Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bone marrow transplantation from unrelated donors is being used increasingly for the treatment of patients with leukemia and several other hematologic disorders. Selection of unrelated bone marrow donors currently relies on serological HLA identity and negative mixed lymphocyte reactions between donor/recipient pairs. As serological HLA-DP typing is not feasible, we used the HLA-DPB1 oligonucleotide typing method to investigate whether the current selection procedure can guarantee complete MHC class II identity. In 40 consecutive patients, one third (62/193) serologically HLA-A, -B, -C, -DR and -DQ identical donors were found to be MLC-negative with a relative response below 5%. HLA-DPB1 oligonucleotide typing of these MLC-negative donors revealed that again only one third (20/62) was also identical for DP with their presumptive recipients. In the majority of pairs a disparity in graft-versus-host direction or in host-versus-graft direction of at least one allele was seen. These data indicate that, in spite of the strict MLC criteria used, the current procedure did not warrant complete MHC class II identity. This implies that oligotyping for DPB1 can improve matching and should be introduced for typing of volunteers.
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PMID:Selection of unrelated bone marrow donors: does the current procedure warrant complete MHC class II identity? 128 25

Bone marrow transplantation from unrelated donors is being used increasingly for the treatment of patients with leukaemia and other disorders of lymphohaemopoiesis. Selection of histocompatible unrelated bone marrow donors currently relies on serological HLA identity and negative mixed lymphocyte cultures (MLC) between potential donor-recipient pairs. Since serological HLA-DP typing is not feasible, we used the HLA-DPB1 oligonucleotide typing method to test whether the current selection procedure can also guarantee identity for HLA-DP. In 40 consecutive patients, one-third (62/193) of the serologically HLA-A, -B, -C, -DR and -DQ identical donors were judged as MLC negative (relative response below 5%) with the presumptive recipient. HLA-DPB1 oligonucleotide typing of the MLC negative donors revealed that only one-third of these (20/62) were also identical for DP. In the majority of the pairs, we found a DPB1 disparity. A difference in the graft-versus-host direction was seen in 25/62 cases in the host-versus-graft direction in 28/62 cases and in both directions in 29/62 cases. These data indicate that, in spite of the strict MLC criteria used, the current procedure did not guarantee complete MHC class II identity. Therefore oligotyping for DPB1 can improve matching for DP and should be introduced for typing of volunteers. We suspect that DP differences may contribute to the higher incidence of graft-versus-host disease or graft rejection in unrelated donor transplants.
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PMID:The incidence of DPB1 differences between serological and mixed lymphocyte culture matched unrelated individuals: implications for selection of bone marrow donors. 138 32

Bone marrow transplantation from unrelated donors is being used increasingly for the treatment of patients with leukemia and several other hematologic disorders. Selection of unrelated bone marrow donors currently relies on serological HLA identity and negative mixed lymphocyte reactions between donor/recipient pairs. As serological HLA-DP typing is not feasible, we used the HLA-DPB1 oligonucleotide typing method to investigate whether the current selection procedure can guarantee complete MHC class II identity. In 40 consecutive patients, one third (62/193) serologically HLA-A, -B, -C, -DR and -DQ identical donors were found to be MLC negative with a relative response below 5%. HLA-DPB1 oligonucleotide typing of these MLC negative donors revealed that again only one third (20/62) was also identical for DP with their presumptive recipients. In the majority of pairs a disparity in graft-versus-host direction or in host-versus-graft direction of at least one allele was seen. These data indicate that in spite of the strict MLC criteria used, the current procedure did not warrant complete MHC class II identity. This implies that oligotyping for DPB1 can improve matching and should be introduced for typing of volunteers. We speculate that DP differences may contribute to the higher incidence of graft-versus-host disease or graft rejection in unrelated transplants.
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PMID:Selection of unrelated bone marrow donors: does the current procedure warrant complete MHC class II identity? 149 53

It has been suggested that childhood leukaemia may be the abnormal outcome of a common infection. Rare events caused by common environmental events such as infections are likely to be influenced by host genetic susceptibility. We have therefore investigated whether immunogenetic susceptibility contributes to the risk of childhood common ALL (c-ALL). In this preliminary study, we report that children with c-ALL (n = 63) carry the HLA-DPB1 locus allele *0201 twice and nearly three times more frequently than adult (n = 92; relative risk (RR) = 2.9, P < 0.05) or infant controls (n = 82; RR = 2.1). Moreover, children with c-ALL are 3-4 times more likely than controls to be heterozygous for DPB1*0201/*0301, /*0401 and /*0402 (RRadult controls = 3.9; RRinfant controls = 2.8). These results suggest that HLA-DPB1*0201 either alone or with other DPB1 alleles contributes to the risk of childhood c-ALL, possibly by increasing susceptibility to an infectious agent.
Leukemia 1995 Mar
PMID:Preliminary evidence of an association between HLA-DPB1*0201 and childhood common acute lymphoblastic leukaemia supports an infectious aetiology. 788 43

