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)

The number of umbilical cord blood transplants is increasing worldwide. The purpose of Eurocord is to evaluate the results and to compare the outcome of umbilical cord blood transplants with allogeneic bone marrow transplants. Data have been reported to Eurocord by multiple transplant centers. Close links have been established with the cord blood banks through Netcord. Bone marrow transplant data have been provided by transplant centers and also through the European Group for Blood and Marrow Transplantation (EBMT) and International Bone Marrow Transplant Registries (IBMTR). Eurocord has analyzed the outcome of unrelated umbilical cord blood transplants from 121 transplant centers and 29 countries. The results showed that survival with unrelated mismatched umbilical cord blood transplants was comparable to that with unrelated bone marrow transplants. Engraftment with cord blood was delayed, resulting in an increased incidence of early transplant complications. The incidence of acute and chronic graft-vs.-host disease was reduced with cord blood grafts even in human leukocyte antigen (HLA)-mismatched transplants and in adults. In patients with leukemia, the rate of relapse was similar to the rate of relapse after bone marrow transplant. The overall event-free survival with umbilical cord blood transplantation was not statistically different when compared to bone marrow transplants. This large registry study confirms the potential benefit of using umbilical cord blood hematopoietic stem cells for allogeneic transplants.
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PMID:Results of unrelated umbilical cord blood hematopoietic stem cell transplantation. 1148 56

Allogeneic hematopoietic transplantation relies on T-cell alloreactions for engraftment and the graft-versus-leukemia (GVL) effect. In human leukocyte antigen (HLA) haplotype-mismatched transplants, extensive T-cell depletion of the graft is essential to prevent GVHD. This raises the question of whether mismatched transplants exert any GVL effect and whether it will ever be possible to reduce the intensity of preparative regimens. Because natural killer (NK) cells are negatively regulated by MHC class I-specific inhibitory receptors, mismatched transplants may trigger NK-cell alloreactivity. HLA class I disparities driving NK-cell alloreactions in the GVH direction mediate strong GVL effects, produce higher engraftment rates, and do not cause GVHD. In murine MHC-mismatched transplant models with no donor T-cell reactivity against the recipient, the pre-transplant infusion of donor-vs-recipient alloreactive NK cells conditioned the recipients to bone marrow transplantation without GVHD. NK-cell alloreactivity may be a unique therapeutic tool for tolerance induction and clearance of leukemia in hematopoietic transplantation.
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PMID:Cellular therapy: exploiting NK cell alloreactivity in transplantation. 1160 75

Hereditary mutations associated with hematologic malignancies are rare. Heterozygous mutations affecting the hematopoietic transcription factor CBFA2 (also AML1/RUNX1) were recently reported to be associated with familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML, MIM 601399). A new 3-generation family with FPD/AML with a novel CBFA2 mutation is described. In this family, AML was diagnosed in a second-generation male. After allogeneic stem cell transplantation from his human leukocyte antigen-identical sister, a donor-derived, genetically identical leukemia developed in the recipient and the donor. Sequencing analysis identified a G-to-T transition within the CBFA2 gene, which involves codon 198, encoding a conserved aspartic acid within the DNA- binding Runt domain. Three of 5 siblings affected with the FPD/AML trait harbored the mutation in a heterozygous form. This experience underscores the necessity of performing mutation analysis of the CBFA2 gene before sibling allogeneic transplantation in families with FPD/AML.
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PMID:A novel CBFA2 single-nucleotide mutation in familial platelet disorder with propensity to develop myeloid malignancies. 1167 61

