109 results on '"Michal Abraham"'
Search Results
2. CDC25C Protein Expression Correlates with Tumor Differentiation and Clinical Outcomes in Lung Adenocarcinoma
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Esther Stern, Guy Pines, Li Or Lazar, Gilad W. Vainer, Nitzan Beltran, Omri Dodi, Lika Gamaev, Ofir Hikri Simon, Michal Abraham, Hanna Wald, Amnon Peled, and Ori Wald
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NSCLC ,CDC25C ,lung adenocarcinoma ,lung cancer ,Biology (General) ,QH301-705.5 - Abstract
Given that, even after multimodal therapy, early-stage lung cancer (LC) often recurs, novel prognostic markers to help guide therapy are highly desired. The mRNA levels of cell division cycle 25C (CDC25C), a phosphatase that regulates G2/M cell cycle transition in malignant cells, correlate with poor clinical outcomes in lung adenocarcinoma (LUAD). However, whether CDC25C protein detected by immunohistochemistry can serve as a prognostic marker in LUAD is yet unknown. We stained an LC tissue array and a cohort of 61 LUAD tissue sections for CDC25C and searched for correlations between CDC25C staining score and the pathological characteristics of the tumors and the patients’ clinical outcomes. Clinical data were retrieved from our prospectively maintained departmental database. We found that high expression of CDC25C was predominant among poorly differentiated LUAD (p < 0.001) and in LUAD > 1cm (p < 0.05). Further, high expression of CDC25C was associated with reduced disease-free survival (p = 0.03, median follow-up of 39 months) and with a trend for reduced overall survival (p = 0.08). Therefore, high expression of CDC25C protein in LUAD is associated with aggressive histological features and with poor outcomes. Larger studies are required to further validate CDC25C as a prognostic marker in LUAD.
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- 2023
- Full Text
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3. Promiscuous Chemokine Antagonist (BKT130) Suppresses Laser-Induced Choroidal Neovascularization by Inhibition of Monocyte Recruitment
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Shira Hagbi-Levi, Michal Abraham, Liran Tiosano, Batya Rinsky, Michelle Grunin, Orly Eizenberg, Amnon Peled, and Itay Chowers
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Immunologic diseases. Allergy ,RC581-607 - Abstract
Background. Age-related macular degeneration (AMD), the most common cause of blindness in the developed world, usually affects individuals older than 60 years of age. The majority of visual loss in this disease is attributable to the development of choroidal neovascularization (CNV). Mononuclear phagocytes, including monocytes and their tissue descendants, macrophages, have long been implicated in the pathogenesis of neovascular AMD (nvAMD). Current therapies for nvAMD are based on targeting vascular endothelial growth factor (VEGF). This study is aimed at assessing if perturbation of chemokine signaling and mononuclear cell recruitment may serve as novel complementary therapeutic targets for nvAMD. Methods. A promiscuous chemokine antagonist (BKT130), aflibercept treatment, or combined BKT130+aflibercept treatment was tested in an in vivo laser-induced model of choroidal neovascularization (LI-CNV) and in an ex vivo choroidal sprouting assay (CSA). Quantification of CD11b+ cell in the CNV area was performed, and mRNA levels of genes implicated in CNV growth were measured in the retina and RPE-choroid. Results. BKT130 reduced the CNV area and recruitment of CD11b+ cells by 30-35%. No effect of BKT130 on macrophages’ proangiogenic phenotype was demonstrated ex vivo, but a lower VEGFA and CCR2 expression was found in the RPE-choroid and a lower expression of TNFα and NOS1 was found in both RPE-choroid and retinal tissues in the LI-CNV model under treatment with BKT130. Conclusions. Targeting monocyte recruitment via perturbation of chemokine signaling can reduce the size of experimental CNV and should be evaluated as a potential novel therapeutic modality for nvAMD.
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- 2019
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4. Development of Novel Promiscuous Anti-Chemokine Peptibodies for Treating Autoimmunity and Inflammation
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Michal Abraham, Hanna Wald, Dalit Vaizel-Ohayon, Valentin Grabovsky, Zohar Oren, Arnon Karni, Lola Weiss, Eithan Galun, Amnon Peled, and Orly Eizenberg
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chemokines ,autoimmunity ,inflammation ,phage display ,peptibodies ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Chemokines and their receptors play critical roles in the progression of autoimmunity and inflammation. Typically, multiple chemokines are involved in the development of these pathologies. Indeed, targeting single chemokines or chemokine receptors has failed to achieve significant clinical benefits in treating autoimmunity and inflammation. Moreover, the binding of host atypical chemokine receptors to multiple chemokines as well as the binding of chemokine-binding proteins secreted by various pathogens can serve as a strategy for controlling inflammation. In this work, promiscuous chemokine-binding peptides that could bind and inhibit multiple inflammatory chemokines, such as CCL2, CCL5, and CXCL9/10/11, were selected from phage display libraries. These peptides were cloned into human mutated immunoglobulin Fc-protein fusions (peptibodies). The peptibodies BKT120Fc and BKT130Fc inhibited the ability of inflammatory chemokines to induce the adhesion and migration of immune cells. Furthermore, BKT120Fc and BKT130Fc also showed a significant inhibition of disease progression in a variety of animal models for autoimmunity and inflammation. Developing a novel class of antagonists that can control the courses of diseases by selectively blocking multiple chemokines could be a novel way of generating effective therapeutics.
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- 2017
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5. Interaction between CXCR4 and CCL20 pathways regulates tumor growth.
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Katia Beider, Michal Abraham, Michal Begin, Hanna Wald, Ido D Weiss, Ori Wald, Eli Pikarsky, Rinat Abramovitch, Evelyne Zeira, Eithan Galun, Arnon Nagler, and Amnon Peled
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Medicine ,Science - Abstract
The chemokine receptor CXCR4 and its ligand CXCL12 is overexpressed in the majority of tumors and is critically involved in the development and metastasis of these tumors. CXCR4 is expressed in malignant tumor cells whereas its ligand SDF-1 (CXCL12) is expressed mainly by cancer associated fibroblasts (CAF). Similarly to CXCR4, the chemokine CCL20 is overexpressed in variety of tumors; however its role and regulation in tumors is not fully clear. Here, we show that the chemokine receptor CXCR4 stimulates the production of the chemokine CCL20 and that CCL20 stimulates the proliferation and adhesion to collagen of various tumor cells. Furthermore, overexpression of CCL20 in tumor cells promotes growth and adhesion in vitro and increased tumor growth and invasiveness in vivo. Moreover, neutralizing antibodies to CCL20 inhibit the in vivo growth of tumors that either overexpress CXCR4 or CCL20 or naturally express CCL20. These results reveal a role for CCL20 in CXCR4-dependent and -independent tumor growth and suggest a therapeutic potential for CCL20 and CCR6 antagonists in the treatment of CXCR4- and CCL20-dependent malignancies.
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- 2009
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6. Supplementary Table 1 from Combination of Imatinib with CXCR4 Antagonist BKT140 Overcomes the Protective Effect of Stroma and Targets CML In Vitro and In Vivo
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Arnon Nagler, Amnon Peled, Orly Eizenberg, Eithan Galun, Ori Wald, Hanna Wald, Michal Abraham, Maya Koren-Michowitz, Orly Blaier, Merav Darash-Yahana, and Katia Beider
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PDF - 43K, Primer sequences.
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- 2023
7. Supplementary Figure 2 from Combination of Imatinib with CXCR4 Antagonist BKT140 Overcomes the Protective Effect of Stroma and Targets CML In Vitro and In Vivo
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Arnon Nagler, Amnon Peled, Orly Eizenberg, Eithan Galun, Ori Wald, Hanna Wald, Michal Abraham, Maya Koren-Michowitz, Orly Blaier, Merav Darash-Yahana, and Katia Beider
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PDF - 32K, BKT140 structure.
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- 2023
8. Data from Combination of Imatinib with CXCR4 Antagonist BKT140 Overcomes the Protective Effect of Stroma and Targets CML In Vitro and In Vivo
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Arnon Nagler, Amnon Peled, Orly Eizenberg, Eithan Galun, Ori Wald, Hanna Wald, Michal Abraham, Maya Koren-Michowitz, Orly Blaier, Merav Darash-Yahana, and Katia Beider
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Functional role of CXCR4 in chronic myelogenous leukemia (CML) progression was evaluated. Elevated CXCR4 significantly increased the in vitro survival and proliferation in response to CXCL12. CXCR4 stimulation resulted in activation of extracellular signal-regulated kinase (Erk)-1/2, Akt, S6K, STAT3, and STAT5 prosurvival signaling pathways. In accordance, we found that in vitro treatment with CXCR4 antagonist BKT140 directly inhibited the cell growth and induced cell death of CML cells. Combination of BKT140 with suboptimal concentrations of imatinib significantly increased the anti-CML effect. BKT140 induced apoptotic cell death, decreasing the levels of HSP70 and HSP90 chaperones and antiapoptotic proteins BCL-2 and BCL-XL, subsequently promoting the release of mitochondrial factors cytochrome c and SMAC/Diablo. Bone marrow (BM) stromal cells (BMSC) markedly increased the proliferation of CML cells and protected them from imatinib-induced apoptosis. Furthermore, BMSCs elevated proto-oncogene BCL6 expression in the CML cells in response to imatinib treatment, suggesting the possible role of BCL6 in stroma-mediated TKI resistance. BKT140 reversed the protective effect of the stroma, effectively promoted apoptosis, and decreased BCL6 levels in CML cells cocultured with BMSCs. BKT140 administration in vivo effectively reduced the growth of subcutaneous K562-produced xenografts. Moreover, the combination of BKT140 with low-dose imatinib markedly inhibited tumor growth, achieving 95% suppression. Taken together, our data indicate the importance of CXCR4/CXCL12 axis in CML growth and CML–BM stroma interaction. CXCR4 inhibition with BKT140 antagonist efficiently cooperated with imatinib in vitro and in vivo. These results provide the rational basis for CXCR4-targeted therapy in combination with TKI to override drug resistance and suppress residual disease. Mol Cancer Ther; 13(5); 1155–69. ©2014 AACR.
