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  • 1
    Electronic Resource
    Electronic Resource
    Promoter of the canine tracheobronchial mucin gene (1996)
    Springer
    Glycoconjugate journal 13 (1996), S. 797-807 
    Details
    ISSN: 1573-4986
    Keywords: cyclic AMP response element ; cystic fibrosis ; epithelial cells ; glycoprotein ; immortalization ; mucin ; papilloma virus vectors ; promoter ; transcription ; transcription factors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The mucin gene is up-regulated in diseases such as cystic fibrosis (CF) and asthma. To understand the mechanisms involved in transcriptional regulation of mucin gene expression we have characterized the region of the mucin gene up-stream of the transcriptional start site and analysed thecis-acting elements required for mucin promoter activity. We isolated clones from a dog genomic library containing the promoter region for the tracheobronchial mucin gene (TBM). The authenticity of the promoter was tested by nucleotide sequencing, primer extension analysis, electrophoretic mobility shift assay (EMSA) and reporter gene expression analysis. The canineTBM promoter is different from housekeeping gene promoters (as it is not rich in GC content and contains TATA- and CAAT-like sequences) and different from that of regulatory genes (because it contains many TATA- and CAAT-like sequences and multiple transcriptional initiation sites). Reporter gene analysis using canineTBM promoter-chloramphenicol acetyltransferase (CAT) fusion plasmids established the regions responsible for promoter activity and verified the positions of the major mucin transcriptional initiation sites. Reporter gene analysis also established that a region of the canineTBM promoter and first exon containing all of the transcriptional initiation sites is more active in mucin expressing cells (e.g. CT1 cells-immortalized canine tracheal epithelial cells, human CFT1 cells-immortalized tracheal epithelial cells from a CF subject, or HBE1 cells-immortalized tracheal epithelial cells from non-CF subject) than in mucin non-expressing cells (COS7, 3T3), suggesting cell specificity. The promoter region contained cAMP response element (CRE) sequences, and theTBM gene transcription was enhanced when cAMP analogs were added to transfected cells. EMSA indicated the presence of at least two DNA binding proteins in CT1 cells. This is the first report describing the characterization of aTBM gene promoter. The information obtained in the present studies will be valuable in understanding mucin gene regulation in normal and pathological conditions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00702344
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  • 2
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    Promoter of the canine tracheobronchial mucin gene (1996)
    Springer
    Details
    Publication Date: 1996-10-01
    Print ISSN: 0282-0080
    Electronic ISSN: 1573-4986
    Topics: Chemistry and Pharmacology
    Published by Springer
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  • 3
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    Ultra-Low Dose IL-2 Safely Expands Regulatory T Cells and CD56bright NK Cells in Healthy Volunteers: Towards Safer Stem Cell Donors? (2012)
    American Society of Hematology
    Details
    Publication Date: 2012-11-16
    Description: Abstract 3283 Donor-derived regulatory T cells (Treg) and natural killer (NK) cells can respectively improve stem cell transplant (SCT) outcome by reducing graft versus host disease (GVHD) severity and exerting a graft-versus-leukemia effect. High frequencies of donor Treg are associated with less GVHD, and low doses of interleukin-2 (IL-2) can expand both NK and Treg after allogeneic SCT. To explore the feasibility of improving the quality of peripheral blood SCT donations, we evaluated the safety and the tolerability of ultra-low dose IL-2 administration to volunteers with the aim of preferentially expanding Treg and NK cells. Twelve healthy volunteers (mean age 34 years; range 22–57) received 0.1 or 0.2 million U/m2/day IL-2 subcutaneously for 5 days (NIH protocol 11-H-0268). Blood samples were collected before and 1, 2, 3, 4, 7 and 28 days after IL-2 injection. Samples were analyzed by multiplex techniques including whole transcriptome gene expression with HumanGene 1.0ST microarrays; serum levels of 69 cytokines and chemokines by Luminex assay; and lymphocyte phenotyping by flow cytometry, to comprehensively characterize the cellular and molecular immune response to IL-2 (“IL-2 