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)

We report our single-center experience with related allogeneic bone marrow transplantation (BMT) in pediatric recipients between April 1998 and December 2004. Allogeneic bone marrow grafts from 19 donors (18 human leukocyte antigen (HLA)-matched sibling donors and 1 one antigen-mismatched related donor) were transplanted into patients aged 3-17 years (16 with leukemia and 3 with non-malignant disease). The patients received a cell dose, with median total nucleated cell dose of 3.9 x 10(8)/kg (range, 0.7 - 8.7 x 10(8)) and median CD 34+ cell dose of 3.0 x 10(6)/g (range, 0.3 - 9.8 x 10(6)). Seventeen patients (89.4%) engrafted after a median of 19 days (range 14-20 days). Acute graft versus host disease (GVHD) grade II to IV developed in 8 patients (42. 1%), and limited chronic GVHD developed in 2 evaluable patients (10.5%). Twelve of the 19 patients were alive at a median follow-up of 1460 days (range, 270-2260 days). Full chimeric hematopoiesis was maintained in 11 of these 12 patients. Six patients (31.6%) had relapse of their underlying malignant disease, and one of them is still alive. Seven patients died (5 because of relapse and/or disease progression and 2 because of infectious complication). The underlying diseases were acute lymphoblastic leukemia (ALL; 4 cases: 3 CR2, 1 Ph+), acute myeloid leukemia (AML; 2 cases: 1 CR2, 1 refractory), and juvenile chronic myelogenous leukemia (JCML; 1 case). Relapsed leukemia at an extramedullary site occurred in 2 patients with ALL after BMT. Although our data should be interpreted cautiously considering the limited number of patients, isolated extramedullary relapse seems to be common after allogeneic BMT.
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PMID:Allogeneic related bone marrow transplantation in children--a single center experience. 1664 37

A novel HLA-B (human leukocyte antigen-B) allele, HLA-B*4442, was identified both in a Czech patient with leukaemia and in his mother. The presence of a novel allele was initially suspected because conflicting results were obtained by serological and DNA typing techniques. The HLA typing using the polymerase chain reaction-sequence-specific primers (PCR-SSP) at the two-digit level indicated an allele belonging to the HLA-B*44 group, whereas serological typing indicated HLA-B21. Typing with PCR-sequence-specific oligonucleotides (PCR-SSO) resulted in a unique reaction pattern that could not be assigned to a known allele, PCR-SSP typing at the four-digit level did not match any known B*44 allele, either. The sequencing-based typing of the HLA-B locus then revealed the novel B*4442 allele that is identical with B*4405 except a single C-->G nucleotide exchange at position 572. This exchange results in an amino acid substitution from serine to tryptophan at position 167 of the expressed HLA-B protein. The B21 serological reactivity of the novel B*4442 allele product was confirmed by employing an additional serological panel of typing sera. Our findings support previous reports claiming that serine at the position 167 in the alpha-2 domain of the HLA-B protein is a major determinant of the HLA-B44(12) serological epitope.
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PMID:A single amino acid exchange shifts the serological reactivity of the novel HLA-B*4442 allele product from HLA-B44 to HLA-B21. 1671 51

