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)

Allogeneic reduced-intensity stem cell transplantation (RISCT) decreases regimen-associated morbidity and mortality, but it is unfortunately still constrained by the same immune T-cell reactions that limit myeloablative transplantation, including graft rejection, graft-versus-host disease (GVHD), and suboptimal graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) effects. Graft rejection is mediated by host T cells, whereas GVHD and GVL/GVT effects are initiated by donor T cells, and to this extent, future advances in RISCT will likely benefit from an ability to modulate both donor and host T-cell immunity. As a step in this direction, we have developed a RISCT approach that first involves chemotherapy-induced host T-cell ablation, and second involves administration of allogeneic inocula enriched for donor CD4(+) Th2 and CD8(+) Tc2 T-cell subsets that in murine studies mediate reduced GVHD. In a pilot clinical trial, "immunoablative" RISCT with human leukocyte antigen (HLA)-matched related allografts resulted in rapid and complete donor chimerism and GVL effects early post-transplant, with GVHD being the primary toxicity. Using this immunoablative RISCT approach, we are now evaluating the feasibility and safety of augmenting allografts with additional donor CD4(+) Th2 cells that are generated in vitro via CD3/CD28 costimulation in the presence of interleukin (IL)-4. We review the biology of host and donor T-cell immunity during allogeneic RISCT and discuss the strategies of host immunoablation and donor Th2 and Tc2 cell therapy as potential means to improve the clinical results in RISCT.
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PMID:Immunoablative reduced-intensity stem cell transplantation: potential role of donor Th2 and Tc2 cells. 1497 Sep 38

The Leukemia and Lymphoma Molecular Profiling Project recently published results from DNA microarray analyses of 240 diffuse large B-cell lymphomas (DLBCLs). Four gene expression "signatures" were identified as correlated with patient outcome, including the major histocompatibility complex (MHC) class II genes (eg, HLA-DRA) which correlated with better survival. We further analyzed the effects of HLA-DRA on survival and correlated gene expression with protein status and tumor-infiltrating lymphocytes. The 5-year overall survival was 24% in the lowest 10% of HLA-DRA expression, 37% in the 10% to 25% group, 50% in the 25% to 50% group, and 55% for patients in the highest 50%. Further analysis demonstrated that the hazard ratio of death was a nonlinear function of HLA-DRA expression. Adjustment for the International Prognostic Index did not alter the impact of HLA-DRA on survival. Other MHC class II genes were found to predict survival similarly. Microarray HLA-DRA expression correlated with the presence or absence of human leukocyte antigen-DR (HLA-DR) protein in 20 of 22 cases assessed. Fewer tumor-infiltrating CD8(+) T cells were detected in MHC class II-negative cases compared with positive cases (2.8% versus 11.0%; P =.001), supporting the hypothesis that loss of tumor immunosurveillance has a devastating effect on patient outcome in DLBCL.
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PMID:Loss of MHC class II gene and protein expression in diffuse large B-cell lymphoma is related to decreased tumor immunosurveillance and poor patient survival regardless of other prognostic factors: a follow-up study from the Leukemia and Lymphoma Molecular Profiling Project. 1497 40