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- 2023
9. Supplementary Figure 1 from Combination of Imatinib with CXCR4 Antagonist BKT140 Overcomes the Protective Effect of Stroma and Targets CML In Vitro and In Vivo
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Arnon Nagler, Amnon Peled, Orly Eizenberg, Eithan Galun, Ori Wald, Hanna Wald, Michal Abraham, Maya Koren-Michowitz, Orly Blaier, Merav Darash-Yahana, and Katia Beider
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PDF - 90K, Demonstrates CXCR4 expression and function in K562 and K562LG-CXCR4 cells.
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- 2023
10. Figure S3 from CXCR4 Promotes Neuroblastoma Growth and Therapeutic Resistance through miR-15a/16-1–Mediated ERK and BCL2/Cyclin D1 Pathways
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Amnon Peled, Yaron Pereg, Eithan Galun, Ori Wald, Orly Eizenberg, Katia Beider, Lola Weiss, Devorah Olam, Yaniv Harel, Hanna Wald, Rinat Abramovitch, Neta Barashi, Ido D. Weiss, Elia Dery, Baruch Bulvik, Michal Abraham, and Shiri Klein
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miR-15a and miR-16-1 expression following antagomiR transfection
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- 2023
11. Data from The Sphingosine-1-Phosphate Modulator FTY720 Targets Multiple Myeloma via the CXCR4/CXCL12 Pathway
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Arnon Nagler, Amnon Peled, Eithan Galun, Michal Abraham, Hanna Wald, Lola Weiss, Devorah Olam, Shiri Klein, Elena Ribakovsky, Maya Koren-Michowitz, Merav Leiba, Avichai Shimoni, Hanna Bitner, Evgenia Rosenberg, and Katia Beider
- Abstract
Purpose: To explore the functional consequences of possible cross-talk between the CXCR4/CXCL12 and the sphingosine-1-phosphate (S1P) pathways in multiple myeloma (MM) cells and to evaluate the effect of S1P targeting with the FTY720 modulator as a potential anti-MM therapeutic strategy.Experimental Design and Results: S1P targeting with FTY720 induces MM cell apoptosis. The combination of FTY720 with the SPHK1 inhibitor SKI-II results in synergistic inhibition of MM growth. CXCR4/CXCL12-enhanced expression correlates with reduced MM cell sensitivity to both FTY720 and SKI-II inhibitors, and with SPHK1 coexpression in both cell lines and primary MM bone marrow (BM) samples, suggesting regulative cross-talk between the CXCR4/CXCL12 and SPHK1 pathways in MM cells. FTY720 was found to directly target CXCR4. FTY720 profoundly reduces CXCR4 cell-surface levels and abrogates the CXCR4-mediated functions of migration toward CXCL12 and signaling pathway activation. Moreover, FTY720 cooperates with bortezomib, inducing its cytotoxic activity and abrogating the bortezomib-mediated increase in CXCR4 expression. FTY720 effectively targets bortezomib-resistant cells and increases their sensitivity to bortezomib, promoting DNA damage. Finally, in a recently developed novel xenograft model of CXCR4-dependent systemic MM with BM involvement, FTY720 treatment effectively reduces tumor burden in the BM of MM-bearing mice. FTY720 in combination with bortezomib demonstrates superior tumor growth inhibition and abrogates bortezomib-induced CXCR4 increase on MM cells.Conclusions: Altogether, our work identifies a cross-talk between the S1P and CXCR4 pathways in MM cells and provides a preclinical rationale for the therapeutic application of FTY720 in combination with bortezomib in patients with MM. Clin Cancer Res; 23(7); 1733–47. ©2016 AACR.
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- 2023
12. Supplementary Figure 3 from Targeting the CD20 and CXCR4 Pathways in Non-Hodgkin Lymphoma with Rituximab and High-Affinity CXCR4 Antagonist BKT140
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Arnon Nagler, Amnon Peled, Orly Eizenberg, Abraham Avigdor, Eithan Galun, Evgenia Rosenberg, Lola Weiss, Hanna Wald, Michal Abraham, Elena Ribakovsky, and Katia Beider
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Supplementary Figure 3 - PDF file 100K, Apoptosis induced by BKT140 and Rituximab
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- 2023
13. Supplementary Figure 4 from Targeting the CD20 and CXCR4 Pathways in Non-Hodgkin Lymphoma with Rituximab and High-Affinity CXCR4 Antagonist BKT140
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Arnon Nagler, Amnon Peled, Orly Eizenberg, Abraham Avigdor, Eithan Galun, Evgenia Rosenberg, Lola Weiss, Hanna Wald, Michal Abraham, Elena Ribakovsky, and Katia Beider
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Supplementary Figure 4 - PDF file 117K, Interaction of NHL cells with BMSCs
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- 2023
14. Supplementary data from The Sphingosine-1-Phosphate Modulator FTY720 Targets Multiple Myeloma via the CXCR4/CXCL12 Pathway
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Arnon Nagler, Amnon Peled, Eithan Galun, Michal Abraham, Hanna Wald, Lola Weiss, Devorah Olam, Shiri Klein, Elena Ribakovsky, Maya Koren-Michowitz, Merav Leiba, Avichai Shimoni, Hanna Bitner, Evgenia Rosenberg, and Katia Beider
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Contains supplementary methods and primer sequences
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- 2023
15. Data from Targeting the CD20 and CXCR4 Pathways in Non-Hodgkin Lymphoma with Rituximab and High-Affinity CXCR4 Antagonist BKT140
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Arnon Nagler, Amnon Peled, Orly Eizenberg, Abraham Avigdor, Eithan Galun, Evgenia Rosenberg, Lola Weiss, Hanna Wald, Michal Abraham, Elena Ribakovsky, and Katia Beider
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Purpose: Chemokine axis CXCR4/CXCL12 is critically involved in the survival and trafficking of normal and malignant B lymphocytes. Here, we investigated the effect of high-affinity CXCR4 antagonist BKT140 on lymphoma cell growth and rituximab-induced cytotoxicity in vitro and in vivo.Experimental Design:In vitro efficacy of BKT140 alone or in combination with rituximab was determined in non-Hodgkin lymphoma (NHL) cell lines and primary samples from bone marrow aspirates of patients with NHL. In vivo efficacy was evaluated in xenograft models of localized and disseminated NHL with bone marrow involvement.Results: Antagonizing CXCR4 with BKT140 resulted in significant inhibition of CD20+ lymphoma cell growth and in the induction of cell death, respectively. Combination of BKT140 with rituximab significantly enhanced the apoptosis against the lymphoma cells in a dose-dependent manner. Moreover, rituximab induced CXCR4 expression in lymphoma cell lines and primary lymphoma cells, suggesting the possible interaction between CD20 and CXCR4 pathways in NHL. Primary bone marrow stromal cells (BMSC) further increased CXCR4 expression and protected NHL cells from rituximab-induced apoptosis, whereas BKT140 abrogated this protective effect. Furthermore, BKT140 showed efficient antilymphoma activity in vivo in the xenograft model of disseminated NHL with bone marrow involvement. BKT140 treatment inhibited the local tumor progression and significantly reduced the number of NHL cells in the bone marrow. Combined treatment of BKT140 with rituximab further decreased the number of viable lymphoma cells in the bone marrow, achieving 93% reduction.Conclusions: These findings suggest the possible role of CXCR4 in NHL progression and response to rituximab and provide the scientific basis for the development of novel CXCR4-targeted therapies for refractory NHL. Clin Cancer Res; 19(13); 3495–507. ©2013 AACR.
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- 2023
16. Data from Single Dose of the CXCR4 Antagonist BL-8040 Induces Rapid Mobilization for the Collection of Human CD34+ Cells in Healthy Volunteers
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Amnon Peled, Reuven Or, Yoseph Caraco, Eithan Galun, Arnon Aharon, Abi Vainstein, Rottem Golan, Arnon Nagler, Katia Beider, Orly Eizenberg, Hana Wald, Inbal Mishalian, Shiri Klein, Baruch Bulvik, Yaron Pereg, and Michal Abraham
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Purpose: The potential of the high-affinity CXCR4 antagonist BL-8040 as a monotherapy-mobilizing agent and its derived graft composition and quality were evaluated in a phase I clinical study in healthy volunteers (NCT02073019).Experimental Design: The first part of the study was a randomized, double-blind, placebo-controlled dose escalation phase. The second part of the study was an open-label phase, in which 8 subjects received a single injection of BL-8040 (1 mg/kg) and approximately 4 hours later underwent a standard leukapheresis procedure. The engraftment potential of the purified mobilized CD34+ cells was further evaluated by transplanting the cells into NSG immunodeficient mice.Results: BL-8040 was found safe and well tolerated at all doses tested (0.5–1 mg/kg). The main treatment-related adverse events were mild to moderate. Transient injection site and systemic reactions were mitigated by methylprednisolone, paracetamol, and promethazine pretreatment. In the first part of the study, BL-8040 triggered rapid and substantial mobilization of WBCs and CD34+ cells in all tested doses. Four hours postdose, the count rose to a mean of 8, 37, 31, and 35 cells/μL (placebo, 0.5, 0.75, and 1 mg/kg, respectively). FACS analysis revealed substantial mobilization of immature dendritic, T, B, and NK cells. In the second part, the mean CD34+ cells/kg collected were 11.6 × 106 cells/kg. The graft composition was rich in immune cells.Conclusions: The current data demonstrate that BL-8040 is a safe and effective monotherapy strategy for the collection of large amounts of CD34+ cells and immune cells in a one-day procedure for allogeneic HSPC transplantation. Clin Cancer Res; 23(22); 6790–801. ©2017 AACR.