There is increasing evidence that the immune response plays a role in the prevention of leukemic relapses after allogeneic bone marrow transplantation (BMT). Producing this effect (referred to as the graft-versus-leukemia reaction or GVL) is a current goal of clinical transplantation. At present, all protocols rely on the injection of donor T cells with unknown specificities. In keeping with this approach, we recently proposed the use of a single allogeneic T cell clone transfected with the HSv-tk gene to target an HLA-DPB1 mismatch in the GVH direction. For this strategy to be successful, HLA-DP antigens must be expressed on leukemic cells, which should be recognised by the HLA-DP-specific T cell clone and subsequently destroyed. In the present study, differential expression of HLA-DR, -DQ and -DP was tested by fluorescence using monoclonal antibodies on a panel of 46 acute myeloid leukemias (AML), 28 acute lymphoblastic leukemias (ALL) and 31 chronic lymphocytic leukemias of B cell origin (B-CLL). The vast majority of leukemic cells expressed HLA-DP antigens although with considerable variability. HLA-DPB1 genotyped leukemic cells were used as target cells for an HLA-DPB1*0401-specific T cell clone. Specific recognition of leukemic blasts was demonstrated for 11 out of 11 B-CLL, 11 out of 19 AML and nine out of 16 ALL. These data show that most leukemic blasts are accessible to direct lysis by allogeneic HLA-DP-specific T cells.
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PMID:Recognition of leukemic blasts by HLA-DPB1-specific cytotoxic T cell clones: a perspective for adjuvant immunotherapy post-bone marrow transplantation. 1038 55

In a previous study, we obtained preliminary evidence in a small series of patients (n = 63) suggesting that susceptibility to childhood common acute lymphoblastic leukaemia (c-ALL) was associated with an allele at the HLA-DPB1 locus, DPB1*0201. We have now tested this hypothesis by comparing the frequency of children with leukaemia (n = 982) who typed for specific DPB1 alleles and two groups of non-leukaemic children, one consisting of children with solid tumours, excluding lymphomas (n = 409), the other consisting of normal infants (n = 864). We found that significantly more children with c-ALL and T-ALL, but not pro-B ALL or acute non-ALL typed for DPB1*0201 as compared with children with solid tumours [odds ratio (OR), 95% confidence interval (CI) for c-ALL: 1.76, 1.20-2.56; T-ALL: 1.93, 1.01-3.80] and normal infants (OR, 95% CI for c-ALL: 1.83, 1.34-2.48; T-ALL: 2.00, 1.10-3.82). In childhood c-ALL, significantly more children than those with solid tumours or normal infants typed for DPB1 alleles coding specific polymorphic amino acids lining the antigen-binding site of the DPbeta1*0201 allotypic protein, suggesting that susceptibility to childhood c-ALL may be influenced by DPbeta ABS amino acid polymorphisms shared by DPbeta1*0201 and other DPbeta1 allotypes. These results point to a mechanism of c-ALL susceptibility that involves the presentation of specific antigenic peptides, possibly derived from infectious agents, by DPbeta1*0201-related allotypic proteins, leading to the activation of helper T cells mediating proliferative stress on preleukaemic cells.
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PMID:Genetic susceptibility to childhood common acute lymphoblastic leukaemia is associated with polymorphic peptide-binding pocket profiles in HLA-DPB1*0201. 1207 3

The responsible human leukocyte antigen (HLA) locus and the role of killer immunoglobulin-like receptor (KIR) ligand matching on transplantation outcome were simultaneously identified by multivariate analysis in 1790 patients with leukemia who underwent transplantation with T-cell-replete marrow from an unrelated donor (UR-BMT) through the Japan Marrow Donor Program. The graft-versus-leukemia (GVL) effect depended on leukemia cell type. HLA-C mismatch reduced the relapse rate in acute lymphoblastic leukemia (ALL) (hazard ratio [HR] = 0.47; P = .003), and HLA-DPB1 mismatch reduced it in chronic myeloid leukemia (CML) (HR = 0.35; P < .001). In contrast, KIR2DL ligand mismatch in the graft-versus-host (GVH) direction (KIR-L-MM-G) increased in ALL (HR = 2.55; P = .017). An increased rejection rate was observed in KIR2DL ligand mismatch in the host-versus-graft direction (HR = 4.39; P = .012). Acute GVH disease (GVHD) was increased not only in the mismatch of HLA-A, -B, -C, and -DPB1, but also in KIR-L-MM-G. As a whole, the mismatch of HLA-A, -B, and -DQB1 locus and KIR-L-MM-G resulted in increased mortality. In conclusion, not only the mismatch of HLA-C and -DPB1, but also KIR-L-MM-G affected leukemia relapse, which should be considered based on leukemia cell type. Furthermore, KIR-L-MM induced adverse effects on acute GVHD (aGVHD) and rejection, and brought no survival benefits to patients with T-cell-replete UR-BMT.
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PMID:Effects of HLA allele and killer immunoglobulin-like receptor ligand matching on clinical outcome in leukemia patients undergoing transplantation with T-cell-replete marrow from an unrelated donor. 1731 85