Retroviral transfer of T cell antigen receptor (TCR) genes selected by circumventing tolerance to broad tumor- and leukemia-associated antigens in human leukocyte antigen (HLA)-A*0201 (A2.1) transgenic (Tg) mice allows the therapeutic reprogramming of human T lymphocytes. Using a human CD8 x A2.1/Kb mouse derived TCR specific for natural peptide-A2.1 (pA2.1) complexes comprising residues 81-88 of the human homolog of the murine double-minute 2 oncoprotein, MDM2(81-88), we found that the heterodimeric CD8 alpha beta coreceptor, but not normally expressed homodimeric CD8 alpha alpha, is required for tetramer binding and functional redirection of TCR- transduced human T cells. CD8+T cells that received a humanized derivative of the MDM2 TCR bound pA2.1 tetramers only in the presence of an anti-human-CD8 anti-body and required more peptide than wild-type (WT) MDM2 TCR+T cells to mount equivalent cytotoxicity. They were, however, sufficiently effective in recognizing malignant targets including fresh leukemia cells. Most efficient expression of transduced TCR in human T lymphocytes was governed by mouse as compared to human constant (C) alphabeta domains, as demonstrated with partially humanized and murinized TCR of primary mouse and human origin, respectively. We further observed a reciprocal relationship between the level of Tg WT mouse relative to natural human TCR expression, resulting in T cells with decreased normal human cell surface TCR. In contrast, natural human TCR display remained unaffected after delivery of the humanized MDM2 TCR. These results provide important insights into the molecular basis of TCR gene therapy of malignant disease.
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PMID:Redirection of T cells by delivering a transgenic mouse-derived MDM2 tumor antigen-specific TCR and its humanized derivative is governed by the CD8 coreceptor and affects natural human TCR expression. 1672 Aug 99

Insufficient T-cell response to human T-cell leukemia virus type-I (HTLV-I) is a potential risk factor in adult T-cell leukemia (ATL). We established an assay system for detecting HTLV-I-specific T-cell response by using recombinant glutathione-S-transferase (GST) proteins fused with HTLV-I Tax protein that was divided into three portions, Tax-A, -B, and -C, corresponding to the N-terminal, central and C-terminal regions, respectively. When splenocytes from rats immunized with plasmids encoding Tax cDNA were incubated with these recombinant proteins, strong interferon gamma (IFN-gamma-producing responses occurred against GST-Tax proteins but not against control GST proteins. No such Tax-specific responses were observed in splenocytes from naive rats. Cocktails of oligopeptides corresponding to the Tax-A, -B, and -C regions also induced IFN-gamma-producing responses when incubated with splenocytes from immunized rats, but required higher amounts of antigens and there were a shorter periods of sustained T-cell responses than with GST-Tax protein-based assay. Although splenocytes from immunized rats predominantly reacted against GST-Tax-B protein, they failed to react with peptide cocktails corresponding to the Tax-B region, likely because the major epitope was interrupted in the initially prepared series of peptides. Using a newly prepared peptide series we found that splenocytes predominantly reacted with a peptide located in the Tax-B region that overlaps with a previously identified cytotoxic T lymphocytes (CTL) epitope of this rat strain. Using this system, we examined peripheral blood mononuclear cells (PBMC) from an ATL patient who underwent complete remission following hematopoietic stem cell transplantation (HSCT). PBMC from this patient produced a significant Tax-specific T-cell response predominantly against GST-Tax-A protein. This is consistent with the previous finding that this patient exhibited a strong HLA-A2-restricted CTL response to Tax 11-19 epitope, which is located in the Tax-A region. This study provides a diagnostic tool, useful for monitoring HTLV-I-specific T-cell immunity in patients and for surveying HTLV-I-carriers to identify an immunological group at high risk for ATL development, regardless of their human leukocyte antigen (HLA) types. It is also useful for predicting the location of T-cell epitopes, which may be applicable in future vaccine strategies.
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PMID:Human T-cell leukemia virus type-I (HTLV-I)-specific T-cell responses detected using three-divided glutathione-S-transferase (GST)-Tax fusion proteins. 1672 35