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- 2023
17. Table S4 from Single Dose of the CXCR4 Antagonist BL-8040 Induces Rapid Mobilization for the Collection of Human CD34+ Cells in Healthy Volunteers
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Amnon Peled, Reuven Or, Yoseph Caraco, Eithan Galun, Arnon Aharon, Abi Vainstein, Rottem Golan, Arnon Nagler, Katia Beider, Orly Eizenberg, Hana Wald, Inbal Mishalian, Shiri Klein, Baruch Bulvik, Yaron Pereg, and Michal Abraham
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Supplemented Table 4A: Absolut number of different subsets of hematopoietic stem cells Supplemented Table 4B: Percentages of different subpopulations of BL-8040 mobilized cells as compared to G-CSF mobilized cells
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- 2023
18. Data from The High-Affinity CXCR4 Antagonist BKT140 Is Safe and Induces a Robust Mobilization of Human CD34+ Cells in Patients with Multiple Myeloma
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Arnon Nagler, Avichai Shimoni, Izhar Hardan, Orly Eizenberg, Howard Laurence Shaw, Eithan Galun, Sigal Aviel, Yaron Ramati, Yossi Riback, Lena Ribakovsky, Lena Tiomkin, Hanna Wald, Katia Beider, Jacob M. Rowe, Irit Avivi, Michal Abraham, and Amnon Peled
- Abstract
Purpose: CXCR4 plays an important role in the retention of stem cells within the bone marrow. BKT140 (4F-benzoyl-TN14003) is a 14-residue bio stable synthetic peptide, which binds CXCR4 with a greater affinity compared with plerixafor (4 vs. 84 nmol/L). Studies in mice demonstrated the efficient and superior mobilization and transplantation of stem cells collected with GCSF-BKT140, compared with those obtained when using stem cells obtained with each one of these mobilizing agent alone. These results have served as a platform for the present clinical phase I study.Experimental Design: Eighteen patients with multiple myeloma who were preparing for their first autologous stem cell transplantation were included. Patients received a standard multiple myeloma mobilization regimen, consisting of 3 to 4 g/m2 cyclophosphamide (day 0), followed by granulocyte colony—stimulating factor (G-CSF) at 5 μg/kg/d starting on day 5 and administered between 8 and 10 pm until the end of stem cell collection. A single injection of BKT140 (0.006, 0.03, 0.1, 0.3, and 0.9 mg/kg) was administered subcutaneously on day 10 in the early morning, followed by G-CSF 12 hours later.Results: BKT140 was well tolerated at all concentrations, and none of the patients developed grade 3 and 4 toxicity. A single administration of BKT140 at the highest dose, 0.9 mg/kg, resulted in a robust mobilization and collection of CD34+ cells (20.6 ± 6.9 × 106/kg), which were obtained through a single apheresis. All transplanted patients received ∼5.3 × 106 CD34+ cells/kg, which rapidly engrafted (n = 17). The median time to neutrophil and platelet recovery was 12 and 14 days, respectively, at the highest dose (0.9 mg/kg).Conclusions: When combined with G-CSF, BKT140 is a safe and efficient stem cell mobilizer that enabled the collection of a high number of CD34+ cells in 1 and 2 aphaeresis procedures, resulting in successful engraftment. Clin Cancer Res; 20(2); 469–79. ©2013 AACR.
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- 2023
19. Supplementary Figure 5 from Targeting the CD20 and CXCR4 Pathways in Non-Hodgkin Lymphoma with Rituximab and High-Affinity CXCR4 Antagonist BKT140
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Arnon Nagler, Amnon Peled, Orly Eizenberg, Abraham Avigdor, Eithan Galun, Evgenia Rosenberg, Lola Weiss, Hanna Wald, Michal Abraham, Elena Ribakovsky, and Katia Beider
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Supplementary Figure 5 - PDF 65K,Apoptosis induction in BL-2 cells infiltrated to the BM
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- 2023
20. Data from CXCR4 Promotes Neuroblastoma Growth and Therapeutic Resistance through miR-15a/16-1–Mediated ERK and BCL2/Cyclin D1 Pathways
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Amnon Peled, Yaron Pereg, Eithan Galun, Ori Wald, Orly Eizenberg, Katia Beider, Lola Weiss, Devorah Olam, Yaniv Harel, Hanna Wald, Rinat Abramovitch, Neta Barashi, Ido D. Weiss, Elia Dery, Baruch Bulvik, Michal Abraham, and Shiri Klein
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CXCR4 expression in neuroblastoma tumors correlates with disease severity. In this study, we describe mechanisms by which CXCR4 signaling controls neuroblastoma tumor growth and response to therapy. We found that overexpression of CXCR4 or stimulation with CXCL12 supports neuroblastoma tumorigenesis. Moreover, CXCR4 inhibition with the high-affinity CXCR4 antagonist BL-8040 prevented tumor growth and reduced survival of tumor cells. These effects were mediated by the upregulation of miR-15a/16-1, which resulted in downregulation of their target genes BCL-2 and cyclin D1, as well as inhibition of ERK. Overexpression of miR-15a/16-1 in cells increased cell death, whereas antagomirs to miR-15a/16-1 abolished the proapoptotic effects of BL-8040. CXCR4 overexpression also increased miR-15a/16-1, shifting their oncogenic dependency from the BCL-2 to the ERK signaling pathway. Overall, our results demonstrate the therapeutic potential of CXCR4 inhibition in neuroblastoma treatment and provide a rationale to test combination therapies employing CXCR4 and BCL-2 inhibitors to increase the efficacy of these agents.Significance: These results provide a mechanistic rationale for combination therapy of CXCR4 and BCL-2 inhibitors to treat a common and commonly aggressive pediatric cancer.Cancer Res; 78(6); 1471–83. ©2017 AACR.
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- 2023
21. Supplementary Figure 1 from Targeting the CD20 and CXCR4 Pathways in Non-Hodgkin Lymphoma with Rituximab and High-Affinity CXCR4 Antagonist BKT140
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Arnon Nagler, Amnon Peled, Orly Eizenberg, Abraham Avigdor, Eithan Galun, Evgenia Rosenberg, Lola Weiss, Hanna Wald, Michal Abraham, Elena Ribakovsky, and Katia Beider
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Supplementary Figure 1 - PDF file 118K, CXCR4 expression in NHL cells
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- 2023
22. Supplementary Figure 2 from Targeting the CD20 and CXCR4 Pathways in Non-Hodgkin Lymphoma with Rituximab and High-Affinity CXCR4 Antagonist BKT140
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Arnon Nagler, Amnon Peled, Orly Eizenberg, Abraham Avigdor, Eithan Galun, Evgenia Rosenberg, Lola Weiss, Hanna Wald, Michal Abraham, Elena Ribakovsky, and Katia Beider
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Supplementary Figure 2 - PDF file 64K, CXCR4 migratory function in NHL cells
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- 2023
23. MiR-122, the regulator of the immune privileged liver
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Maytal Gefen, Shanny Layani, Emma Klahr, Mor Hindi, Nofar Rosenberg, Rinat Abramovitch, Nathalie Nachmansson, Adi Yehezkel, Amnon Peled, Jacob Rachmilewitz, Michal Abraham, Michael Berger, Daniel Goldenberg, Nicola Gagliani, Samuel Huber, Irm Hermans-Borgmeyer, Rebecca Haffner-Krausz, Shifra Ben-Dor, Yuval Nevo, Shrona Elgavish, Hadar Benyamini, Mathias Heikenwälder, Stefan Rose-John, Dirk Schmist-Arras, Achim Krüger, Michael Stürzl, Elisabeth Naschberger, Frank Tacke, Hilla Giladi, and Eithan Galun
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Hepatology - Published
- 2022
24. Brief ex vivo Fas-ligand incubation attenuates GvHD without compromising stem cell graft performance
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Anastasia Rodin, Jerry Stein, Amnon Peled, Yuval Baar, Liat Shachnai-Pinkas, Alex Saar, Nitzan Marelly, Tsila Zuckerman, Galina Rodionov, Shai Yarkoni, Michal Rosenzwaig, Michal Abraham, Liron Gez, Tamar Katz, Hila Wildbaum, Ronit Bakimer-Kleiner, Inbal Mishalian, and Hilit Levy-Barazany
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0301 basic medicine ,Fas Ligand Protein ,Bone marrow transplantation ,T cell ,Graft vs Host Disease ,chemical and pharmacologic phenomena ,Ligands ,Article ,Fas ligand ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Mice, Inbred NOD ,Cell death and immune response ,medicine ,Animals ,IL-2 receptor ,Transplantation ,business.industry ,Stem Cells ,Haematopoietic stem cells ,Hematopoietic Stem Cell Transplantation ,CD28 ,hemic and immune systems ,Hematology ,medicine.disease ,Fas receptor ,Haematopoiesis ,surgical procedures, operative ,030104 developmental biology ,Graft-versus-host disease ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,Stem cell ,business ,Haematological diseases - Abstract
Graft versus host disease (GvHD) remains a limiting factor for successful hematopoietic stem cell transplantation (HSCT). T cells and antigen-presenting cells (APCs) are major components of the hematopoietic G-CSF mobilized peripheral blood cell (MPBC) graft. Here we show that a short incubation (2 h) of MPBCs with hexameric Fas ligand (FasL) selectively induces apoptosis of specific donor T cell subsets and APCs but not of CD34+ cells. FasL treatment preferentially induces apoptosis in mature T cell subsets which express high levels of Fas (CD95), such as T stem cell memory, T central memory, and T effector memory cells, as well as TH1 and TH17 cells. Anti-CD3/CD28 stimulated T cells derived from FasL-treated-MPBCs express lower levels of CD25 and secrete lower levels of IFN-γ as compared to control cells not treated with FasL. FasL treatment also induces apoptosis of transitional, naïve, memory and plasmablastoid B cells leading to a reduction in their numbers in the graft and following engraftment in transplanted mice. Most importantly, ex vivo treatment of MPBCs with FasL prior to transplant in conditioned NOD-scid IL2Rγnull (NSG) mice prevented GvHD while preserving graft versus leukemia (GvL) effects, and leading to robust stem cell engraftment.