Most childhood B cell precursor (BCP) acute lymphoblastic leukaemia (ALL) cases carry the reciprocal translocation t(12;21)(p13;q22) ( approximately 25%), or a high hyperdiploid (HeH) karyotype (30%). The t(12;21) translocation leads to the expression of a novel fusion gene, TEL-AML1 (ETV6-RUNX1), and HeH often involves tri- and tetrasomy for chromosome 21. The presence of TEL-AML1+ and HeH cells in utero prior to the development of leukaemia suggests that these lesions play a critical role in ALL initiation. Based on our previous analysis of HLA-DP in childhood ALL, and evidence from in vitro studies that TEL-AML1 can activate HLA-DP-restricted T cell responses, we hypothesised that the development of TEL-AML1+ ALL might be influenced by the child's DPB1 genotype. To test this, we analysed the frequency of six HLA-DPB1 supertypes in a population-based series of childhood leukaemias (n = 776) classified by their karyotype (TEL-AML1+, HeH and others), in comparison with newborn controls (n = 864). One DPB1 supertype (GKD) conferred significant protection against TEL-AML1+ ALL (odds ratio (OR), 95% confidence interval (95% CI): 0.42, 0.22-0.81; p < 0.005) and HeH ALL (OR; 95% CI: 0.44, 0.30-0.65; p < 0.0001). These negative associations were almost entirely due to a single allele, DPB1*0101. Our results suggest that DPB1*0101 may afford protection from the development of TEL-AML1+ and HeH BCP ALL, possibly as the result of a DP-restricted immune response to BCP ALL-associated antigen(s), the identification of which could have important implications for the design of prophylactic vaccines.
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PMID:HLA-DPB1 supertype-associated protection from childhood leukaemia: relationship to leukaemia karyotype and implications for prevention. 1762 27

Mismatching for human leukocyte antigen (HLA)-DPB1 in unrelated donor hematopoietic stem cell transplantation (URD-SCT) has been associated with a decreased risk of disease relapse, indicating that HLA-DP may represent a target for graft-versus-leukemia (GVL) reactivity in HLA class II-expressing hematological malignancies. To investigate whether HLA-DP-specific T cells could mediate GVL reactivity following HLA-DPB1-mismatched URD-SCT and donor lymphocyte infusion (DLI), we analyzed the immune response in a patient with leukemic lymphoplasmacytic lymphoma responding to DLI without graft-versus-host disease. The emergence of leukemia-reactive CD4+ T cells during the clinical immune response was demonstrated by interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot(ELISPOT)analysis. Following clonal isolation of these leukemia-reactive CD4+ T cells, blocking studies, panel studies and retroviral transduction experiments of both mismatched HLA-DPB1 alleles identified HLA-DPB1(*)0201 and HLA-DPB1(*)0301 as the targets of this immune response. The HLA-DPB1-specific CD4+ T-cell clones were capable of recognizing and lysing several HLA-DP-expressing myeloid and lymphoid hematological malignant cells. Since HLA-DP expression is mainly restricted to hematopoietic cells, HLA-DP may be used as a specific target for immunotherapy following T-cell-depleted URD-SCT. Therefore, in patients with HLA class II-expressing hematological malignancies HLA-DP-mismatched SCT may be preferable over fully matched SCT allowing DLI to induce a GVL effect.
Leukemia 2008 Jul
PMID:HLA-DP as specific target for cellular immunotherapy in HLA class II-expressing B-cell leukemia. 1841 6

The finding that the risk of relapse in hematologic malignancy decreases after allogeneic hematopoietic stem cell transplantation (HSCT) has lead to the concept of a graft-versus-leukemia (GVL) effect. However, this beneficial effect is considered to be frequently offset by graft-versus-host disease (GVHD). Thus, improving HSCT outcomes by separating GVL from GVHD is a key clinical issue. This cohort study registered 4643 patients with hematologic malignancies who received transplants from unrelated donors. Six major human leukocyte antigen (HLA) loci were retrospectively genotyped. We identified 4 HLA-Cw and 6 HLA-DPB1 mismatch combinations responsible for a decreased risk of relapse; of these, 8 of 10 combinations were different from those responsible for severe acute GVHD, including all 6 of the HLA-DPB1 combinations. Pairs with these combinations of HLA-DPB1 were associated with a significantly better overall survival than were completely matched pairs. Moreover, several amino acid substitutions on specific positions responsible for a decreased risk of relapse were identified in HLA-Cw, but not in HLA-DPB1. These findings might be crucial to elucidating the mechanism of the decreased risk of relapse on the basis of HLA molecule. Donor selection made in consideration of these results might allow the separation of GVL from acute GVHD, especially in HLA-DPB1 mismatch combinations.
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PMID:HLA mismatch combinations associated with decreased risk of relapse: implications for the molecular mechanism. 1899 70


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