Donor lymphocyte transfusion has gained considerable interest as adoptive cellular immunotherapy for prevention or treatment of relapse after allogeneic stem cell transplantation. This study was designed to compare the yield of CD3(+), CD3(+)4(+), CD3(+)8(+), CD19(+), CD3(-)56(+)16(+), and CD34(+) cells contained in apheresis products from 61 consecutive non-cytokine treated, human leukocyte antigen (HLA)-matched donors for lymphocyte collection with the corresponding apheresis-derived cell yield from 112 consecutive, HLA-matched donors for blood stem cell collection who received recombinant human granulocyte colony stimulating factor (rhG-CSF, filgrastim) 6 microg/kg every 12 hours until cell collection was completed. Apheresis was started on day 4 or 5 of rhG-CSF treatment. The yield of lymphoid subsets was significantly different in the two sample groups, rhG-CSF treated product yields exceeding untreated product yields by a median of 2.1-fold (range: 1.3-2.6). However, the CD34(+) cell yield in rhG-CSF-treated apheresis products exceeded untreated products by 26-fold. A single untreated apheresis procedure was usually sufficient to collect a target dose of 1 x 10(8)/kg CD3(+) cells. Untreated apheresis products contained a median of 0.2 x 10(6)/kg CD34(+) cells. A potential engraftment dose of > or =0.5 x 10(6) CD34(+) cells per kg of recipient body weight was contained in 16% of 57 untreated apheresis products. One single apheresis performed in a normal, untreated donor provides a sufficient amount of CD3(+) cells for adoptive immunotherapy. Compared with that of an rhG-CSF stimulated apheresis product, the CD34(+) cell count is usually, but not always, below the engraftment dose range. RhG-CSF treatment has little effect on the yield of lymphoid subsets collected by apheresis but is highly selective of the release of CD34(+) cells. This report provides baseline data for studies that will show whether other cytokines such as granulocyte macrophage colony stimulating factor (GM-CSF) and/or Flt-3 Ligand can immunomodulate allotransfusates in vivo to improve the graft-vs.-leukemia (GVL) effect after allogeneic stem cell transplantation, while lowering the incidence and severity of graft-vs.-host disease (GVHD).
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PMID:Donor lymphocyte apheresis for adoptive immunotherapy compared with blood stem cell apheresis. 1174 33

The graft-vs-tumor effect is an important part of the curative potential of allogeneic transplantation. We characterized the effect of transplanted donor mononuclear cells on relapse- and event-free survival after allogeneic bone marrow transplantation (BMT). We studied 113 consecutive patients with hematologic malignancies who received non-T-cell-depleted BMT from human leukocyte antigen (HLA)-matched siblings. Most patients (n = 103) received busulfan (Myleran)-based conditioning, and all patients received standard short-course methotrexate and tacrolimus (Prograf) as graft-vs-host disease prophylaxis. Sixty-four patients had low-risk diagnoses (acute lymphoblastic leukemia/acute myeloid leukemia [first complete remission], myelodysplastic syndrome [refractory anemia/refractory anemia with ring sideroblasts], and chronic myeloid leukemia [first chronic phase]); 49 patients had high-risk diagnoses (all others). Cox regression analyses evaluated risk strata, age, gender, and the numbers of nucleated cells, CD3-positive T cells, CD34-positive hematopoietic cells, and type 2 dendritic cells (DC2) as covariates for event-free survival, relapse, and nonrelapse mortality. Recipients of larger numbers of DC2 cells had significantly lower event-free survival, a lower incidence of chronic graft-vs-host disease, and an increased incidence of relapse. Recipients of larger numbers of CD34-positive cells had improved event-free survival; recipients of fewer CD34-positive cells had delayed hematopoietic engraftment and increased death from infections. In conclusion, content of donor DC2 cells was associated with decreased chronic graft-vs-host disease and graft-vs-leukemia effects consistent with Th2/Tc2 polarization of donor Tcells following allogeneic bone marrow transplantation.
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PMID:DC2 effect on survival following allogeneic bone marrow transplantation. 1182 82

Minor histocompatibility antigens (mHags) are immunogenic peptides from polymorphic cellular proteins that induce strong T-cell responses after human leukocyte antigen (HLA)-matched, mHag-mismatched stem-cell transplantation. mHags with broad or limited tissue expression are target antigens for graft-versus-host (GvH) and graft-versus-leukemia (GvL) reactivities. Separation of these activities is crucial for adoptive immunotherapy of leukemia without GvH disease. Therefore, using a skin-explant assay we investigated the in situ activities of cytotoxic T lymphocytes (CTLs) specific for the ubiquitously expressed mHag H-Y and for the hematopoietic-restricted mHags HA-1 and HA-2. H-Y-specific CTLs, visualized by tetrameric HLA-mHag peptide complexes, infiltrated male skin sections within 24 hours, induced severe GvH reactions of grade III-IV and produced high levels of IFN-gamma. In contrast, CTLs specific for the hematopoietic system-specific mHags HA-1 and HA-2 induced no or low GvH reactions above background and produced little or no interferon-gamma, unless the skin sections were preincubated with HA-1/HA-2 synthetic peptides. These results provide the first in situ dissection of GvH effects by mHag-specific CTLs and show that ubiquitously expressed mHags are the prime targets of GvH disease.
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PMID:In situ dissection of the graft-versus-host activities of cytotoxic T cells specific for minor histocompatibility antigens. 1192 49