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- 2020
25. BL-8040 CXCR4 antagonist is safe and demonstrates antileukemic activity in combination with cytarabine for the treatment of relapsed/refractory acute myelogenous leukemia: An open-label safety and efficacy phase 2a study
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Osnat Bohana-Kashtan, Margaret M. Showel, Martin S. Tallman, Jessica K. Altman, Abi Vainstein-Haras, James M. Foran, Avichai Shimoni, Arnon Aharon, Michal Abraham, Yaron Pereg, Shaul Kadosh, Arnon Nagler, Ella Sorani, Yishai Ofran, Galia Oberkovitz, Naveen Pemmaraju, Amnon Peled, Ahmed AlRawi, Emil Samara, Geoffrey L. Uy, Tzipi Lustig, Michael Andreeff, Irit Glicko-Kabir, Stephen Shaw, Jorge E. Cortes, Carlos E. Bueso-Ramos, Adam Foley-Comer, Gautam Borthakur, John F. DiPersio, and Jacob M. Rowe
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Receptors, CXCR4 ,Acute myelogenous leukemia (AML) ,medicine.medical_treatment ,Bone Marrow Cells ,Gastroenterology ,Drug Administration Schedule ,03 medical and health sciences ,Myelogenous ,0302 clinical medicine ,Refractory ,Recurrence ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,030212 general & internal medicine ,Aged ,Chemotherapy ,CXCR4 antagonist ,business.industry ,Remission Induction ,Cytarabine ,Middle Aged ,medicine.disease ,Hematopoietic Stem Cell Mobilization ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Female ,Bone marrow ,business ,Peptides ,medicine.drug - Abstract
Background CXCR4 mediates the retention and survival of acute myelogenous leukemia blasts in bone marrow and contributes to their resistance to chemotherapy. The authors evaluated a combination of the high-affinity CXCR4 antagonist BL-8040 with high-dose cytarabine (HiDAC) chemotherapy in a phase 2a study of patients with relapsed and refractory AML. Methods Forty-two patients received treatment with BL-8040 monotherapy for 2 days followed by a combination of BL-8040 with HiDAC for 5 days. Six escalating BL-8040 dose levels were investigated (0.5, 0.75, 1.0, 1.25, 1.5, and 2.0 mg/kg), and 1.5 mg/kg was selected as the dose for the expansion phase (n = 23). Results BL-8040 in combination with HiDAC was safe and well tolerated at all dose levels. Clinical response was observed with BL-8040 doses ≥1.0 mg/kg. The composite response rate (complete remissions plus complete remissions with incomplete hematologic recovery of platelets or neutrophils) was 29% (12 of 42) in all patients and 39% (9 of 23) in the 1.5-mg/kg phase. The median overall survival was 8.4 months for all patients, 10.8 months in the 1.5-mg/kg phase, and 21.8 months for responding patients in the 1.5-mg/kg cohort. Two days of BL-8040 monotherapy triggered the mobilization of blasts into peripheral blood, with significantly higher mean fold-changes in responders versus nonresponders. This was accompanied by a decrease in bone marrow blasts. Conclusions The current results demonstrate the efficacy of CXCR4 targeting with BL-8040 and support continued clinical development in acute myelogenous leukemia.
- Published
- 2020
26. The High Affinity CXCR4 Inhibitor, BL-8040, Impairs the Infiltration, Migration, Viability, and Differentiation of Regulatory T Cells
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Abi Vainstein, Michal Abraham, Orly Eizenberg, Amnon Peled, Inbal Mishalian, Liron Shemesh-Darvish, and Ella Sorani
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CXCR4 Inhibitor ,Chemistry ,Immunology ,medicine ,chemical and pharmacologic phenomena ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Infiltration (medical) ,Molecular biology - Abstract
Introduction: Regulatory T (Treg) cells, an immunosuppressive subset of CD4+ T cells characterized by the expression of the master transcription factor forkhead box protein P3 (FOXP3), are a component of the immune system with essential roles in maintaining self-tolerance. Treg cells which are indispensable for preventing autoimmunity, also suppress effective tumor immunity (Togashi et al. Nat Rev Clin Oncol 2019) Treg cells abundantly infiltrate into tumor tissues, present in the tumor microenvironment where they promote tumor development and progression by dampening antitumor immune responses. The abundantly infiltrate of Treg cells into tumor tissues is often associated with poor prognosis in cancer patients (Tanaka et al Eur. J. Immunol. 2019). The chemokine receptor CXCR4 and its ligand, stromal cell-derived factor-1 (SDF-1/CXCL12) are critically involved in immune cell trafficking. CXCR4 overexpression, which has been identified in multiple cancer types, also supports cancer metastasis, recurrence and therapeutic resistance. More importantly, CXCR4 was shown to enhance tumor immune evasion by recruiting Treg (Santagata et al. Oncotarget. 2017) Objective: To study the effect of the high affinity CXCR4 antagonist, BL-8040, on the biology of Treg cells. To study how BL-8040 affects the ability of these cells to penetrate into the tumors, their migratory ability, their survival and also the differentiation of naive T cells towards Treg. Methods:C57BL/6 mice bearing LivMet pancreatic tumors and control mice were used for in-vivo study. In-vitro study was done with CD4 +CD25 hiFOXP3 + (Treg) cells which were isolated from fresh whole blood. CD4 +CD25 - cells were served as T conventional cells (Tconv). Differentiation of Treg cells was done from Naïve CD4+ T cells which were isolated from cord blood and stimulated with anti-CD3/CD28, TGF-b, IL-2 with or without BL-8040 for 6 days. Results: When mice bearing pancreatic cancer were treated with BL-8040, we found a significant reduction in the number of infiltrating Treg into the tumor. Following treatment with BL-8040 there was no alteration in the number of Treg in the blood neither in control mice nor in mice bearing tumors. To further understand the mechanism by which BL-8040 effected Treg cells we isolated Treg and Tconv cells and found that Treg cells express lower level of CXCR4, as compared to Tconv (Figure1). Further to, when we compared their motility, we found that Treg migration less efficiently towards CXCL12. Despite this, BL8040 more efficiently suppressed CXCL12 induced migration of Treg compared to Tconv. 100 nM of BL8040 was found to inhibits the migration of 82 % from the Treg compared to only 56.6% of Tconv cells (Figure 2). CXCR4 involves classical pathways of cell survival. In order to study the role of CXCR4 in the viability of Treg, we incubated Treg and Tconv cells in the presence of BL-8040 for 24 hr. We found that Treg cells are more sensitive to BL-8040 treatment with 19.2% of cell death compared to only 3.5% of Tconv cell death (Figure 3). Treg are one of the lineages of T helper (Th) cells which differentiated from naïve CD4 T cells. We found that BL-8040 inhibits the differentiation of naive CD4 T cells toward Treg. 10uM of BL-8040 shows a 5-fold inhibition in Treg differentiation from naïve CD4 T cells (Figure 4). Conclusions: In this work we show that the CXCR4 antagonist, BL-8040, can act as an immunomodulator by affecting the biology of regulatory T cells. BL8040 reduce the amount of infiltrating Treg into the tumors, impaired the migratory capacity of Treg toward CXCL12 and induces their cell death. Furthermore, BL-8040 was found to inhibit the differentiation of naïve CD4 T cells toward Treg. Taking all these together, BL-8040 may therefore improve the anticancer immune response, without impairing the activity of Tconv and thus can potentially serve as an effective immunomodulatory agent for cancer. Figure 1 Figure 1. Disclosures Abraham: Biokine Therapeutics: Current Employment. Vainstein: BioLineRx LTD: Current Employment. Shemesh-Darvish: BioLineRx LTD: Current Employment. Sorani: BioLineRx LTD: Current Employment. Eizenberg: Biokine Therapeutics Ltd: Current Employment. Peled: Biokine Therapeutics Ltd: Current Employment; Gamida Cell: Research Funding.