immunome”). Treg subsets were determined within the CD4+ T cell population using FoxP3, Helios, CD45RA and CD31 to identify thymus-derived natural Treg (nTreg), induced Tregs (iTreg) and their recent thymic emigrants (RTE). NK cell subsets were determined within CD56+CD3- population using NKG2A, KIR2DL1, KIR2DL2/3, KIR3DL1 and CD57 to identify CD56bright, CD56dim NKG2A+KIR-, and CD56dim KIR+CD57+ cells. All subjects tolerated ultra-low dose IL-2 with minimal adverse events (mainly grade 1–2 injection site reactions). The fraction of FoxP3+Treg in CD4 rose significantly above baseline peaking at 4 days (3.7% vs 5.8%; p=0.0004) after the first dose of IL-2. Treg subset analysis demonstrated that the fraction of nTreg and RTE nTreg in CD4 expanded significantly in the lower dose cohort compared to the higher dose cohort (p=0.004 and p=0.005 respectively). %CD56bright NK significantly increased at 7 days (p=0.008), whereas CD56dimNKG2A+KIR-, and CD56dimKIR+CD57+ NK cells remained at baseline. The Ki67 proliferation marker further verified a significant in vivo expansion of CD56bright NK cells with ultra-low dose IL-2. Cytokine and chemokine profiling demonstrated significant increase circulating level of IP-10 (P=0.0018) through day 2 to 4 after IL-2 injections. In contrast, circulating levels of IL-2, IL-6, IL-10, IL-15 and IL-17 remained unchanged after IL-2 injection. Gene expression microarray studies revealed significant changes in 24 genes (P value 〈 0.1 corrected by false discovery rate (FDR) for multiple testing), including up-regulation of IL-2RA and FOXP3 as early as 2 days after IL-2 injections. Gene Set Analysis (GSA) revealed significant changes (P value 〈 0.1 after FDR) in innate immune response pathways, including Toll-like receptor signaling and interferon signaling. This is the first study to show that ultra-low dose IL-2 could be safely administrated to healthy volunteers to expand thymic-derived natural Treg and CD56bright NK cells. These results raise the possibility of using ultra-low dose IL-2 to boost Treg and NK cells in stem cell donors. Disclosures: No relevant conflicts of interest to declare.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 4
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    Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug (2014)
    American Society of Hematology
    Details
    Publication Date: 2014-03-20
    Description: Key Points Eltrombopag promotes hematopoiesis in patients with severe aplastic anemia by stimulating stem and progenitor cells. Eltrombopag can be discontinued safely in robust responders with maintenance of hematopoiesis.
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    Electronic ISSN: 1528-0020
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  • 5
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    Eltrombopag Can Stimulate Trilineage Hematopoiesis with Transfusion Independence in Patients with Refractory Severe Aplastic Anemia: Results From a Phase II Trial (2011)
    American Society of Hematology
    Details
    Publication Date: 2011-11-18
    Description: Abstract 54 Severe aplastic anemia (SAA) is characterized by trilineage marrow hypoplasia and a paucity of hematopoietic stem cell (HSC) progenitors. SAA is treated with immunosuppressive therapy (IST) or allogeneic HSC transplantation (HSCT), with a successful outcome after either treatment in a majority of patients. However, 20–40% of patients without a suitable donor for HSCT and a suboptimal response to IST may have persistent severe thrombocytopenia. Thrombopoietin (TPO) is the principal regulator of platelet production, and it exerts its effects through binding the megakaryocyte progenitor TPO receptor mpl, which stimulates production of mature megakaryocytes and platelets. Several lines of evidence support the concept that signaling through mpl also influences expansion and maintenance of primitive HSCs and multi-potent progenitor cells. Eltrombopag, is a small molecule TPO receptor agonist that stimulates mpl, and increases platelet counts in patients with chronic immune thrombocytopenic purpura (ITP). It is approved for the treatment of chronic ITP (Promacta®). We conducted a non-randomized, pilot phase II study of eltrombopag in SAA patients who remained severely thrombocytopenic at least six months after one or more rounds of IST (clinical trials.gov identifier NCT00922883). Consecutive patients fulfilling the inclusion criteria received eltrombopag 50mg daily with dose escalation every two weeks to a maximum dose of 150mg daily. Primary end points assessed