To improve the clinical outcome of allogeneic hematopoietic stem cell transplantation from an unrelated donor, the identification of human leukocyte antigen (HLA) alleles responsible for immunologic events such as graft-versus-host disease (GVHD), engraftment failure, and graft-versus-leukemia effect is essential. Genomic typing of HLA-A, -B, -C, -DRB1, and -DQB1 was retrospectively performed in 1298 donor-patient pairs in cases where marrow was donated from serologically HLA-A, -B, and -DR compatible donors. Single disparities of the HLA-A, -B, -C, or -DRB1 allele were independent risk factors for acute GVHD, and the synergistic effect of the HLA-C allele mismatch with other HLA allele mismatches on acute GVHD was remarkable. HLA-A and/or HLA-B allele mismatch was found to be a significant factor for the occurrence of chronic GVHD. HLA class I (A, B, and/or C) allele mismatch caused a significantly higher incidence of engraftment failure than HLA match. Significant association of HLA-C allele mismatch with leukemia relapse was not observed. As the result of these events, HLA-A and/or HLA-B allele mismatch reduced overall survival remarkably in both standard-risk and high-risk leukemia cases, whereas the HLA-C mismatch or HLA-class II (DRB1 and/or DQB1) mismatch did not. Furthermore, multiple mismatch of the HLA locus was found to reduce survival in leukemia cases. Thus, the role of the HLA class I allele in unrelated bone marrow transplantation was elucidated. Notably, HLA-C alleles had a different mode from HLA-A or -B alleles for acute GVHD and survival.
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PMID:The clinical significance of human leukocyte antigen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors. 1201 Aug 26

Allogeneic bone marrow transplantation (BMT) is a treatment modality with the potential of curing otherwise lethal diseases. The predominant indications for BMT are haematological malignancies. In BMT alloreactivity plays a pivotal role for the outcome. Graft-versus-host disease (GvHD) and graft-versus-leukaemia (GvL) are correlated manifestations of alloreactivity. Severe GvHD is one of the main causes of morbidity and mortality post-BMT. In the absence of GvL the risk of relapse is high. The main effector cells are T lymphocytes. Donor leukocyte infusion (DLI) for treatment of leukaemic relapse after BMT can induce durable remissions. DLI causes GvHD in the majority of the responding patients. However, a GvL effect may be present without evidence of GvHD and vise versa. The importance of alloreactivity for the treatment outcome prompted the interest for a predictive test of alloreactivity. Interleukin 2 (IL-2) producing helper T lymphocyte precursor (HTLp) frequencies determined by limiting dilution analysis (LDA) in the graft-versus-host direction were explored. The HTLp assay was optimized and the sources of error minimized to ensure sensitive and reproducible results. The IL-2 dependent cell line, CTLL-2 was optimized to detect 0.6 pg IL-2. UV-B irradiation of the cells was demonstrated to effectively terminate proliferation of the responder cells and thus allow IL-2 to be detected in the whole culture volume. The design of the assay was explored by Monte Carlo simulations resulting in a design yielding frequencies with a coefficient of variation of 20% in the range of 1:20,000-1:1,000,000. The influence of autoreactivity of the donor and recipient cells was minimized as well as the risk of the stimulator cells producing IL-2. The HTLp frequencies correlated with the degree of human leukocyte antigen (HLA) disparity and the assays were able to detect minor histocompatibility antigen mismatches. The HTLp frequencies of 28 HLA-identical sibling BMT pairs and 20 HLA-matched unrelated and partially HLA-matched related BMT pairs were determined. HTLp frequencies from the HLA-identical sibling BMT pairs had a median of 1:557,362 (range 1:9.511 to < 1:2,500,000). The HTLp frequencies from the HLA-matched unrelated and partially HLA-matched related BMT pairs had a median of 1:88,110 (range 1:4.139-1:736,123). Analysis of the HLA-identical sibling BMT pairs in a high and a low HTLp frequency group above and below 1:500,000 showed a trend towards a higher risk of acute GvHD > or = grade II and a significantly higher risk of chronic GvHD in the high HTLp frequency group. This group had a significantly lower risk of relapse as well as a significantly better overall survival and leukaemia free survival. The HLA-matched unrelated and partially HLA-matched related BMT pairs were split evenly in a high and a low HTLp frequency group above and below 1:90,000. There was a significantly higher risk of acute GvHD > or = grade II and a trend towards a higher treatment related mortality (TRM) in the high HTLp frequency group. There were no differences in chronic GvHD, risk of relapse, overall survival and leukaemia free survival. Analyzing all 48 patients the risk of acute GvHD > or = grade II and TRM was significantly higher with HTLp frequencies > 1:100,000 and there was a trend towards a higher risk of relapse with low HTLp frequencies < 1:400,000. Patients in the intermediate HTLp frequency group 1:100,000-1:400,000 had a trend towards improved survival. The HTLp frequency seems to detect clinically significant differences in alloreactivity, that can be useful in donor selection, graft-engineering, T cell add-back and the pharmacological immunosuppression used after BMT.
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PMID:Alloreactivity and the predictive value of anti-recipient specific interleukin 2 producing helper T lymphocyte precursor frequencies for alloreactivity after bone marrow transplantation. 1206 93