Minor histocompatibility antigens have to be considered as key molecules in the stem cell-based immunotherapy of malignancies. Allogeneic stem cell transplantation (SCT) is a well-established and effective therapy for advanced hematologic malignancies. The apparent powerful graft-versus-leukemia effect of SCT led clinicians to apply SCT for the treatment of metastatic solid tumors. The SCT-based graft-versus-tumor reaction in the allogeneic human leukocyte antigen-matched SCT setting is mediated by allo-immune effectorcells directed against tumor-related target antigens. The target molecules involved in the allo-immune graft-versus-tumor reaction are tumor-specific antigens, tumor-associated antigens, and tissue- and cell-specific minor histocompatibility antigens. The power of the minor histocompatibility antigens in the human leukocyte antigen-identical, stem cell-based immunotherapy for malignancies is their "allo-ness." As opposed to tumor-associated self antigens, the complexes of MHC and allo-target peptide are likely to be more immunogeneic than the major histocompatibility complex and self-target peptide complexes. Moreover, minor histocompatibility allo-antigens are not subject to self tolerance. Earlier minor histocompatibility antigens were seen as alien entities, disturbing the success of the so ideally matched organ and SCT donor-recipient combinations. To date, minor histocompatibility antigens can be set in the favorable light of useful tools for immunotherapy for cancer. The first clinical application of the hematopoietic minor histocompatibility antigens HA-1 and HA-2 is currently being explored in a stem cell-based setting for hematologic malignancies. Because HA-1 is also expressed on carcinoma cells, a stem cell-based vaccination trial for patients with metastatic breast or renal cancer is about to start as well. The immunotherapeutic potential of minor histocompatibility antigens demands serious searches for new minor histocompatibility antigens and analyses of their phenotype frequency, tissue distribution, and functional membrane expression. The minor histocompatibility antigens meeting the prerequisites for specific immunotherapy for malignancies, such as membrane expression and tissue and/or cell specificity, may offer the curative tools for stem cell-based immunotherapy for various hematologic and nonhematologic malignancies.
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PMID:Minor histocompatibility antigens: allo target molecules for tumor-specific immunotherapy. 1500 Apr 88

In order to determine whether matching/mismatching for microsatellite polymorphism provides useful information on acute graft-vs-host disease (GVHD), survival, and leukemia relapse in hematopoietic stem cell (HSC) transplantation, we genotyped for polymorphisms at 13 microsatellite loci within the major histocompatibility complex (MHC) of 100 unrelated HSC transplant donor-recipient pairs who were matched at five classical human leukocyte antigen (HLA) loci. A high percentage of allele matching was obtained for five microsatellite loci, DQCARII (96%), MICA (93%), MIB (89%), C1-3-1 (93%), and D6S510 (97%), that are localized within 100 kb of the HLA-DR, HLA-DQ, HLA-B, HLA-C, or HLA-A locus. In contrast, the other eight microsatellites are located farther away from the HLA classical loci and have much lower percentages of allele matching [e.g. tumor necrosis factor a (TNFa) (73%), TNFd (74%), D6S273 (64%), C3-2-11 (46%), C5-3-1 (50%), C5-4-5 (63%), C5-2-7 (68%), and D6S265 (81%)]. Therefore, there were at least eight microsatellite markers with relatively high percentages of mismatches in the donor/recipient pairs with acute or chronic GVHD, poor graft survival, and leukemia relapse. However, there were no statistically significant associations between mismatched donor-recipient pairs at the 13 microsatellite loci and acute or chronic GVHD, graft survival, and leukemia relapse. Nevertheless, allele matching at the microsatellite TNFd locus near the TNFa gene was found by the Fisher's exact double-sided test to be significantly associated with decreased survival in the grade III/IV acute GVHD group. Overall, these results suggest that the matching of microsatellite polymorphisms within the HLA region, especially the ones farthest from the classical HLA loci, was not useful indicator for the outcome of HSC transplantation from unrelated donors. In this regard, the future determination of the genome-wide microsatellite genotypes in HLA-matched donor-recipient pairs, outside the MHC, may be a better possibility for identifying minor histocompatibility genes in linkage disequilibria with microsatellites as potential predictive markers for the occurrence of acute GVHD and survival rate in HSC transplantation.
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PMID:Association of polymorphic MHC microsatellites with GVHD, survival, and leukemia relapse in unrelated hematopoietic stem cell transplant donor/recipient pairs matched at five HLA loci. 1500 8

