Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the role of endogenous or exogenous nitric oxide (NO) on human lymphocyte function. We used sodium nitroprusside, nitroglycerine, S-nitroso-N-acetylpenicillamine, sodium nitrite and S-nitroso-L-glutathione as NO-generating compounds. All agents were used at doses that do not produce direct cytotoxicity as measured by trypan blue exclusion as well as chromium-51 release assay. The immune responses examined were peripheral blood lymphocytes (PBL) proliferation and IL-2 production after activation with OKT3 and PHA; allogeneic mediated proliferation and cell mediated cytotoxicity (CML) in MLR; IgG and IgM production after PBL activation with Con-A; proliferation and expression of IFN-gamma and IL-4 mRNA after activation of allogeneic CD4+T cell clones. Cytokine mRNA expression was measured by reverse transcriptase PCR. Our results show that proliferating lymphocytes do not produce a detectable amount of NO as measured by the Griess reaction. In separate experiments, the addition of NG-monomethyl-L-arginine (L-NMMA) did not affect lymphocyte proliferation. Sodium nitroprusside and nitroglycerine exerted a dose dependent antimitogenic effect, inhibited cytokine production and expression, CML generation and antibody production. DNA gel electrophoresis showed no evidence for enhanced programmed cell death. The antimitogenic effect could not be blocked by the NO scavengers, hemoglobin or methylene blue. In contrast, the other nitric oxide generating compounds did not inhibit lymphocyte mitogenesis. The results suggest that human lymphocytes do not produce appreciable amounts of NO to affect lymphocyte mitogenesis. Sodium nitroprusside and nitroglycerine have a potent but nonspecific immunoinhibitory effect on human lymphocyte function by a mechanism other than NO production. In addition, pharmacological levels of NO do not inhibit human lymphocyte mitogenesis.
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PMID:Analysis of the in vitro effect of exogenous nitric oxide on human lymphocytes. 920 99

Twenty to 25% of patients with chronic myelogenous leukemia (CML) treated with interferon-alpha (IFN-A) achieve a complete cytogenetic response (CCR). However, cells bearing rearrangement of BCR/ABL can still be detected many years after achieving a CCR despite the absence of clinical evidence of active disease. It has been suggested that the disease is kept in a dormant state by immune mechanisms. How this is achieved is not known, but it has been speculated that p210BCR/ABL might be presented by malignant cells through HLA molecules, thus making them the target for specific immune cell killing. Because specific peptides will be expressed in association with certain HLA molecules, different HLA phenotypes could be associated with different response rates to IFN-A. The response to IFN-A-based therapies in 239 patients with chronic phase CML was analyzed according to their HLA phenotype. One hundred and ninety-four (81%) achieved complete hematologic response, 142 (59%) had a cytogenetic response which was major (MCR) in 93 patients (39%): complete (CCR) in 71 (30%) and partial (PCR) in 22 (9%). Patients with an HLA-B27 phenotype had the best response rate to IFN-A: 10 of 14 (71%) had an MCR, including eight (57%) with a CCR (P=0.02). Patients with HLA-B35, -A3, and -A31 also showed a trend towards a higher response rate, whereas patients with HLA-B18 had the lowest response rate (MCR 17%). Patients with HLA-B27 and those with HLA-A31 showed a trend for better survival, whereas patients with HLA-A2, -B7, or -B18 had a trend for shorter survival. We conclude that response to IFN-A in patients with CML may be associated with the HLA phenotype. However, a much larger population would be required to determine if the impact of HLA phenotype on survival is independent of other clinical prognostic features. These findings could be relevant for the understanding of immune mechanisms of control of CML and possibly the design of immune therapy for this disease.
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PMID:Association of HLA phenotype and response to interferon-alpha in patients with chronic myelogenous leukemia. 955 1

