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)

Following a human leucocyte antigen (HLA)-identical allogeneic stem cell transplantation (allo-SCT), minor histocompatibility antigens (mHags) play an important role in the induction of graft-versus-leukaemia (GvL) and graft-versus-myeloma (GvM). Many mHags show ubiquitous tissue expression and are associated with GvL and graft-versus-host disease. Here we describe a cytotoxic CD4(+) T lymphocyte line and a cytotoxic, CD4(+) T cell clone (CTC), 3AB11, which recognized a tissue-restricted mHag. This CTC was isolated from a multiple myeloma patient with clinical GvM following an HLA-matched allo-SCT. CTC 3AB11 was activated in a HLA-DP*0401 restricted fashion and the antigen was expressed by 27% of HLA-DP*0401 positive Epstein-Barr virus (EBV)-transformed B-cell lines (EBV-B). Tissue distribution analysis of antigen 3AB11 showed it to be expressed by patient-derived EBV-transformed B cell lines (EBVp), the myeloma plasma cell-line UM9 and monocytes. It was weakly expressed by peripheral blood-derived phytohaemagglutinin-induced T-cell blasts and absent on CD40L stimulated peripheral B (CD40L B) cells and stromal cells. The relatively high prevalence of the HLA class II-restricted 3AB11 antigen, together with its apparent haematopoietic-restricted expression, makes it an antigen of interest for cellular immunotherapy.
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PMID:A class II-restricted cytotoxic T-cell clone recognizes a human minor histocompatibility antigen with a restricted tissue distribution. 1560 52

Several leukaemia-specific antigens have been discovered in the recent past, which raised the possibility for T-cell-based immunotherapy for leukaemia. However, failure of such approaches involving interleukin-2 and/or T-cell-based immunotherapy indicated the importance of investigation of the human leucocyte antigen (HLA) status of the haematopoietic malignant cells. Considerable number of reports indicate that both HLA class I and class II are down-regulated in different cases of leukaemias, enabling them to evade immuno-surveillance. However, locus-specific down-regulation in leukaemia has not been widely investigated, although majority of cytotoxic T lymphocyte (CTL) responses are modulated by HLA-A and HLA-B, whereas expression of only HLA-C is unable to block natural killer (NK)-cell-mediated cytotolysis. Therefore, using RT-PCR, we have investigated the HLA class I transcriptional expression in a locus-specific manner, along with HLA-associated accessory molecules beta2-microglobulin and transporter-associated antigen processing molecule (TAP1). Our data suggest that in several newly diagnosed untreated leukaemic patients, HLA-C and beta2-microglobulin are expressed, but not the locus HLA-A or -B. Moreover, TAP1 and beta2-microglobulin were observed to be down-regulated in a number of cases of leukaemia. Our flow cytometric analysis of HLA-ABC also indicates a decrease in mean fluorescent intensity but no complete loss in surface expression of HLA class Ia on the leukaemic cells. Therefore, the observed low surface expression of HLA-ABC may be due to the down-regulation of transcription of HLA-A or -B itself and/or transcriptional suppression of the accessory molecules.
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PMID:Analysis of HLA class Ia transcripts in human leukaemias. 1613 50

Bone marrow transplantation including autologous, allogeneic and syngeneic has evolved over the past 30 years into an effective therapy for patients with a variety of hematologic malignancies. A total of 51 patients with hematologic disorders were treated with myeloablation and transplantation with either unrelated human leucocyte antigen (HLA) partially matched umbilical cord blood or HLA-matched unrelated donor grafts during 1997-2003. In evaluation of survival of these patients, the log rank and Wilcoxon tests lead to ambiguous results, which also happen in other applications. While the asymptotic properties of these tests are well understood, it is not clear how they behave in a small and specific sample. To resolve the ambiguity and to better understand our patient sample, we compare the power of the two tests by simulation in small samples with piecewise log-logistic and Weibull distributions and with different censoring distributions. Our simulation study confirms the well known fact that when the hazards of underlying survival distributions are non-proportional early on, say t < t(0), but proportional when t> or = t(0), the Wilcoxon test has more power than log rank test. But the importance of our simulation is to gain insight into the time point and impact of t(0) with respect to our transplantation study of leukemia cancer patients. We now conclude that overall survivals of patients with two graft sources are statistically significantly different, in part due to the delay of neutrophil recovery of one patient population immediately after transplantation. Thus, we recommend that Wilcoxon test should be used in future studies of similarly designed clinical trials.
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PMID:Comparison of survival times in a transplant study of hematologic disorders. 1632 44