Natural killer (NK) cells were identified 30 years ago based on their ability to "spontaneously" kill tumor cells. The basis for NK cell recognition and activation is due to a variety of receptors that bind to specific ligands on tumor cells and normal cells. Some of these receptors have the ability to inhibit NK cell function, and other receptors activate NK cell function. Therapeutic strategies for cancer therapy are being developed based on preventing NK cell inhibition or using NK cell receptors to activate NK cells or T cells. There are intriguing clinical data from studies of bone marrow transplantation that support the idea that preventing NK cell inhibition by human leukocyte antigen (HLA) class I molecules can be a means to promote graft-versus-leukemia (GvL) effects and limit graft-versus-host disease (GvHD) in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) patients. Experimental findings also support the blockade of NK cell inhibitory receptors as a way to protect against leukemia relapse. It may be possible to use our knowledge of NK cell activating receptors and their ligands to immunize patients with modified tumor cells to promote beneficial NK cell responses and development of host antitumor cytotoxic T lymphocytes (CTLs). Finally, new data support the idea of using modified NK cell receptors as a means to target patients' T cells against their own tumor cells and induce long-term immunity against them. Tumors are essentially tissues that have overcome normal regulation mechanisms, and therefore the ability to distinguish normal cells from abnormal cells is a key part of selectively attacking tumor cells. NK cells have various receptor systems designed to recognize infected and abnormal cells. Understanding NK cell receptors and their recognition mechanisms provides new tools for the development of immunotherapies against cancer.
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PMID:NK cell receptors as tools in cancer immunotherapy. 1686 Jun 60

We hypothesized that reducing the dosage of prophylaxis for graft-versus-host disease (GVHD) would reduce the risk of relapse and toxicity after bone marrow transplantation (BMT) from human leukocyte antigen (HLA)-identical siblings. In a prospective phase II trial, 21 patients with leukemia and myelodysplastic syndrome underwent BMT from HLA-identical siblings and received GVHD prophylaxis consisting of low-dose (1.5 mg/kg per day) cyclosporin A (CSP) with short-term methotrexate (MTX) treatment. This low-dose group was compared with a group of retrospective control patients (n = 22) who received a standard CSP dosage (3.0 mg/kg per day) and MTX. One patient died of transplantation-related causes within 100 days. The regimen-related toxicity was quite tolerable. Although acute GVHD of grades II to III was more frequent in the low-dose group (47.6%) than in the control group (22.7%), the increase in acute GVHD did not significantly contribute to morbidity or mortality. There were no differences between the groups in the incidence and severity of chronic GVHD. The probabilities of relapse and survival of the groups were similar according to the risk for relapse at the time of transplantation. A prospective randomized study is required to determine whether low-dose or standard-dose CSP in combination with MTX is optimal for Japanese patients who undergo allogeneic BMT from HLA-identical siblings.
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PMID:Low-dose cyclosporin A with short-term methotrexate for graft-versus-host disease prophylaxis in allogeneic bone marrow transplantation from human leukocyte antigen-identical siblings: a prospective phase II study in Japanese patients. 1686 9

Many patients who require allogeneic hematopoietic stem cell transplantation (allo-HSCT) lack a human leukocyte antigen (HLA)-matched donor. Here, we report a protocol for haploidentical allo-HSCT that combines granulocyte-colony stimulating factor primed bone marrow (G-BM) and peripheral blood stem cells (PBSC) without in vitro T-cell depletion (TCD). In this study, 171 patients, including 86 in high-risk group, underwent transplantation from haploidentical family donors. All patients achieved sustained, full donor chimerism. One hundred and eleven patients were alive in remission at a median of 682 (253-1502) days. The cumulative incidence of grade III-IV acute graft-versus-host disease (GVHD) was 23% and that of extensive chronic GVHD, 47%; these were not influenced by HLA disparity. Patients younger than 15 years had less grade III-IV acute GVHD than older patients (P=0.044). The 2-year probability of relapse was 12% for standard-risk disease and 39% for high-risk disease. The 2-year probability of leukemia-free survival (LFS) was 68% for standard-risk patients and 42% for high-risk patients (P=0.0009). Grade III-IV acute GVHD was associated with better LFS (P=0.0017). The results require confirmation and show that G-BM combined with PBSC from haploidentical family donors, without in vitro TCD, may be used as a good source of stem cells for allo-HSCT.
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PMID:Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. 1688 12