The Human Combinatorial Antibody Library (HuCAL) was screened for antibodies specific to human leukocyte antigen-DR (HLA-DR) that induce programmed death of lymphoma/leukemia cells expressing the target antigen. The active Fab fragments were affinity-matured, and engineered to IgG(4) antibodies of sub-nanomolar affinity. The antibodies exhibited potent in vitro tumoricidal activity on several lymphoma and leukemia cell lines and on chronic lymphocytic leukemia patient samples. They were also active in vivo in xenograft models of non-Hodgkin lymphoma. Cell death occurred rapidly, without the need for exogenous immunological effector mechanisms, and was selective to activated/tumor-transformed cells. Although the expression of HLA-DR on normal hematopoietic cells is a potential safety concern, the antibodies caused no long-lasting hematological toxicity in primates, in vivo. Such monoclonal antibodies offer the potential for a novel therapeutic approach to lymphoid malignancies.
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PMID:Fully human, HLA-DR-specific monoclonal antibodies efficiently induce programmed death of malignant lymphoid cells. 1215 28

The ability to achieve complete hematopoietic engraftment in the allogeneic setting without intensive myeloablative chemotherapy will have a profound effect on the practice of allogeneic hematopoietic cell transplantation (HCT). Novel methods to induce antigen-specific T-cell tolerance provide promise to ensure engraftment and reduce GVHD without producing generalized and other toxicities caused by myeloablative conditioning regimens. Compelling experimental evidence indicates that the antigen receptors on T-lymphocytes have dual potential to transmit crucial activation signals for initiating immune responses and to discharge equally potent inactivating signals to abort or inhibit immune responses. Many events impact on this fundamental decision-making process and one of the great challenges for modern immunology is to decipher the molecular wiring that integrates and converts the extrinsic and intrinsic variables into positive or negative cellular responses termed immunity and anergy, respectively. Our currently expanding understanding of the biochemical and molecular basis of T-cell anergy provides great promise to improve our ability to design novel clinical therapeutic approaches in order to induce antigen-specific tolerance in vivo. Importantly, strategies now exist to segregate graft versus tumor (GVT) effects from GVHD. Therefore, achievement of limited and specific tolerance to host alloantigens by selectively inactivating the indicated subsets of alloantigen-specific T-lymphocytes will prevent GVHD but retain the GVT effect of the graft. Such treatment approaches will expand the donor pool, because they will allow transplantation between individuals with increasing human leukocyte antigen (HLA) disparity, enable reduction of the need for non-specific immunosuppression, and reduce the risk of opportunistic infections and relapse of leukemia.
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PMID:Induction of immunologic tolerance for allogeneic hematopoietic cell transplantation. 1215 83


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