CD94/NKG2A is an inhibitory receptor expressed by most human natural killer (NK) cells and a subset of T cells that recognizes human leukocyte antigen E (HLA-E) on potential target cells. To elucidate the cell surface dynamics of CD94/NKG2A receptors, we have expressed CD94/NKG2A-EGFP receptors in the rat basophilic leukemia (RBL) cell line. Photobleaching experiments revealed that CD94/NKG2A-EGFP receptors move freely within the plasma membrane and accumulate at the site of contact with ligand. The enriched CD94/NKG2A-EGFP is markedly less mobile than the nonligated receptor. We observed that not only are lipid rafts not required for receptor polarization, they are excluded from the site of receptor contact with the ligand. Furthermore, the lipid raft patches normally observed at the sites where FcepsilonR1 activation receptors are cross-linked were not observed when CD94/NKG2A was coengaged along with the activation receptor. These results suggest that immobilization of the CD94/NKG2A receptors at ligation sites not only promote sustenance of the inhibitory signal, but by lipid rafts exclusion prevent formation of activation signaling complexes.
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PMID:Exclusion of lipid rafts and decreased mobility of CD94/NKG2A receptors at the inhibitory NK cell synapse. 1513 25

Recurrent cytogenetic abnormalities in leukemic blasts make these an attractive source for dendritic cells (DC) to induce a leukemia-specific immune response. In this study, three leukemic cell lines were investigated: Kasumi-1 and SKNO-1 (two acute myeloid leukemia (AML) cell lines carrying the (8;21)-chromosomal translocation, resulting in the expression of the leukemia-specific fusion protein AML1-eight-twenty-one) and REH, an acute lymphoblastic leukemia cell line with the (12;21)-chromosomal translocation and expression of translocation ETS-like leukemia-AML1. These fusion proteins are implicated in the pathogenesis of the leukemic state by recruiting corepressors and histone deacetylases (HDAC), which interfere with normal cell differentiation. In vitro generation of DC was achieved using a cytokine cocktail containing tumor necrosis factor alpha, granulocyte macrophage-colony stimulating factor, c-kit ligand, and soluble CD40 ligand; yet, addition of the HDAC inhibitor (Hdi) trichostatin A enhanced DC differentiation with retention of the fusion transcripts. These leukemic DC showed high-level CD83 and human leukocyte antigen (HLA)-DR expression and had a high allostimulatory potential. Only DC generated from these cell lines after Hdi induced blast-specific cytotoxic T cell responses in HLA-A-matched T cells with a cytotoxicity of 42% in parental Kasumi-1 and 83% in parental REH cells, respectively. This model system suggests that the Hdi supports the in vitro differentiation of DC from leukemic blasts with AML1-containing fusion proteins.
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PMID:Histone deacetylase inhibition improves dendritic cell differentiation of leukemic blasts with AML1-containing fusion proteins. 1519 37

Effective antitumor responses need the activation of CD4+ T cells. MHC class II antigen presentation requires the release of class II-associated invariant chain peptide (CLIP) from the antigen-binding site. In antigen-presenting cells, human leukocyte antigen DM (HLA-DM; abbreviated DM in this article) catalyzes CLIP dissociation. In B cells, HLA-DO (DO) down-modulates DM function. Cell surface CLIP:HLA-DR (DR) ratio correlates to DO:DM ratio and the efficacy of antigen presentation. We examined 111 blood and bone marrow samples of patients with newly diagnosed acute myeloid leukemia (AML) for the expression of CLIP, DR, DM, and DO by flow cytometry. Patients with DR+/CLIP- blasts had a significant longer disease-free survival than patients with DR+/CLIP+ blasts. DO, until now believed to be restricted to lymphoid cells, could be demonstrated at protein level as well as by reverse transcription-PCR. DO:DM ratio correlated to CLIP:DR ratio, suggesting that, unlike in other antigen-presenting cells of the nonlymphoid cell type, both DO and DM mediate regulation of CLIP expression in AML blasts. We hypothesize that DR+/CLIP- AML blasts are able to present leukemia-specific antigens to CD4+ T helper cells initiating an effective and long-lasting antitumor response resulting in a prolonged disease-free survival.
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PMID:Class II-associated invariant chain peptide expression on myeloid leukemic blasts predicts poor clinical outcome. 1531 88

