In:
Blood, American Society of Hematology, Vol. 113, No. 10 ( 2009-03-05), p. 2312-2323
Abstract:
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-γ 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.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood-2008-04-153825
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2009
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7