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- 2021
27. Single Dose of the CXCR4 Antagonist BL-8040 Induces Rapid Mobilization for the Collection of Human CD34+ Cells in Healthy Volunteers
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Shiri Klein, Inbal Mishalian, Hanna Wald, Reuven Or, Orly Eizenberg, Yoseph Caraco, Arnon Aharon, Katia Beider, Eithan Galun, Rottem Golan, Michal Abraham, Amnon Peled, Yaron Pereg, Arnon Nagler, Abi Vainstein, and Baruch Bulvik
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0301 basic medicine ,Cancer Research ,business.industry ,medicine.medical_treatment ,CD34 ,Leukapheresis ,Hematopoietic stem cell transplantation ,Pharmacology ,Granulocyte colony-stimulating factor ,Transplantation ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,Immunophenotyping ,Oncology ,CXCR4 Antagonist BL-8040 ,030220 oncology & carcinogenesis ,Medicine ,business - Abstract
Purpose: The potential of the high-affinity CXCR4 antagonist BL-8040 as a monotherapy-mobilizing agent and its derived graft composition and quality were evaluated in a phase I clinical study in healthy volunteers (NCT02073019). Experimental Design: The first part of the study was a randomized, double-blind, placebo-controlled dose escalation phase. The second part of the study was an open-label phase, in which 8 subjects received a single injection of BL-8040 (1 mg/kg) and approximately 4 hours later underwent a standard leukapheresis procedure. The engraftment potential of the purified mobilized CD34+ cells was further evaluated by transplanting the cells into NSG immunodeficient mice. Results: BL-8040 was found safe and well tolerated at all doses tested (0.5–1 mg/kg). The main treatment-related adverse events were mild to moderate. Transient injection site and systemic reactions were mitigated by methylprednisolone, paracetamol, and promethazine pretreatment. In the first part of the study, BL-8040 triggered rapid and substantial mobilization of WBCs and CD34+ cells in all tested doses. Four hours postdose, the count rose to a mean of 8, 37, 31, and 35 cells/μL (placebo, 0.5, 0.75, and 1 mg/kg, respectively). FACS analysis revealed substantial mobilization of immature dendritic, T, B, and NK cells. In the second part, the mean CD34+ cells/kg collected were 11.6 × 106 cells/kg. The graft composition was rich in immune cells. Conclusions: The current data demonstrate that BL-8040 is a safe and effective monotherapy strategy for the collection of large amounts of CD34+ cells and immune cells in a one-day procedure for allogeneic HSPC transplantation. Clin Cancer Res; 23(22); 6790–801. ©2017 AACR.
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- 2017
28. The CXCR4 inhibitor BL-8040 induces the apoptosis of AML blasts by downregulating ERK, BCL-2, MCL-1 and cyclin-D1 via altered miR-15a/16-1 expression
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O. Eizenberg, Amnon Peled, Yaron Pereg, Katia Beider, Ido D. Weiss, Michal Abraham, Arnon Nagler, Lola Weiss, Ori Wald, Abraham Avigdor, Eithan Galun, Hanna Wald, Shiri Klein, Baruch Bulvik, Ohad Benjamini, Devorah Olam, and Sigal Tavor
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0301 basic medicine ,MAPK/ERK pathway ,Receptors, CXCR4 ,Cancer Research ,Programmed cell death ,Down-Regulation ,Apoptosis ,Biology ,Real-Time Polymerase Chain Reaction ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Cell Line, Tumor ,hemic and lymphatic diseases ,medicine ,Humans ,Cyclin D1 ,Extracellular Signal-Regulated MAP Kinases ,Protein kinase B ,Myeloid leukemia ,Hematology ,medicine.disease ,Leukemia, Myeloid, Acute ,MicroRNAs ,Haematopoiesis ,Leukemia ,030104 developmental biology ,Proto-Oncogene Proteins c-bcl-2 ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Myeloid Cell Leukemia Sequence 1 Protein ,Peptides - Abstract
CXCR4 is a key player in the retention and survival of human acute myeloid leukemia (AML) blasts in the bone marrow (BM) microenvironment. We studied the effects of the CXCR4 antagonist BL-8040 on the survival of AML blasts, and investigated the molecular mechanisms by which CXCR4 signaling inhibition leads to leukemic cell death. Treatment with BL-8040 induced the robust mobilization of AML blasts from the BM. In addition, AML cells exposed to BL-8040 underwent differentiation. Furthermore, BL-8040 induced the apoptosis of AML cells in vitro and in vivo. This apoptosis was mediated by the upregulation of miR-15a/miR-16-1, resulting in downregulation of the target genes BCL-2, MCL-1 and cyclin-D1. Overexpression of miR-15a/miR-16-1 directly induced leukemic cell death. BL-8040-induced apoptosis was also mediated by the inhibition of survival signals via the AKT/ERK pathways. Importantly, treatment with a BCL-2 inhibitor induced apoptosis and act together with BL-8040 to enhance cell death. BL-8040 also synergized with FLT3 inhibitors to induce AML cell death. Importantly, this combined treatment prolonged the survival of tumor-bearing mice and reduced minimal residual disease in vivo. Our results provide a rationale to test combination therapies employing BL-8040 and BCL-2 or FLT3 inhibitors to achieve increased efficacy of these agents.
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- 2017
29. The mTOR inhibitor everolimus overcomes CXCR4-mediated resistance to histone deacetylase inhibitor panobinostat through inhibition of p21 and mitotic regulators
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Lola Weiss, Valeria Voevoda-Dimenshtein, Avichai Shimoni, Evgenia Rosenberg, Jonathan Canaani, Michal Abraham, Amnon Peled, Hila Magen, Yaarit Sirovsky, Arnon Nagler, Olga Ostrovsky, Noya Shilo, Katia Beider, Michael Milyavsky, and Hanna Bitner
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0301 basic medicine ,rho GTP-Binding Proteins ,Programmed cell death ,Receptors, CXCR4 ,medicine.drug_class ,Mitosis ,Antineoplastic Agents ,Bone Marrow Cells ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Panobinostat ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Everolimus ,PI3K/AKT/mTOR pathway ,Cells, Cultured ,Pharmacology ,Dose-Response Relationship, Drug ,Cell growth ,TOR Serine-Threonine Kinases ,Histone deacetylase inhibitor ,Cell cycle ,Xenograft Model Antitumor Assays ,Histone Deacetylase Inhibitors ,030104 developmental biology ,chemistry ,Apoptosis ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Multiple Myeloma ,medicine.drug - Abstract
Although having promising anti-myeloma properties, the pan-histone deacetylase inhibitor (HDACi) panobinostat lacks therapeutic activity as a single agent. The aim of the current study was to elucidate the mechanisms underlying multiple myeloma (MM) resistance to panobinostat monotherapy and to define strategies to overcome it. Sensitivity of MM cell lines and primary CD138+ cells from MM patients to panobinostat correlated with reduced expression of the chemokine receptor CXCR4, whereas overexpression of CXCR4 in MM cell lines increased their resistance to panobinostat. Decreased sensitivity to HDACi was associated with reversible G0/G1 cell growth arrest while response was characterized by apoptotic cell death. Analysis of intra-cellular signaling mediators revealed the pro-survival mTOR pathway to be regulated by CXCR4 overexpression. Combining panobinostat with mTOR inhibitor everolimus abrogated the resistance to HDACi and induced synergistic cell death. The combination of panobinostat/everolimus resulted in sustained DNA damage and irreversible suppression of proliferation accompanied by robust apoptosis. Gene expression analysis revealed distinct genetic profiles of single versus combined agent exposure. Whereas panobinostat increased the expression of the cell cycle inhibitor p21, co-treatment with everolimus abrogated the increase in p21 and synergistically downregulated the expression of DNA repair genes and mitotic checkpoint regulators. Importantly, the combination of panobinostat with everolimus effectively targeted CXCR4-expressing resistant MM cells in vivo in the BM niche. In summary, our results uncover the mechanism responsible for the strong synergistic anti-MM activity of dual HDAC and mTOR inhibition and provide the rationale for a novel potential therapeutic approach to treat MM.