Wilms tumor protein 1 (WT1) is a transcription factor overexpressed in several types of leukemia and solid tumors. For this reason, WT1 is an attractive target for immunotherapy. Four peptide nonamers from WT1 have been identified by others to generate a WT1-specific cytotoxic response in the context of human leukocyte antigen (HLA)-A0201 and A2402. However, as WT1 is a self-antigen, breaking tolerance is a potential obstacle to vaccination. Here, we use a strategy to circumvent tolerance by designing synthetic immunogenic analog peptides that could crossreact to the native peptides (a heteroclitic response). A number of synthetic peptides derived from nonamer sequences of the WT1 protein were designed in which single amino-acid substitutions were introduced at HLA-A0201 major histocompatibility complex (MHC)-binding positions. Several of new peptides could stabilize MHC class I A0201 molecules better than native sequences. Some analogs were also able to elicit WT1-specific T-cell recognition and cytotoxic T-cell lymphocytes more effectively than native sequences. Importantly, T cells stimulated with the new analogs crossreacted with the native WT1 peptide sequence and were able to kill HLA-matched chronic myeloid leukemia cell lines. In conclusion, analog heteroclitic WT1 peptides with increased immunogenicity can be synthesized and are potential cancer vaccine candidates.
Leukemia 2006 Nov
PMID:Improved human T-cell responses against synthetic HLA-0201 analog peptides derived from the WT1 oncoprotein. 1699 Jul 79

The number of clinical manifestations associated with human T-cell lymphotrophic virus type 1 infection continues to expand, as does the number of regulatory genes that human T-cell lymphotrophic virus 1 either transactivates or binds to directly. The relationship with the immunogenetics of the host is becoming more crucial with specific human leukocyte antigen types determining the risk of developing tropical spastic paraparesis/human T-cell lymphotrophic virus 1 associated myelopathy or adult T-cell leukaemia and lymphoma. Perhaps surprisingly, given the complexity of the virus-host interaction and the poor response to treatment of human T-cell lymphotrophic virus 1 associated conditions so far, a really remarkable response to azathioprine and alpha-interferon is reported for patients with adult T-cell leukaemia. Other reverse transcriptase inhibitors may also be effective in adult T-cell leukaemia and lymphoma and tropical spastic paraparesis/human T-cell lymphotrophic virus 1 associated myelopathy, although the fact that adult T-cell leukaemia is a monoclonal expansion disease that no longer requires virus replication per se, raises the question as to whether or not azathioprine is acting as an anti-cancer agent, which was its original role before the anti-HIV screening programme.
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PMID:Human T-cell lymphotrophic virus type 1: infections and pathogenesis. 1703 89

Loss or down-regulation of human leukocyte antigen (HLA) class I expression has been demonstrated in a variety of solid tumors. To date, such altered HLA expression has not been studied extensively in freshly isolated leukemic blasts. If it occurs, leukemic cells could escape T-cell surveillance as a consequence. Genotypes of nine leukemic cell lines were determined using a polymerase chain reaction for HLA classes I and II. Cells were also examined for HLA beta2-microglobulin, and allele-specific HLA protein expression using flow cytometry. Next, 44 samples of freshly isolated leukemic blasts from 43 patients with malignant hematological diseases were examined for allele-specific HLA expression using flow cytometry. Microsatellite analysis was performed to determine heterozygosity in the HLA region on chromosome 6. Genotype analysis for HLA class I together with microsatellite analysis demonstrated loss of HLA haplotype in HL-60 cells. No loss of HLA haplotype was observed in 44 samples of freshly isolated leukemic blasts. As reported previously, flow cytometric analysis rarely demonstrated loss or down-regulation of HLA expression at initial diagnosis (3/39; 7.7%); however, this was evident in two of five cases in relapse (40.0%), which contrasts with previous reports. In one patient with acute leukemia, HLA-A2 cell surface expression was present at initial diagnosis, lost at relapse, and completely restored after 48 h of culture in the presence of interferon-gamma. These results suggest loss of allele-specific HLA expression may be involved in the pathogenesis of relapse in patients with leukemia. The findings should be valuable in designing new strategies for clinical immunotherapy.
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PMID:Loss or down-regulation of HLA class I expression at the allelic level in freshly isolated leukemic blasts. 1708 64


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