Cytotoxic T lymphocyte (CTL) lines specific for allogeneic antigens were generated by in vitro stimulation of donor-derived peripheral blood mononuclear cells obtained from patients who received human leucocyte antigen (HLA)-matched allogeneic haematopoietic stem cell transplantation (HSCT). One of the allogeneic antigen-specific CD4+ CTL lines, CTL-A, generated from a patient with T cell acute lymphoblastic leukaemia, recognised HLA-DPB1*0501-positive Epstein-Barr virus-immortalised human B cell line (EBV-B cells), phytohaemagglutinin blasts and leukaemia cells, but not interferon-gamma (IFN-gamma) treated HLA-DPB1*0501-positive fibroblasts, indicating that this CD4+ T-cell line recognised a minor histocompatibility antigen (mHa) that is preferentially expressed in haematopoietic cells in an HLA-DPB1*0501-restricted manner. The other CD4+ CTL line, CTL-B, generated from a patient with chronic myeloid leukaemia, recognised mismatched HLA-DQB1*0303 on EBV-B cells and phytohaemagglutinin (PHA) blasts. Interestingly, this CTL line did not recognise IFN-gamma-treated recipient's skin fibroblasts, as HLA-DQ was merely upregulated even after IFN-gamma stimulation in non-haematopoietic cells including fibroblasts, endothelial cells and hepatocytes. These results suggest that these CD4 positive CTLs, specific for mismatch HLA-DQ and mHa that are preferentially expressed on haematopoietic cells, may play an important role in induction of selective graft-versus-leukaemia effect without development of graft-versus-host disease after allogeneic HSCT.
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PMID:Possible involvement of allogeneic antigens recognised by donor-derived CD4 cytotoxic T cells in selective GVL effects after stem cell transplantation of patients with haematological malignancy. 1637 Oct 20

Most acute myeloid leukaemia (AML) patients lack human leucocyte antigen-identical sibling donors for transplantation. Autotransplants and unrelated donor (URD) transplants are therapeutic options. To compare autologous versus URD transplantation for AML in first (CR1) or second complete remission (CR2), we studied the outcomes of 668 autotransplants were compared with 476 URD transplants reported to the Center for International Blood and Marrow Transplant Research. Proportional hazards regression adjusted for differences in prognostic variables. In multivariate analyses transplant-related mortality (TRM) was significantly higher and relapse lower with URD transplantation. Adjusted 3-year survival probabilities were: in CR1 57 (53-61)% with autotransplants and 44 (37-51)% URD (P = 0.002), in CR2 46 (39-53)% and 33 (28-38)% respectively (P = 0.006). Adjusted 3-year leukaemia-free survival (LFS) probabilities were: CR1 53 (48-57)% with autotransplants and 43 (36-50)% with URD (P = 0.021), CR2 39 (32-46)% and 33 (27-38)% respectively (P = 0.169). Both autologous and URD transplantation produced prolonged LFS. High TRM offsets the superior antileukaemia effect of URD transplantation. This retrospective, observational database study showed that autotransplantation, in general, offered higher 3-year survival for AML patients in CR1 and CR2. Cytogenetics, however, were known in only two-thirds of patients and treatment bias cannot be eliminated.
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PMID:Autotransplantation versus HLA-matched unrelated donor transplantation for acute myeloid leukaemia: a retrospective analysis from the Center for International Blood and Marrow Transplant Research. 1648 77