after three months of treatment were changes in peripheral blood counts (platelets, hemoglobin, absolute neutrophil counts), with hematologic response criteria defined a priori for each lineage. Secondary endpoints included the incidence of bleeding events, and health related quality of life. Patients who achieved hematologic responses were maintained on eltrombopag through an extended access protocol. We completed our planned accrual of twenty five patients, and 22 are evaluable for response to date. Median age was 45 years old (range 18–77 years), and the median time from the last course of IST was 13 months (range 6–54 months). Median follow up time was 9 months (range 1–24 months). Nine of twenty two patients (41%) achieved hematologic responses: seven of twenty-two patients (32%) achieved platelet responses with transfusion independence for eight weeks or greater; six patients had improved hemoglobin levels after starting treatment (mean hemoglobin increase of 3.8 g/dL) and 4 patients who were previously dependent on red blood cell transfusions have achieved transfusion-independence. Five neutropenic patients had increased neutrophil counts after treatment with eltrombopag (mean increase 660 cells/uL). Plasma TPO levels did not predict for hematologic response to eltrombopag. Serial bone marrow biopsies performed on patients with hematologic responses demonstrated normalization of trilineage hematopoiesis and cellularity in three of four responders receiving a year or more of therapy, with no increase in reticulin fibrosis (Figure 1). These results represent the first evidence that TPO stimulation can expand the HSC pool in humans, with clinically meaningful trilineage hematologic improvements in patients with SAA, resulting in transfusion-independence and improved quality of life with a simple daily oral regimen. Updated response data on the full 25 patients will be presented at the Society's meeting. Disclosures: Off Label Use: Eltrombopag for severe aplastic anemia.
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    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 6
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    T-cell immune responses to Wilms tumor 1 protein in myelodysplasia responsive to immunosuppressive therapy (2011)
    American Society of Hematology
    Details
    Publication Date: 2011-03-03
    Description: Clinical observations and laboratory evidence link bone marrow failure in myelodysplastic syndrome (MDS) to a T cell–mediated immune process that is responsive to immunosuppressive treatment (IST) in some patients. Previously, we showed that trisomy 8 MDS patients had clonally expanded CD8+ T-cell populations that recognized aneuploid hematopoietic progenitor cells (HPC). Furthermore, microarray analyses showed that Wilms tumor 1 (WT1) gene was overexpressed by trisomy 8 hematopoietic progenitor (CD34+) cells compared with CD34+ cells from healthy donors. Here, we show that WT1 mRNA expression is up-regulated in the bone marrow mononuclear cells of MDS patients with trisomy 8 relative to healthy controls and non–trisomy 8 MDS; WT1 protein levels were also significantly elevated. In addition, using a combination of physical and functional assays to detect the presence and reactivity of specific T cells, respectively, we demonstrate that IST-responsive MDS patients exhibit significant CD4+ and CD8+ T-cell responses directed against WT1. Finally, WT1-specific CD8+ T cells were present within expanded T-cell receptor Vβ subfamilies and inhibited hematopoiesis when added to autologous patient bone marrow cells in culture. Thus, our results suggest that WT1 is one of the antigens that triggers T cell–mediated myelosuppression in MDS.
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  • 7
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    Effects of Granulocyte Colony Stimulating Factor (G-CSF) On Monosomy 7 Aneuploidy and T Cell Subsets in Healthy Donors. (2009)
    American Society of Hematology
    Details
    Publication Date: 2009-11-20
