A Human Minor Histocompatibility Antigen Specific for B Cell Acute Lymphoblastic Leukemia

Department of Hematology, University Hospital Nijmegen, 6500 HB Nijmegen, The Netherlands.
Journal of Experimental Medicine (Impact Factor: 12.52). 02/1999; 189(2):301-8. DOI: 10.1084/jem.189.2.301
Source: PubMed


Human minor histocompatibility antigens (mHags) play an important role in the induction of cytotoxic T lymphocyte (CTL) reactivity against leukemia after human histocompatibility leukocyte antigen (HLA)-identical allogeneic bone marrow transplantation (BMT). As most mHags are not leukemia specific but are also expressed by normal tissues, antileukemia reactivity is often associated with life-threatening graft-versus-host disease (GVHD). Here, we describe a novel mHag, HB-1, that elicits donor-derived CTL reactivity in a B cell acute lymphoblastic leukemia (B-ALL) patient treated by HLA-matched BMT. We identified the gene encoding the antigenic peptide recognized by HB-1-specific CTLs. Interestingly, expression of the HB-1 gene was only observed in B-ALL cells and Epstein-Barr virus-transformed B cells. The HB-1 gene-encoded peptide EEKRGSLHVW is recognized by the CTL in association with HLA-B44. Further analysis reveals that a polymorphism in the HB-1 gene generates a single amino acid exchange from His to Tyr at position 8 within this peptide. This amino acid substitution is critical for recognition by HB-1-specific CTLs. The restricted expression of the polymorphic HB-1 Ag by B-ALL cells and the ability to generate HB-1-specific CTLs in vitro using peptide-loaded dendritic cells offer novel opportunities to specifically target the immune system against B-ALL without the risk of evoking GVHD.

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Available from: Francis Brasseur, Oct 05, 2015
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    • "KIAA0020 Broad Hematopoietic cells Fibroblasts HB-1 H/Y HLA-B * 44 Dolstra et al. 1999 [24] — Unknown Restricted B cell ALL, EBV-BLCLs ACC-1 HLA-A * 24 Akatsuka et al. 2003 [25] "
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    ABSTRACT: We have examined the alleles of eleven minor histocompatibility antigens (MiHAs) and investigated the occurrence of immunogenic MiHA disparities in 62 recipients of allogeneic hematopoietic cell transplantation (allo-HCT) with myeloablative conditioning performed between 2000 and 2008 and in their HLA-matched sibling donors. Immunogenic MiHA mismatches were detected in 42 donor-recipient pairs: in 29% MiHA was mismatched in HVG direction, in another 29% in GVH direction; bidirectional MiHA disparity was detected in 10% and no MiHA mismatches in 32%. Patients with GVH-directed HY mismatches had lower both overall survival and disease-free survival at 3 years than patients with compatible HY; also higher incidence of both severe acute GvHD and extensive chronic GVHD was observed in patients with GVH-directed HY mismatch. On contrary, GVH-directed mismatches of autosomally encoded MiHAs had no negative effect on overall survival. Results of our study help to understand why posttransplant courses of allo-HCT from siblings may vary despite the complete high-resolution HLA matching of a donor and a recipient.
    11/2012; 2012:257086. DOI:10.1155/2012/257086
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    • "The B-cell Non-Hodgkin lymphoma cell lines SU-DHL-6 and SU-DHL-8, purchased from DSMZ (German Collection of Microorganisms and Cell Cultures, Braunschweig, GER), were cultivated in RPMI 1640 supplemented with 10% FCS and 1% Pen Strep. The same culture conditions were used for all the other lymphoma and leukemia cell lines Raji [10], [11], Ramos [10], [11], KG-1 [10], [12], [13], [14], KG-1a [14], HL-60 [10], [12], [13], BV173 [10], [11], NALM-1 [12], [13] and K562 [10], [12], [13], which were kindly provided by P. Valent (Medical University of Vienna, Vienna, AUT) and are all previously published cell lines available either from ATCC (American Type Culture Collection, Manassas, VA, USA) or DSMZ. Hs27, a normal fibroblast cell line, was provided by D. Barlow (Research Center for Molecular Medicine, Vienna, AUT) and was grown in DMEM with 10% FCS and 1% Pen Strep [15], [16]. "
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    ABSTRACT: The new molecular entity quinoxalinhydrazide derivative NVX-412 was identified as a promising drug candidate for the treatment of various cancer types due to its strong cytotoxic activity and relative specificity. Here, we provide first data about the mechanisms of action of NVX-412. We show that NVX-412 exerts its anti-neoplastic activity in a p53-independent manner and induces S-phase arrest and DNA damage as assessed by γH2AX staining. We suggest a bi-modal (dose-dependent) mode of action of NVX-412, being primarily cytostatic at lower and predominantly cytotoxic at higher concentrations. Based on the broad and consistent anti-neoplastic activity observed, NVX-412 holds promise as an effective drug candidate for the treatment of various cancer types, especially for hematological malignancies with highly unmet medical need.
    PLoS ONE 09/2012; 7(9):e45015. DOI:10.1371/journal.pone.0045015 · 3.23 Impact Factor
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    • "In brief, 106 target cells were resuspended in 2 ml virus supernatant and transferred to retronectin-coated dishes. After 24 h of incubation, cells were collected and incubated with fresh virus supernatant and used in CTL stimulation assays [29]. Release of IFNγ was determined by ELISA (Pierce Endogen, Rockford, IL). "
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    ABSTRACT: Nonmyeloablative allogeneic stem cell transplantation (SCT) can induce remission in patients with renal cell carcinoma (RCC), but this graft-versus-tumor (GVT) effect is often accompanied by graft-versus-host disease (GVHD). Here, we evaluated minor histocompatibility antigen (MiHA)-specific T cell responses in two patients with metastatic RCC who were treated with reduced-intensity conditioning SCT followed by donor lymphocyte infusion (DLI). One patient had stable disease and emergence of SMCY.A2-specific CD8+ T cells was observed after DLI with the potential of targeting SMCY-expressing RCC tumor cells. The second patient experienced partial regression of lung metastases from whom we isolated a MiHA-specific CTL clone with the capability of targeting RCC cell lines. Whole genome association scanning revealed that this CTL recognizes a novel HLA-B7-restricted MiHA, designated ZAPHIR, resulting from a polymorphism in the splice donor site of the ZNF419 gene. Tetramer analysis showed that emergence of ZAPHIR-specific CD8+ T cells in peripheral blood occurred in the absence of GVHD. Furthermore, the expression of ZAPHIR in solid tumor cell lines indicates the involvement of ZAPHIR-specific CD8+ T cell responses in selective GVT immunity. These findings illustrate that the ZNF419-encoded MiHA ZAPHIR is an attractive target for specific immunotherapy after allogeneic SCT.
    PLoS ONE 06/2011; 6(6):e21699. DOI:10.1371/journal.pone.0021699 · 3.23 Impact Factor
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