center, Leiden; and 3 Department of Hematology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands 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- 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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