    Description: Abstract 3147 Poster Board III-84 Recent reports of chromosomal and immunological abnormalities in healthy donors receiving granulocyte colony stimulating factor (G-CSF) have raised concerns among hematologists that this popular cytokine may promote genomic instability or alter immune surveillance (Pampilon D et al Transfusion 2008; 48(7):1495-501). We previously reported that G-CSF altered the Th1:Th2 ratio in healthy individuals following short-term administration (Blood 2000 Apr 1;95(7):2269-74), but reported no new karyotypic abnormities after in vitro culture of bone marrow mononuclear cells with pharmacological doses of G-CSF (Proc Natl Acad Sci 2006 Sep 26;103(39):14483-8). There is no systematic study of the long-term effects of administering granulocyte colony stimulating factor (G-CSF) to healthy individuals. We examined CD34 cells of 10 healthy stem cell donors after they had received 10 mcg/kg G-CSF for 4 days; fluorescent in situ hybridization (FISH) was the method employed to monitor chromosomal changes. We also studied 37 healthy granulocyte donors who received G-CSF (5ug/Kg x 1 day) and dexamethosone for up to 42 times (median= 15; range 6-42) using FISH to examine chromosomes 7 and 8 and flow cytometry to define their T cell subsets. FISH did not detect chromosomal abnormalities in the CD34 cells of 10 donors mobilized with G-CSF; neither could monosomy 7 cells be isolated after culturing cells in media with 400 ng/mL G-CSF (previously shown to support outgrowth of monosomy 7 cells) for two weeks. Furthermore, FISH did not detect aneuploidy in the 37 regular granulocyte donors. Evaluation of T cell subsets by flow cytometry demonstrated similar percentages of CD4+ T cells in 18 granulocyte donors as compared to 23 untreated controls (57.5% vs 56.5%). However, donors had increased numbers of CD4+TNFαa+ Th1 T cells and decreased CD4+IL-6+ Th2 T cells (4.2% vs 1.6%, P= 0.0003 and 11% vs. 35%, P=0.04 respectively), while the donor Th2 subset expressed significantly more IL-6 per cell (P
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  • 8
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    Eltrombopag Can Stimulate Trilineage Hematopoiesis In Patients with Refractory Severe Aplastic Anemia (2010)
    American Society of Hematology
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    Publication Date: 2010-11-19
    Description: Abstract 4427 Severe aplastic anemia (SAA) is characterized by trilineage marrow hypoplasia and a paucity of hematopoietic stem cell progenitors. SAA is treated with immunosuppression or allogeneic stem cell transplantation (SCT), with a successful outcome in a majority. However, 20–40% of patients without a suitable donor for SCT do not respond to immunosuppression and may have persistent severe thrombocytopenia. Thrombopoietin (TPO) is the principal regulator of platelet production, and it exerts its effects through binding the megakaryocyte progenitor TPO receptor mpl, which stimulates production of mature megakaryocytes and platelets. Eltrombopag, a small molecule TPO mimetic that binds to mpl, increases platelet counts in healthy subjects, and in patients with chronic immune thrombocytopenic purpura. Both TPO and eltrombopag stimulate more primitive multilineage progenitors and stem cells in vitro. Patients with SAA and thrombocytopenia have very elevated TPO levels; nevertheless, we asked whether pharmacologic doses of eltrombopag could stimulate hematopoiesis in these patients without other options. We are conducting a pilot phase II study of eltrombopag in SAA patients with severe thrombocytopenia refractory to immunosuppressive therapy. Consecutive eligible adult patients were treated with oral eltrombopag at an initial dose of 50 mg daily, with escalation to a maximum dose 150 mg daily, with the goal of maintaining a platelet count of 〉20,000/uL above baseline. Treatment response was measured after three months and was defined as platelet count increases to 20,000/uL above baseline, or stable platelet counts with transfusion-independence for a minimum of 8 weeks. Nine patients have been enrolled and six are evaluable for response to date. Two patients did not respond to treatment. Three patients achieved platelet responses by 12 weeks of treatment, and all have sustained their responses (median follow up 10 months). Four patients exhibited improved hemoglobin levels 12 weeks after starting treatment (median hemoglobin increase of 2.1 g/dL) and two patients who were previously dependent on packed red blood cell transfusions have achieved transfusion-independence. Three neutropenic patients exhibited increased neutrophil counts after treatment with eltrombopag (median increase 0.46K cells/uL). These results provide evidence that eltrombopag can improve platelet counts in patients with severe refractory thrombocytopenia, and perhaps more surprisingly, have a clinically relevant impact on erythropoiesis and myelopoiesis. Updated data will be presented at the Society's meeting. Disclosures: Off Label Use: Eltrombopag for thrombocytopenia in refractory severe aplastic anemia patients.