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- 2019
30. Promiscuous Chemokine Antagonist (BKT130) Suppresses Laser-Induced Choroidal Neovascularization by Inhibition of Monocyte Recruitment
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Amnon Peled, Michelle Grunin, Orly Eizenberg, Itay Chowers, Liran Tiosano, Batya Rinsky, Shira Hagbi-Levi, and Michal Abraham
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Male ,Vascular Endothelial Growth Factor A ,CCR2 ,Chemokine ,genetic structures ,Nitric Oxide Synthase Type I ,Monocytes ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Movement ,Immunology and Allergy ,Aflibercept ,Aged, 80 and over ,0303 health sciences ,CD11b Antigen ,biology ,General Medicine ,Middle Aged ,Vascular endothelial growth factor ,Vascular endothelial growth factor A ,Choroidal neovascularization ,medicine.anatomical_structure ,Female ,Chemokines ,medicine.symptom ,Research Article ,medicine.drug ,lcsh:Immunologic diseases. Allergy ,Article Subject ,Receptors, CCR2 ,Recombinant Fusion Proteins ,Immunology ,Retina ,03 medical and health sciences ,medicine ,Animals ,Humans ,Rats, Long-Evans ,Aged ,030304 developmental biology ,Tumor Necrosis Factor-alpha ,business.industry ,Lasers ,Macrophages ,Monocyte ,Choroidal Neovascularization ,eye diseases ,Rats ,Mice, Inbred C57BL ,Receptors, Vascular Endothelial Growth Factor ,chemistry ,030221 ophthalmology & optometry ,Cancer research ,biology.protein ,sense organs ,business ,lcsh:RC581-607 ,Ex vivo - Abstract
Background. Age-related macular degeneration (AMD), the most common cause of blindness in the developed world, usually affects individuals older than 60 years of age. The majority of visual loss in this disease is attributable to the development of choroidal neovascularization (CNV). Mononuclear phagocytes, including monocytes and their tissue descendants, macrophages, have long been implicated in the pathogenesis of neovascular AMD (nvAMD). Current therapies for nvAMD are based on targeting vascular endothelial growth factor (VEGF). This study is aimed at assessing if perturbation of chemokine signaling and mononuclear cell recruitment may serve as novel complementary therapeutic targets for nvAMD. Methods. A promiscuous chemokine antagonist (BKT130), aflibercept treatment, or combined BKT130+aflibercept treatment was tested in an in vivo laser-induced model of choroidal neovascularization (LI-CNV) and in an ex vivo choroidal sprouting assay (CSA). Quantification of CD11b+ cell in the CNV area was performed, and mRNA levels of genes implicated in CNV growth were measured in the retina and RPE-choroid. Results. BKT130 reduced the CNV area and recruitment of CD11b+ cells by 30-35%. No effect of BKT130 on macrophages’ proangiogenic phenotype was demonstrated ex vivo, but a lower VEGFA and CCR2 expression was found in the RPE-choroid and a lower expression of TNFα and NOS1 was found in both RPE-choroid and retinal tissues in the LI-CNV model under treatment with BKT130. Conclusions. Targeting monocyte recruitment via perturbation of chemokine signaling can reduce the size of experimental CNV and should be evaluated as a potential novel therapeutic modality for nvAMD.
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- 2019
31. Role of CXCL12 and CXCR4 in the pathogenesis of hematological malignancies
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Katia Beider, Michal Abraham, Amnon Peled, Jan A. Burger, and Shiri Klein
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0301 basic medicine ,Receptors, CXCR4 ,Stromal cell ,Cell Survival ,Immunology ,Apoptosis ,Biochemistry ,CXCR4 ,Metastasis ,03 medical and health sciences ,Chemokine receptor ,0302 clinical medicine ,hemic and lymphatic diseases ,Glioma ,medicine ,Tumor Microenvironment ,Immunology and Allergy ,Humans ,Molecular Biology ,business.industry ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Prognosis ,Leukemia, Lymphocytic, Chronic, B-Cell ,Chemokine CXCL12 ,Lymphoma ,Leukemia ,Leukemia, Myeloid, Acute ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Hematologic Neoplasms ,Cancer research ,Disease Progression ,Bone marrow ,business ,Multiple Myeloma - Abstract
The chemokine receptor CXCR4 and its ligand stromal cell-derived factor-1 (SDF-1/CXCL12) are important players in the cross-talk among lymphoma, myeloma and leukemia cells and their microenvironments. In hematological malignancies and solid tumors, the overexpression of CXCR4 on the cell surface has been shown to be responsible for disease progression, increasing tumor cell survival and chemoresistance and metastasis to organs with high CXCL12 levels (e.g., lymph nodes and bone marrow (BM)). Furthermore, the overexpression of CXCR4 has been found to have prognostic significance for disease progression in many type of tumors including lymphoma, leukemia, glioma, and prostate, breast, colorectal, renal, and hepatocellular carcinomas. In leukemia, CXCR4 expression granted leukemic blasts a higher capacity to seed into BM niches, thereby protecting leukemic cells from chemotherapy-induced apoptosis, and was correlated with shorter disease-free survival. In contrast, neutralizing the interaction of CXCL12/CXCR4 with a variety of antagonists induced apoptosis and differentiation and increased the chemosensitivity of lymphoma, myeloma, and leukemia cells. The role of CXCL12 and CXCR4 in the pathogenesis of hematological malignancies and the clinical therapeutic potential of CXCR4 antagonists in these diseases is discussed.
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- 2017
32. In the Hunt for Therapeutic Targets: Mimicking the Growth, Metastasis, and Stromal Associations of Early-Stage Lung Cancer Using a Novel Orthotopic Animal Model
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Michal Abraham, Yoav Smith, Sara W. Feigelson, Amnon Peled, Oz M. Shapira, Amir Bar-Shai, Ido D. Weiss, Zippora Shlomai, Uzi Izhar, Ronen Alon, Ezra Ella, Ori Wald, Gideon Zamir, Elias Shezen, Hanna Wald, and Omri Dominsky
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Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,Lung Neoplasms ,Stromal cell ,Transplantation, Heterologous ,Metastasis ,Carcinoma, Lewis Lung ,Mice ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Carcinoma ,medicine ,Animals ,Humans ,Neoplasm Metastasis ,Lung cancer ,Lung ,Tumor microenvironment ,business.industry ,Non–small-cell lung cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,Mice, Inbred C57BL ,Transplantation ,Disease Models, Animal ,medicine.anatomical_structure ,Oncology ,Cancer cell ,Orthotopic animal model ,business - Abstract
Background The existing shortage of animal models that properly mimic the progression of early-stage human lung cancer from a solitary confined tumor to an invasive metastatic disease hinders accurate characterization of key interactions between lung cancer cells and their stroma. We herein describe a novel orthotopic animal model that addresses these concerns and consequently serves as an attractive platform to study tumor–stromal cell interactions under conditions that reflect early-stage lung cancer. Methods Unlike previous methodologies, we directly injected small numbers of human or murine lung cancer cells into murine's left lung and longitudinally monitored disease progression. Next, we used green fluorescent protein-tagged tumor cells and immuno-fluorescent staining to determine the tumor's microanatomic distribution and to look for tumor-infiltrating immune cells and stromal cells. Finally, we compared chemokine gene expression patterns in the tumor and lung microenvironment. Results We successfully generated a solitary pulmonary nodule surrounded by normal lung parenchyma that grew locally and spread distally over time. Notably, we found that both fibroblasts and leukocytes are recruited to the tumor's margins and that distinct myeloid cell attracting and CCR2-binding chemokines are specifically induced in the tumor microenvironment. Conclusion Our orthotopic lung cancer model closely mimics the pathologic sequence of events that characterizes early-stage human lung cancer propagation. It further introduces new means to monitor tumor–stromal cell interactions and offers unique opportunities to test therapeutic targets under conditions that reflect early-stage lung cancer. We argue that for such purposes our model is superior to lung cancer models that are based either on genetic induction of epithelial transformation or on ectopic transplantation of malignant cells.
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- 2015
33. Differences in State Anxiety Responses to Combat Pictures between Young Adult Israeli Jews and Israeli Palestinian Arabs
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Dorit Hadar Souval, Orrie Dan, Yona Moshe David, and Michal Abraham
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Judaism ,media_common.quotation_subject ,Significant group ,Israeli jews ,General Medicine ,State (polity) ,Military operation ,medicine ,Anxiety ,Young adult ,medicine.symptom ,Situational ethics ,Psychology ,Social psychology ,media_common - Abstract
The purpose of the current study was to investigate whether the different political realities of Israeli Jewish citizens and of Israeli Palestinian Arab citizens had differential impacts on the situational anxiety elicited by video clips of military operations. The pictures were taken during the November 2012 Pillar of Defense military operation in Gaza and southern Israel. Participants included 75 (49 female) students at an Israeli college. Of these, 39 were Israeli Jews and 36 were Israeli Arabs. Participants completed the State-Trait Anxiety Inventory (Spielberger, 1983) and then watched a video clip containing combat pictures. After that they completed the State Anxiety Inventory again. The results showed no differences between Israeli Jewish participants and Israeli Palestinian Arab participants on trait anxiety. Analysis revealed a significant group (Israeli Jews/ Israeli Palestinian Arabs) X condition (before/after watching the video clip pictures) interaction effect. Before watching the video clip, the groups exhibited no difference in state anxiety. After watching the clip, the Israeli Palestinian Arab participants showed greater state anxiety compared with the Israeli Jews.