Twenty-two patients with acute myeloid leukaemia were recruited into a phase I/II clinical trial investigating the vaccination of patients in complete remission (CR) with autologous dendritic-like leukaemia cells (DLLC). At trial entry, leukaemia cells were harvested and tested for their ability to undergo cytokine-induced dendritic cell differentiation. Patients were then treated with intensive chemotherapy. Five patients achieved both CR and had leukaemia cells that successfully underwent differentiation and therefore proceeded to vaccination. Four escalating doses of DLLC were administered weekly by subcutaneous injection. Vaccination was generally well tolerated although one patient developed extensive eczema and an increased antinuclear factor titre possibly indicating induction of autoimmunity. Development of anti-leukaemic T-cell responses was assessed by enzyme-linked immunospot analysis of gamma-interferon secreting T lymphocytes and by human leucocyte antigen tetramer analysis for WT1-specific T cells. Increases in anti-leukaemic T-cell responses were demonstrated in four patients, but only two of the five remained in remission more than 12 months postvaccination. The study has demonstrated that generation of DLLC is feasible in only a subgroup of patients and is currently neither broadly applicable or clinically effective.
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PMID:Phase I/II study of vaccination with dendritic-like leukaemia cells for the immunotherapy of acute myeloid leukaemia. 1682 93

Minor histocompatibility antigens (mHags) play crucial roles in the induction of graft versus host disease (GVHD) and/or graft versus leukaemia (GVL) effects following human leucocyte antigen (HLA)-identical haematopoietic stem cell transplantation (HSCT). Using HLA-A*3101- and -A*3303-restricted cytotoxic T lymphocyte (CTL) clones generated from different post-HSCT recipients, we identified two novel mHag epitopes encoded by the leader sequence of cathepsin H (CTSH) isoform a. The nonameric sequence ATLPLLCAR was defined as an HLA-A*3101-restricted epitope (CTSH(R)/A31), while a decameric peptide featuring a one N-terminal amino acid extension, WATLPLLCAR, was presented by HLA-A*3303 (CTSH(R)/A33). The immunogenicity of both epitopes was totally dependent on the polymorphic C-terminal arginine residue and substitution with glycine completely abolished binding to the corresponding HLA molecules. Thus, the immunogenicity of this mHag is exerted by differential HLA binding capacity. CTSH is relatively ubiquitously expressed at protein levels, thus it may be involved in GVHD and anti-leukaemic/tumour responses. Interestingly, however, CTL clones predominantly lysed targets of haematopoietic cell origin, which could not be explained in terms of the immunoproteasome system. Although the mechanisms involved in the differential susceptibility remain to be determined, these data suggest that CTSH-encoded mHags could be targets for GVL effects.
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PMID:The human cathepsin H gene encodes two novel minor histocompatibility antigen epitopes restricted by HLA-A*3101 and -A*3303. 1682 83

Haploidentical stem cell transplantation is an alternative transplant strategy for patients without an human leucocyte antigen-matched donor. The historical experience with haploidentical stem cell transplantation has been characterised by the immunological consequences of crossing a major histocompatibility barrier, namely graft-versus-host disease (GVHD), graft rejection and impaired immune reconstitution. Ex vivo T-cell depletion of the graft may reduce the risk of GVHD, but at the expense of a higher risk of engraftment failure and relapse of the underlying malignancy. Myeloablative transplant strategies using vigorously T-cell-depleted 'megadose' stem cells appear to have improved the outcomes of selected patients with acute leukaemia. Non-myeloablative stem cell transplantation strategies, in which mixed chimaerism as a platform for adoptive cellular immunotherapy is intentionally induced, show promise for limiting GVHD and lessening transplant-related mortality. Future approaches, based on promising preclinical and early clinical observations, may include selective allodepletion of the graft, and manipulation of the cellular environment post-transplant using selected cellular populations or immunomodulatory soluble factors.
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PMID:Current status of haploidentical stem cell transplantation. 1698 91