A study was conducted to clarify the mechanism of donor specific immunological unresponsiveness in renal transplant recipients with a well functioning kidney, since this might provide a clue to the nature of donor specific immunosuppression. Peripheral blood lymphocytes (PBL) were obtained from three renal transplant recipients, the donors (mother), the fathers and healthy volunteers as 3rd party and used in the present study. PBL from one of the three renal transplant recipients, which were donor specific unresponsive in MLR (Mixed Lymphocyte Reaction) and CML (Cell Mediated Lympholysis), suppressed the MLR, CML and synthesis of IL-2 from 3rd party PBL in a double chamber assay only when stimulated by the donor PBL. This suppression was abolished by the treatment with CD3 or CD8 antibodies and complement. RT-PCR was performed to investigate the suppressive effect of the recipient's PBL on IL-2 mRNA expression. In the double chamber MLR, expression of IL-2 mRNA by the PBL from 3rd party was also suppressed only when the recipient's PBL were stimulated by the donor PBL. These results indicate that one of the mechanisms responsible for donor specific immunological unresponsiveness is the presence of donor specific suppressor T cells in recipient's PBL and that these cells project suppressive effect on lymphocytes by producing a humoral suppressive factor(s) that suppress the expression of the IL-2 mRNA only when stimulated by donor PBL.
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PMID:[The mechanism of donor specific unresponsiveness in renal transplant recipients]. 975 14

Dendritic cells (DC) are potent antigen-presenting cells responsible for the initiation of primary antigen-specific immune responses. In chronic myeloid leukaemia DC have been generated from Ph+ cells and these Ph+ DC are capable of stimulating cytolytic T-cell responses against the parent leukaemia cells. The prevalence of this phenomenon in acute leukaemia (AL) is unknown and we have therefore studied a variety of acute leukaemias to determine their potential for DC development. Peripheral blood mononuclear cells (PBMC) from 21 cases of AL were cultured in GM-CSF + TNF alpha. Of these cases, 15 were viable in culture and cells with typical DC morphology were observed in 12 of these 15 cases. DC growing in culture expressed either CDla and/or CD83 and were HLA-DR+ CD40+ CD80+ CD86+ typical of mature DC. In 9/12 cases the cultured cells possessed potent antigen-presenting capacity as measured in the allo-MLR. The malignant origin of the cultured DC was confirmed by FISH analysis in two cases (one 5q- and one Ph+ AL) and by persistent aberrant expression of CD19 in two cases of biphenotypic leukaemia. Functional DC may be derived from AL blasts in a significant number of patients and such DC may be capable of inducing leukaemia-specific immune responses with potential for clinically beneficial effects.
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PMID:The in-vitro generation of dendritic cells from blast cells in acute leukaemia. 985 28

We measured using a competitive quantitative polymerase chain reaction-capillary electrophoresis (PCR-CE)-based assay, the levels of bcr-abl transcripts in 44 patients with chronic myeloid leukemia (CML) after interferon-alpha (IFN-alpha) therapy, who achieved a major (10 patients, MCR group) or complete (34 patients, CCR group) cytogenetic response. All 34 CCR patients had molecular evidence of residual disease detected in bone marrow samples at the time of best karyotypic response. The median number of bcr-abl transcripts of 34 evaluable patients in the CCR group at the time of complete cytogenetic remission was 4/microg RNA (range 3-4600), while the median number of bcr-abl transcripts of 10 patients in the MCR group at the time of best cytogenetic response was 4490/microg RNA (range 600-23 900) (P = 0.000024). In nine CCR and five MCR patients we were able to quantify the amount of bcr-abl transcript both at diagnosis and after interferon therapy: no statistical difference (P = 0.18) was found between the two groups at diagnosis (median bcr-abl transcripts/microg RNA was 30 000 vs. 39 650, respectively). During IFN-alpha therapy, the two groups were evaluable at the time of major karyotypic conversion: at this point, there was a statistical difference of expression of bcr-abl transcript between the CCR group (17 patients) (median 2700; range 76-40 000) and the MCR group (10 patients) (median 4490; range 600-23 900), respectively (P = 0.046). No differences of bcr-abl amount of transcript were found in patients with CCR obtained either by IFN-alpha therapy alone (20 patients) vs. IFN-alpha plus ABMT (13 patients) (P = 0.47). We firstly demonstrated that although the CCR and MCR groups were clinically, cytogenetically and molecularly indistinguishable at diagnosis, the two groups could be recognized successfully during interferon therapy based on the level of bcr-abl transcript.
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PMID:Quantification of BCR-ABL transcripts in CML patients in cytogenetic remission after interferon-alpha-based therapy. 1074 58