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- 2015
34. Sex Differences in the Effectiveness of Angiotensin‐Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers, and Sacubitril–Valsartan for the Treatment of Heart Failure
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Zahra N. Sohani, Hassan Behlouli, Cristiano Soares de Moura, Michal Abrahamowicz, and Louise Pilote
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heart failure ,observational study ,sacubitril–valsartan ,sex differences ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Background PARAGON‐HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) suggested a potential benefit of sacubitril–valsartan in women with preserved ejection fraction. Among patients with heart failure previously treated with angiotensin‐converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), we studied whether effectiveness of treatment with sacubitril–valsartan compared with ACEI/ARB monotherapy differed between men and women for both preserved and reduced ejection fraction. Methods and Results Data were derived from the Truven Health MarketScan Databases between January 1, 2011, and December 31, 2018. We included patients with a primary diagnosis of heart failure on treatment with ACEIs, ARBs, or sacubitril–valsartan on the basis of the first prescription after diagnosis. A total of 7181 patients treated with sacubitril–valsartan, 25 408 patients using an ACEI, and 16 177 patients treated with ARBs were included. A total of 790 readmissions or deaths occurred among 7181 patients in the sacubitril–valsartan group and 11 901 events in 41 585 patients treated with an ACEI/ARB. Adjusted for covariates, the hazard ratio (HR) for treatment with sacubitril–valsartan compared with an ACEI or ARB was 0.74 (95% CI, 0.68–0.80). The protective effect of sacubitril–valsartan was evident for men and women (women: HR, 0.75 [95% CI, 0.66–0.86]; P
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- 2023
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35. Natural and induced immunization against CCL20 ameliorate experimental autoimmune encephalitis and may confer protection against multiple sclerosis
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Amnon Peled, Karin Mausner-Fainberg, Arnon Karni, Ido D. Weiss, and Michal Abraham
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0301 basic medicine ,Receptors, CCR6 ,Multiple Sclerosis ,T-Lymphocytes ,Immunology ,chemical and pharmacologic phenomena ,Peptide ,C-C chemokine receptor type 6 ,Hashimoto Disease ,Biology ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,medicine ,Cell Adhesion ,Immunology and Allergy ,Animals ,Autoimmune encephalitis ,chemistry.chemical_classification ,Mice, Knockout ,Mice, Inbred BALB C ,Chemokine CCL20 ,Multiple sclerosis ,Computational Biology ,hemic and immune systems ,respiratory system ,medicine.disease ,Vaccination ,CCL20 ,030104 developmental biology ,chemistry ,biology.protein ,bacteria ,Encephalitis ,Female ,Immunization ,Protein A ,030217 neurology & neurosurgery - Abstract
Th-17 type immune response that occurs in multiple sclerosis (MS) is linked to CCR6-CCL20 interaction. We confirmed the dependency on CCR6 in EAE development. Vaccination of mice with hCCL20, but not mCCL20, produced anti-murine CCL20 and ameliorated EAE. The EAE clinical score negatively correlated with anti CCL20 levels. A beneficial effect was transferred by sera from hCCL20-immunized mice. Immunized mice with cyclic peptide that include a bacterial outer membrane protein A (ompA), that share homology sequence with hCCL20 produced anti CCL20, anti ompA and anti-cyclic peptide. Immunization of mice with ompA or the cyclic peptide ameliorated EAE. The cyclic peptide inhibited CCL20 activity in an adhesion assay. A significantly higher level of anti CCL20 were found in healthy individuals compared to RR-MS patients. There was no similar difference for anti-CXCL10. Natural or induced immunization against CCL20 confer protection against EAE and may be beneficial in MS.
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- 2017
36. CXCR4 Promotes Neuroblastoma Growth and Therapeutic Resistance through miR-15a/16-1-Mediated ERK and BCL2/Cyclin D1 Pathways
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Baruch Bulvik, Yaron Pereg, Shiri Klein, Neta Barashi, Michal Abraham, Lola Weiss, Katia Beider, Eithan Galun, Devorah Olam, Yaniv Harel, Rinat Abramovitch, Elia Dery, Amnon Peled, Hanna Wald, Orly Eizenberg, Ido D. Weiss, and Ori Wald
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Cancer Research ,Programmed cell death ,Receptors, CXCR4 ,Combination therapy ,MAP Kinase Signaling System ,medicine.disease_cause ,03 medical and health sciences ,Mice ,Neuroblastoma ,0302 clinical medicine ,Cyclin D1 ,Downregulation and upregulation ,Cell Line, Tumor ,Medicine ,Animals ,Humans ,CXCR4 antagonist ,business.industry ,Brain Neoplasms ,medicine.disease ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,Oncology ,Proto-Oncogene Proteins c-bcl-2 ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,business ,Carcinogenesis ,Peptides - Abstract
CXCR4 expression in neuroblastoma tumors correlates with disease severity. In this study, we describe mechanisms by which CXCR4 signaling controls neuroblastoma tumor growth and response to therapy. We found that overexpression of CXCR4 or stimulation with CXCL12 supports neuroblastoma tumorigenesis. Moreover, CXCR4 inhibition with the high-affinity CXCR4 antagonist BL-8040 prevented tumor growth and reduced survival of tumor cells. These effects were mediated by the upregulation of miR-15a/16-1, which resulted in downregulation of their target genes BCL-2 and cyclin D1, as well as inhibition of ERK. Overexpression of miR-15a/16-1 in cells increased cell death, whereas antagomirs to miR-15a/16-1 abolished the proapoptotic effects of BL-8040. CXCR4 overexpression also increased miR-15a/16-1, shifting their oncogenic dependency from the BCL-2 to the ERK signaling pathway. Overall, our results demonstrate the therapeutic potential of CXCR4 inhibition in neuroblastoma treatment and provide a rationale to test combination therapies employing CXCR4 and BCL-2 inhibitors to increase the efficacy of these agents. Significance: These results provide a mechanistic rationale for combination therapy of CXCR4 and BCL-2 inhibitors to treat a common and commonly aggressive pediatric cancer.Cancer Res; 78(6); 1471–83. ©2017 AACR.
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- 2017
37. Multiple myeloma cells recruit tumor-supportive macrophages through the CXCR4/CXCL12 axis and promote their polarization toward the M2 phenotype
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Amnon Peled, Odit Gutwein, Hanna Wald, Katia Beider, Olga Ostrovsky, Arnon Nagler, Eithan Galun, Maya Koren-Michowitz, Hanna Bitner, Michal Abraham, and Merav Leiba
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Adult ,Male ,Chemokine ,Receptors, CXCR4 ,Stromal cell ,Macrophage polarization ,Apoptosis ,Cell Line, Tumor ,medicine ,M2 macrophages ,Humans ,Scavenger receptor ,Aged ,Cell Proliferation ,CXCR4 ,biology ,Monocyte ,Macrophages ,Cell Polarity ,Middle Aged ,MM ,Molecular biology ,Chemokine CXCL12 ,medicine.anatomical_structure ,Phenotype ,Oncology ,Immunology ,biology.protein ,Tumor necrosis factor alpha ,Female ,Bone marrow ,Multiple Myeloma ,CD163 ,Research Paper ,Signal Transduction - Abstract
// Katia Beider 1 , Hanna Bitner 1 , Merav Leiba 1 , Odit Gutwein 1 , Maya Koren-Michowitz 1 , Olga Ostrovsky 1 , Michal Abraham 3 , Hanna Wald 3 , Eithan Galun 2 , Amnon Peled 2 and Arnon Nagler 1 1 Hematology Division and CBB, Guy Weinshtock Multiple Myeloma Foundation, Chaim Sheba Medical Center, Tel-Hashomer, Israel 2 Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel 3 Biokine Therapeutics Ltd., Science Park, Ness Ziona, Israel Correspondence: Arnon Nagler, email: // Keywords : MM, M2 macrophages, CXCR4 Received : May 21, 2014 Accepted : July 11, 2014 Published : July 12, 2014 Abstract Multiple myeloma (MM) cells specifically attract peripheral-blood monocytes, while interaction of MM with bone marrow stromal cells ( BMSCs) significantly increased monocyte recruitment (p
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- 2014
38. System-level performance measures of access to rheumatology care: a population-based retrospective study of trends over time and the impact of regional rheumatologist supply in Ontario, Canada, 2002–2019
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Claire E. H. Barber, Diane Lacaille, Ruth Croxford, Cheryl Barnabe, Deborah A. Marshall, Michal Abrahamowicz, Hui Xie, J. Antonio Avina-Zubieta, John M. Esdaile, Glen Hazlewood, Peter Faris, Steven Katz, Paul MacMullan, Dianne Mosher, and Jessica Widdifield
- Subjects
Rheumatoid arthritis ,Quality care ,Access to care ,Performance measure ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
Abstract Objective To determine whether there were improvements in rheumatology care for rheumatoid arthritis (RA) between 2002 and 2019 in Ontario, Canada, and to evaluate the impact of rheumatologist regional supply on access. Methods We conducted a population-based retrospective study of all individuals diagnosed with RA between January 1, 2002 and December 31, 2019. Performance measures evaluated were: (i) percentage of RA patients seen by a rheumatologist within one year of diagnosis; and (ii) percentage of individuals with RA aged 66 years and older (whose prescription drugs are publicly funded) dispensed a disease modifying anti-rheumatic drug (DMARD) within 30 days after initial rheumatologist visit. Logistic regression was used to assess whether performance improved over time and whether the improvements differed by rheumatology supply, dichotomized as
- Published
- 2022
- Full Text
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39. External Validation of the Lupus Multivariable Outcome Score for Systemic Lupus Erythematosus Trials
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Michal Abrahamowicz, Maria Izabela Abrahamowicz, and Peter E. Lipsky
- Subjects
Diseases of the musculoskeletal system ,RC925-935 - Abstract