T-cell large granular lymphocyte leukaemia (T-LGL) is a chronic clonal proliferation of cytotoxic T lymphocytes (CTL). T-LGL presents with cytopenias, often accompanied by autoimmune diseases, suggesting clonal transformation arising from an initially polyclonal immune response. Various immunogenetic predisposition factors, previously described for both immune-mediated bone marrow failure and autoimmune conditions, may promote T-LGL evolution and/or development of cytopenias. The association of T-LGL was analysed with a number of immunogenetic factors in 66 patients, including human leucocyte antigen (HLA) and killer-cell immunoglobulin-like receptor (KIR) genotype, KIR/KIR-L mismatch, CTLA-4 (+49 A/G),CD16-158V/F, CD45 polymorphisms, cytokine single nucleotide polymorphisms including: TNF-alpha (-308G/A), TGF-beta1 (codons 10 C/T, 25 G/C), IL-10 (-1082 G/A), IL-6 (-174 C/G), and IFN-gamma(+874 T/A). A statistically significant increase in A/A genotype for TNF-alpha-308, IL-10-1082, andCTLA-4 +49 was observed in T-LGL patients compared with control, suggesting that the G allele serves a protective role in each case. No association was found between specific KIR/HLA profile and disease. KIR/KIR-L analysis revealed significant mismatches between KIR3DL2 and KIR2DS1 and their ligands HLA-A3/11 and HLA-C group 2 (P = 0.03 and 0.01 respectively); the biological relevance of this finding is questionable. The significance of additional genetic polymorphisms and their clinical correlation to evolution of T-LGL requires future analysis.
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PMID:Immunogenetic factors determining the evolution of T-cell large granular lymphocyte leukaemia and associated cytopenias. 1715 96

In the human leucocyte antigen (HLA)-matched haematopoietic stem cell transplantation (HSCT) setting, minor histocompatibility antigen (mHA) disparities between recipient and donor can lead to graft-vs-host disease (GVHD) or graft rejection. Graft-vs-leukaemia (GVL) effect is a beneficial T-cell-mediated immune response that can also occur following HLA-matched HSCT. mHAs with tissue expression restricted to cells of the haematopoietic system are particularly relevant as immunotherapeutic targets for destroying malignant cells without inducing GVHD. Therefore, it is important to identify further haematopoietic-restricted polymorphic mHAs, which may have the potential to be used clinically for adoptive immunotherapy. Polymorphic mismatching of minor antigens, such as the B-cell-specific protein, the kappa immunoglobulin light chain (kappa) may play a role in the incidence of GVL and therefore the survival of transplant recipients following transplantation for B-cell malignancies. Polymorphisms in the constant region of the immunoglobulin kappa polypeptide chain have been defined involving single amino acid changes at positions 153 and 191. In this study, 51 HLA-matched B-cell malignancy transplant pairs were kappa typed by polymerase chain reaction and restriction enzyme digestion to investigate the association between kappa allotype disparity and outcome after transplantation. Kappa allotype disparity between transplant pairs may be associated with an increased survival compared with pairs not mismatched for kappa, as kappa mismatched recipients had a higher percentage of complete remissions and a decreased level of relapse in comparison with the nonmismatched recipients. HLA peptide prediction software was used to determine which HLA types were the best binders for kappa peptides. It was observed that patients with tissue types predicted to bind the kappa Km(1,2) peptides had better survival outcomes and no relapse compared with those with tissue types not predicted to bind the kappa Km(1,2) peptides. This study may contribute to the assessment of the clinical role of kappa with regard to the outcome of allogeneic transplantation for B-cell malignancies.
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PMID:Kappa immunoglobulin light chain polymorphisms and survival after allogeneic transplantation for B-cell malignancies: a potential graft-vs-leukaemia target. 1721 8


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