For the management of chronic myeloid leukemia (CML), prediction or early determination of the response to interferon-alpha (IFN-alpha) treatment is important for identifying nonresponder patients to whom alternative therapy may be proposed. In this study, the levels of expression of both BCR-ABL and subunit 2c of IFN-alpha receptor (IFN-alphaR2c) genes were analyzed at diagnosis in 74 patients with chronic phase CML treated with an IFN-alpha monotherapy. By using blood samples, real-time quantitative polymerase chain reaction was performed to quantify BCR-ABL, IFN-alphaR2c, and G6PDH mRNA as external control. The results were compared with hematologic and cytogenetic responses to IFN-alpha. A wide variation in the BCR-ABL/G6PDH ratio was observed at diagnosis (median, 6.68%; range, 0.18%-41.31%), but no significant association with response to IFN-alpha was observed. In contrast, the variation of IFN-alphaR2c/G6PDH ratio at diagnosis was significantly associated with the achievement of major cytogenetic response (MCR; 34% or lower Ph(+) metaphases). Median values of IFN-alphaR2c/G6PDH ratio for patients achieving MCR and for those who did not achieve it were 110.75% (range, 9.47%-612.30%) and 64.42% (range, 5.96%-425.40%), respectively (P =.037). In addition, this novel molecular factor, combined with the achievement of complete hematologic response at 3 months, makes it possible to predict MCR achievement with high probability by Kaplan-Meier analysis (91% +/- 17% at 24 months; P =.0001). (Blood. 2001;97:3568-3573)
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PMID:Expression of interferon-alpha (IFN-alpha) receptor 2c at diagnosis is associated with cytogenetic response in IFN-alpha-treated chronic myeloid leukemia. 1136 52

We have analysed the outcome of 581 autologous stem cell transplants (SCT) for chronic myeloid leukaemia (CML) in first chronic phase reported to the European Group for Blood and Marrow Transplantation between 1983 and 1998. Out off 207 patients evaluable for cytogenetics within 6 months of SCT, 36 patients (17%) were in complete cytogenetic remission (CCR), 34 (16%) in major remission (MCR), 74 (36%) in minor remission (mCR) and 63 (31%) had no cytogenetic response (NR). Interferon (IFN) was given post SCT to 267 patients. Results of the cytogenetic analysis within 1-2 years from SCT were available for 117 patients, the majority of whom (n = 101) received IFN post SCT: 17 (15%) were in CCR, 18 (15%) in MCR, 24 (20%) in mCR and 58 (50%) NR. The median survival in this series was 96 months (71-125) from SCT. There was no difference in survival according to cytogenetic status pre- and immediately post SCT. However, patients in CCR or MCR at 1-2 years post SCT had a 10-year survival of 66% compared with 36% for patients in mCR or NR (P = 0.003). The 5-year survival for patients receiving IFN post SCT was 72% compared with 61% for patients not treated with IFN (P = 0.01). Out of 155 patients refractory to IFN pre SCT, 70% achieved a cytogenetic response post SCT, which was complete or major in 31%. IFN refractory patients who sustained a CCR or MCR for 1-2 years after SCT had an excellent outcome.
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PMID:The post-transplant cytogenetic response to interferon is a major determinant of survival after autologous stem cell transplantation for chronic myeloid leukaemia in chronic phase. 1218 Oct 43

The purpose of this study was to investigate the function of dendritic cells derived from chronic myeloid leukemia (CML-DC). Mononuclear cells were prepared from bone marrow and peripheral blood of 24 patients with CML, and the DCs were obtained by incubation of MNCs with media containing GM-CSF, IL-4 and TNF-alpha. The phenotype of CML-DCs was identified by flow cytometry. FITC-dextran uptake, (3)H-TdR incorporation or MTT assay and lactate dehydrogenase release assay were used to detect uptake of exogenous antigen in immature DCs, the antigen presenting ability in mature DCs and specific cytotoxicity of CTL to leukemic cells, respectively. The DCs with high expression of CD1a, CD86, CD80, HLA-DR, CD54 and CD4 were obtained from marrow and blood of patients with CML. The uptake of FITC-DX was observed in early DCs. There was a potent stimulation to allo-MLR in DCs cultured for 7 - 10 days, and a lightly lower stimulation to auto-MLR. CML-DCs can induce the generation of specific cytotoxic T cells. These results suggest that CML-DCs are functional DCs with the ability to induce anti-leukemia effect.
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PMID:[The Function of Dendritic Cells Derived from Chronic Myeloid Leukemia] 1257 75