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  • 9
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    Persistent Elevation of Plasma Thrombopoietin Levels in Severe Aplastic Anemia, Even with Hematologic Recovery (2015)
    American Society of Hematology
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    Publication Date: 2015-12-03
    Description: In bone marrow failure, levels of circulating hematopoietic growth factors (HGFs) are extremely elevated, in compensation for low blood counts. In general, administration of recombinant HGFs is not effective in aplastic anemia (AA) and related syndromes. We have established the utility of eltrombopag, a thrombopoietin (Tpo) mimetic, in severe AA (SAA) refractory to immunosuppression (IST) (Olnes, N Engl J Med, 2012; Desmond, Blood, 2014). Eltrombopag in combination with standard IST also appears to increase the rate and speed of recovery in treatment-naive SAA (Townsley, EHA. 2015). These clinical results are surprising, as plasma Tpo is markedly increased in SAA (Feng, Haematologica, 2011). In investigating possible mechanisms of action of eltrombopag, we studied HGF dynamics over time in SAA patients undergoing various treatment regimens and manifesting a range of hematologic responses. In a cohort of 37 treatment-naive SAA patients who were treated with either standard IST (horse antithymocyte globulin/cyclosporine A:ATG/CsA, n = 10) alone or with the addition of eltrombopag (n = 27), among whom 8 were non-responders and 29 responders at 6 months, we measured plasma Tpo, granulocyte-colony stimulating factor (G-CSF) and erythropoietin (Epo) using magnetic multiplex assays. Concentrations of these HGFs were greatly elevated before treatment. In a majority of patients, G-CSF declined rapidly to the normal range by 6 months, with no difference between responders and non-responders, and no correlation between G-CSF and absolute neutrophil counts. Epo concentrations decreased to the normal range at 6, 12, and 24 months post treatment in responders, to a significantly greater degree than in non-responders (p = 0.001, 0.0012, 0.038, respectively). There was a negative correlation between Epo and hemoglobin (r2 = 0.3126, p
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  • 10
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    Alemtuzumab Treatment of Intermediate-1 (INT-1) Myelodysplasia Patients Is Associated with Sustained Improvement in Blood Counts and Cytogenetic Remissions. (2009)
    American Society of Hematology
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    Publication Date: 2009-11-20
    Description: Abstract 116 Myelodysplastic syndromes (MDS) are a diverse group of disorders characterized by cytopenias and ineffective hematopoiesis. Experimental evidence links bone marrow failure in a portion of MDS patients to a T cell-dominated autoimmune process. Immunosuppressive therapy (IST) can improve cytopenias in selected patients. Features associated with responsiveness to horse ATG in MDS are young age, low IPSS score, and the presence of HLA DR15 (Sloand E et al J Clin Oncol 2008 26(15):2505-11). The addition of cyclosporine to ATG improves response but continued use of this drug is associated with nephrotoxicity. Alemtuzumab, an anti-CD52 antibody, produces more profound lasting immunosuppression compared to ATG that is associated with transient lymphopenia. We conducted a non-randomized, off label, pilot, Phase II study of alemtuzumab (Campath®) in MDS patients who fit the criteria of those likely to respond to IST (Saunthararajah Y et al Blood. 2003 102(8):3025-7). Consecutive patients fulfilling the inclusion criteria received alemtuzumab 10mg IV for 10 days. Primary endpoints were changes in peripheral blood counts (platelets, absolute neutrophil count, reticulocyte count, hemoglobin). Secondary endpoints (in transfusion-dependent patients) included improvement in the transfusion requirements, duration of response, and late effects of treatment, relapse and survival. Median follow-up time was 11 months (range 1-46 months). Fifteen of 16 (93%) int-1 patients and 2 of 5 (40%) int-2 patients responded by 3 months following infusion. All responders were transfusion independent. Five of seven patients with abnormal cytogenetics at start of treatment had complete cytogenetic remission. One patient with monosomy 7 (constituting 65% of his bone marrow mononuclear cells by FISH) had a complete cytogenetic remission that has lasted 3.8 years thus far. Five of 9 (55%) patients evaluable at 9 months had completely normal blood counts. One patient developed immune thrombocytopenic purpura responsive to rituximab. Two int-2 patients developed leukemia and an additional int-2 patient with a history of smoking succumbed to small cell lung cancer. One death occurred in a non-responding int-1 patient due to disease progression. Two patients had declines in their counts (but not to pretreatment levels) and both responded to CsA. We monitored blood for EBV and CMV reactivation by polymerase chain reaction (PCR) weekly and 4 of the 22 patients became transiently positive for EBV but none developed disease and none of our patients had a significant infection while on drug. The response rate of int-1 patients at 3 months was superior to our previous study using ATG (53%; p=0.0071) but comparable to our results with ATG and CsA (93% p=1.0). Relapse was defined as requirement for additional treatment including cyclosporine; relapse-free survival of responders did not differ from those given ATG or ATG and CsA. The results from this pilot study indicate that Alemtuzumab is highly effective in producing durable responses in selected patients with int-1 MDS. Disclosures: No relevant conflicts of interest to declare.
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