The immune system of females is capable of recognizing and reacting against the male-specific minor histocompatibility antigen (mHA), HY. Thus, cytotoxic T-lymphocytes (CTLs) recognizing this antigen may be useful in eradicating leukemic cells of a male patient if they can be generated in vivo or in vitro from a human leukocyte antigen (HLA)-identical female donor. The HLA-A*0201-restricted HY antigen, FIDSYICQV, is a male-specific mHA. Using HLA-A2/HY peptide tetrameric complexes, we reveal a close association between the emergence of HY peptide-specific CD8(+) T cells in peripheral blood and molecular remission of relapsed BCR/ABL(+) chronic myelogenous leukemia in lymphoid blast crisis in a patient who underwent female-to-male transplantation. Assessment of intracellular cytokine levels identified T cells that produce interferon-gamma in response to the HY peptide during the presence of HY tetramer-positive T cells. These results indicate that transplant with allogeneic HY-specific CTLs has therapeutic potential for relapsed leukemia, and that expansion of such T cells may be involved in the development of a graft-versus-leukemia response against lymphoblastic leukemia cells.
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PMID:Expansion and activation of minor histocompatibility antigen HY-specific T cells associated with graft-versus-leukemia response. 1532 66

To study the early stages of development from stem cells of the CD56+ cell population [which includes natural killer (NK) cells], granulocyte-colony stimulating factor-mobilized peripheral blood CD34+ cells from healthy donors were sorted to >99% purity and cultured in the presence of stem cell factor and interleukin (IL)-2. After 3 weeks in culture, the majority of cells acquired CD33, with or without human leukocyte antigen-DR and CD14. In 20 stem cell donors tested, 8.7 +/- 8.8% of cells were CD56+. Two major CD56+ subsets were identified: CD56(bright), mainly CD33- cells (7+/-10%, n=11) with large, granular lymphocyte morphology, and CD56dim, mainly CD33+ (2.5+/-2, n=11) cells with macrophage morphology. The CD56bright population had cytoplasmic granzyme A but lacked killer inhibitory receptor, suggesting they were immature NK cells. The CD56dim, CD33+, population lacked NK markers. They may represent a minor subset of normal monocytes at a developmental stage comparable with the rare CD56+ CD33+ hybrid myeloid/NK cell leukemia. Consistent with a monocyte nature, CD56dimCD33+ proliferated and produced a variety of cytokines upon lipopolysaccharide stimulation, including IL-8, IL-6, monocyte chemoattractant protein-1, and macrophage-derived chemokine but not interferon-gamma. In a short-term cytotoxicity assay, they failed to kill but powerfully inhibited the proliferation of the NK-resistant cell line P815. The generation of CD56+ cells was negatively regulated by hyaluronic acid and IL-4, indicating that extracellular matrix may play an important role in the commitment of CD34+ cells into CD56 myeloid and lymphoid lineages.
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PMID:G-CSF-mobilized CD34+ cells cultured in interleukin-2 and stem cell factor generate a phenotypically novel monocyte. 1534 23

To investigate which factors impact on survival, relapse, relapse free survival, transplant-related mortality (TRM) and graft-versus-host disease (GVHD) in children who undergo allogeneic stem cell transplantation, we included all 181 children transplanted due to leukemia at our unit. At the end of follow up 54% of the patients were alive, 27% had died due to relapse while 19% had died of other causes. Survival was similar in recipients of related (55%) and unrelated grafts (48%). Risk factors identified in univariate analysis were brought into a multivariable analysis. However, an unrelated donor was not identified as a risk factor for any of the five end-points analysed. A donor positive for three to four herpes viruses increased the risk of acute GVHD, TRM and death. A female to male transplant increased the risk of TRM, particularly if combined with a mismatch. Early stage of disease as well as human leukocyte antigen (HLA)-matching independently predicted survival. The risk of relapse increased after 1992. Chronic GVHD independently decreased the risk of relapse (relative risk RR, 0.39) and death (RR 0.42). We conclude that in children with leukemia other specific donor characteristics such as HLA-matching, gender, parity, and exposure to herpes viruses were more important for outcome than relationship.
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PMID:Risk factors in pediatric stem cell transplantation for leukemia. 1536 82


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