This study was aimed to investigate and compare the anti-leukemic effect mediated by dendritic cells (DC) derived from multidrug resistant (MDR) leukemia K562/A02 cells with high expression of p-glycoprotein (P-gp) and sensitive K562 cells. Multidrug resistant K562/A02 cell line and sensitive K562 cell line from chronic myeloid leukemia (CML) were induced for differentiating to DC in complete RPMI 1640 culture medium supplemented with GM-CSF (1 000 U/ml), IL-4 (500 U/ml) and TNF-alpha (100 ng/ml) for 14 days. The morphologic features of DC were observed by means of optical microscopy and the phenotype of DC was detected by flow cytometry. T-cell stimulating activity was determined by allogeneic lymphocyte reaction (allo-MLR). Cytotoxic activity was measured by MTT assay. The results indicated that DC derived from K562/A02 cells and K562 cells similarly showed the typical morphology of dendritic cell and expressed the surface differentiation antigens and costimulatory molecules CD1a, CD83, HLA-DR, CD80 and CD86 of DC. In allo-MLR, K562/A02-DC had a higher capacity to induce lymphocyte proliferation, compared with K562-DC (P < 0.05). K562/A02-DC and K562-DC could similarly generate specific cytotoxic activity against K562/A02 cells or K562 cells respectively, but low reactivity against HL-60 cells. More importantly, the cytotoxic activity mediated by K562/A02-DC was stronger than that by K562-DC against K562/A02 cells or HL-60/VCR cells (P < 0.01, respectively). It is concluded that functional DC can be differentiated from multidrug resistant leukemia K562/A02 cells as well as sensitive K562 cells in the presence of GM-CSF, IL-4 and TNF-alpha. Especially, DC derived from K562/A02 cells can induced a p-glycoprotein specific anti-leukemic immunity.
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PMID:[Induction of anti-leukemic immunity of dendritic cells derived from multidrug resistant leukemia K562/A02 cells with high expression of P-glycoprotein and sensitive K562 cells]. 1640 71

Clinical composite tissue allotransplantation can adequately reconstruct defects that are not possible by other means. However, immunosuppressant toxicity limits the use of these techniques. Clinical attempts to reduce the amount of immunosuppression required by induction of an immunologically permissive state have so far been unsuccessful. The aim of this study was to induce tolerance in a preclinical large animal model. Donor hematopoietic stem cell (HSC) engraftment was induced by T-cell depletion, irradiation, and a short course of cyclosporine administered to the recipient, along with a hematopoietic cell infusion from a single haplotype major histocompatibility complex (MHC) mismatched donor. Skin was then allotransplanted from the donor. Both primarily vascularized skin flaps and secondarily vascularized conventional skin grafts were allotransplanted to investigate if the mode of transplantation affected outcome. Control animals received the skin allotransplants without conditioning. Tolerance was defined as no evidence of rejection at 90 days following transplantation. Conventional skin grafts only achieved prolonged survival (<65 days) in HSC-engrafted animals (P < .01). In contrast, there was indefinite skin flap survival with the achievement of tolerance in HSC-engrafted animals; this was confirmed on histology with donor-specific unresponsiveness on MLR and CML. Furthermore, a conventional skin donor graft subsequently applied to an animal tolerant to a skin flap was not rejected and did not trigger skin flap rejection. To our knowledge, this is the first time skin tolerance has been achieved across a MHC barrier in a large animal model. This is a significant step toward the goal of clinical skin tolerance induction.
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PMID:Induction of tolerance to an allogeneic skin flap transplant in a preclinical large animal model. 1932 21


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