Objective Development of new systemic lupus erythematosus (SLE) treatments requires an effective responder index. Toward this end, we have recently developed a new Lupus Multivariable Outcome Score (LuMOS) to optimize discrimination between actively treated patients and those on placebo. We now report on external validation of LuMOS in two independent clinical trials. Methods Validation was performed with the Illuminate data sets that evaluated tabalumab (TB) in SLE. To accommodate laboratory results assessed on different platforms, we developed a standardized LuMOS 2.0 model that uses z score transformations of biomarker values. For validation, we calculated LuMOS 2.0 scores at week 52 for all participants. Effect size (ES), with 95% confidence intervals (CIs), compared the ability of LuMOS and the SLE Responder Index‐5 (SRI‐5) to discriminate between outcomes in patients randomized to TB dosage and outcomes in those randomized to a placebo. Results Mean LuMOS 2.0 scores were significantly higher (P 0.4) in contrast to weak SRI‐5 effects (
- Published
- 2022
- Full Text
- View/download PDF
40. A Population‐Based Study Evaluating Retention in Rheumatology Care Among Patients With Rheumatoid Arthritis
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Claire E. H. Barber, Diane Lacaille, Ruth Croxford, Cheryl Barnabe, Deborah A. Marshall, Michal Abrahamowicz, Hui Xie, J. Antonio Avina‐Zubieta, John M. Esdaile, Glen Hazlewood, Peter Faris, Steven Katz, Paul MacMullan, Dianne Mosher, and Jessica Widdifield
- Subjects
Diseases of the musculoskeletal system ,RC925-935 - Abstract
Objective The study objective was to assess adherence to system‐level performance measures measuring retention in rheumatology care and disease modifying anti‐rheumatic drug (DMARD) treatment in rheumatoid arthritis (RA). Methods We used a validated health administrative data case definition to identify individuals with RA in Ontario, Canada, between 2002 and 2014 who had at least 5 years of potential follow‐up prior to 2019. During the first 5 years following diagnosis, we assessed whether patients were seen by a rheumatologist yearly and the proportion dispensed a DMARD yearly (in those aged ≥66 for whom medication data were available). Multivariable logistic regression analyses were used to estimate the odds of remaining under rheumatologist care. Results The cohort included 50,883 patients with RA (26.1% aged 66 years and older). Over half (57.7%) saw a rheumatologist yearly in all 5 years of follow‐up. Sharp declines in the percentage of patients with an annual visit were observed in each subsequent year after diagnosis, although a linear trend to improved retention in rheumatology care was seen over the study period (P
- Published
- 2022
- Full Text
- View/download PDF
41. Inflammation-induced hepatocellular carcinoma is dependent on CCR5 in mice
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Hanna Wald, Shiri Klein, Katia Beider, Evelyne Zeira, Michal Abraham, Ido D. Weiss, Daniel Goldenberg, Neta Barashi, Amnon Peled, Eli Pikarsky, Rinat Abramovitch, Jonathan H. Axelrod, Eithan Galun, and Ori Wald
- Subjects
Liver Cirrhosis ,CCR1 ,ATP Binding Cassette Transporter, Subfamily B ,Carcinoma, Hepatocellular ,Receptors, CCR5 ,Receptors, CCR1 ,Inflammation ,Biology ,medicine.disease_cause ,Mice ,Chemokine receptor ,Fibrosis ,medicine ,Animals ,Chemokine CCL5 ,Hepatitis, Chronic ,Mice, Knockout ,Hepatology ,Incidence ,Liver Neoplasms ,Cancer ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,Liver ,Hepatocellular carcinoma ,Immunology ,Disease Progression ,Cancer research ,medicine.symptom ,Liver cancer ,Carcinogenesis - Abstract
Human hepatocellular carcinoma (HCC) is an inflammation-induced cancer, which is the third-leading cause of cancer mortality worldwide. We investigated the role of the chemokine receptors, CCR5 and CCR1, in regulating inflammation and tumorigenesis in an inflammation-induced HCC model in mice. Multidrug resistance 2 gene (Mdr2)-knockout (Mdr2-KO) mice spontaneously develop chronic cholestatic hepatitis and fibrosis that is eventually followed by HCC. We generated two new strains from the Mdr2-KO mouse, the Mdr2:CCR5 and the Mdr2:CCR1 double knockouts (DKOs), and set out to compare inflammation and tumorigenesis among these strains. We found that in Mdr2-KO mice lacking the chemokine receptor, CCR5 (Mdr2:CCR5 DKO mice), but not CCR1 (Mdr2:CCR1 DKO), macrophage recruitment and trafficking to the liver was significantly reduced. Furthermore, in the absence of CCR5, reduced inflammation was also associated with reduced periductal accumulation of CD24+ oval cells and abrogation of fibrosis. DKO mice for Mdr2 and CCR5 exhibited a significant decrease in tumor incidence and size. Conclusions: Our results indicate that CCR5 has a critical role in both the development and progression of liver cancer. Therefore, we propose that a CCR5 antagonist can serve for HCC cancer prevention and treatment. (Hepatology 2013;53:1021–1030)
- Published
- 2013
42. Ccr5 deficiency regulates the proliferation and trafficking of natural killer cells under physiological conditions
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Ido D. Weiss, Katia Beider, Eithan Galun, Neta Barashi, Ori Wald, Arnon Nagler, Hadas Shoham, Michal Abraham, Hanna Wald, and Amnon Peled
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Chemokine ,Receptors, CCR5 ,Immunology ,Apoptosis ,Biology ,Models, Biological ,Biochemistry ,CD49b ,Interferon-gamma ,Mice ,Interleukin 21 ,NK-92 ,Cell Movement ,medicine ,Animals ,Immunology and Allergy ,Interferon gamma ,Lymphocytes ,Molecular Biology ,Cell Proliferation ,Lymphokine-activated killer cell ,Janus kinase 3 ,Hematology ,Cell biology ,Killer Cells, Natural ,Mice, Inbred C57BL ,Phenotype ,Poly I-C ,Gene Expression Regulation ,Liver ,Virus Diseases ,Interleukin 12 ,biology.protein ,Female ,Spleen ,medicine.drug - Abstract
Chemokines were shown to govern the trafficking of immune cells and may also play important roles in the survival and activation of these cells. We report here that under physiological conditions, the bone marrow (BM), spleen, blood and liver of Ccr5, but not of Ccr1-deficient mice, contain reduced numbers of NK cells. NK cells in the BM of Ccr5-deficient mice proliferate to a lesser extent compared to WT mice. Furthermore, spleen NK cells derived from Ccr5-deficient mice that were transplanted into irradiated recipients failed to proliferate in the host. Ccr5, but not Ccr1-deficient NK cells, failed to migrate in vitro in response to RANTES and MIP-1β but not MIP-1β or SDF-1 and had reduced activation, lower expression levels of NK cell markers and a slightly reduced capacity to adhere to target cells and stimulate their killing. Using the polyI:C mouse model for NK trafficking, we found that in the absence of Ccr5, but not Ccr1, NK cells failed to accumulate in the liver. In contrast, using the influenza viral infection as a model to evaluate NK cell proliferation, we found that Ccr5-deficient NK cells in the BM had a higher proliferation rate than WT NK cells. These results suggest a role for Ccr5 in NK cell proliferation and circulation under physiological conditions and a complex role for Ccr5 in determining the fate of NK cells under pathological conditions.
- Published
- 2011
43. IFN-γ Treatment at Early Stages of Influenza Virus Infection Protects Mice from Death in a NK Cell-Dependent Manner
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Eithan Galun, Amnon Peled, Ido D. Weiss, Hanna Wald, Arnon Nagler, Ori Wald, Katia Beider, and Michal Abraham
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Cytotoxicity, Immunologic ,T-Lymphocytes ,medicine.medical_treatment ,Immunology ,Cell Count ,Spleen ,Inflammation ,Biology ,Lymphocyte Depletion ,Virus ,Immunophenotyping ,Interferon-gamma ,Mice ,Orthomyxoviridae Infections ,Virology ,medicine ,Animals ,Lung ,Cell Proliferation ,Hemagglutination Tests ,Cell Biology ,Viral Load ,Natural killer T cell ,Killer Cells, Natural ,Mice, Inbred C57BL ,Vaccination ,medicine.anatomical_structure ,Cytokine ,Influenza A virus ,Bone marrow ,medicine.symptom - Abstract
Influenza pandemics are imminent and represent a major world health concern. Since vaccinations are expected to be less efficient in the coming years due to newly emerging influenza virus strains, novel antiviral therapies are urgently needed. Here, we show that influenza-infected mice, capable of clearing the virus in the early stages of infection, failed to control inflammation and death. Sequential administration of Interferon-gamma (IFN-gamma) at early stage of the infection protected infected mice from death in a NK cell-dependent manner. IFN-gamma treatment stimulated NK cell proliferation and function and increased their number in the bone marrow, blood, spleen, and infected lungs, keeping viral clearance intact. In parallel, IFN-gamma treatment significantly reduced the number of T cells and NKT cells in the lungs at the inflammatory phase following infection. Thus, rapidly clearing the virus and reducing inflammation by shaping the cellular and cytokine profiles in the early stages of infection may favorably change the fate of influenza pathogenesis.
- Published
- 2010
44. Matrix metalloproteinase 12 promotes tumor propagation in the lung
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Ofra Benny, David Yoon, Uzi Izhar, Ori Wald, Hyun-Sung Lee, Oz M. Shapira, Hanna Wald, Ezra Ella, Adi Karsch-Bluman, Yaniv Harel, Dive Vincent, Amnon Peled, Bryan M. Burt, Michal Abraham, David J. Sugarbaker, Gail Amir, and Devel Laurent
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Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Lung Neoplasms ,Context (language use) ,Endogeny ,Matrix metalloproteinase ,medicine.disease_cause ,Gene Expression Regulation, Enzymologic ,Carcinoma, Lewis Lung ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Matrix Metalloproteinase 12 ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,Lung cancer ,Mice, Knockout ,Tumor microenvironment ,Lung ,business.industry ,Lewis lung carcinoma ,respiratory system ,medicine.disease ,respiratory tract diseases ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Surgery ,Cardiology and Cardiovascular Medicine ,Carcinogenesis ,business ,Signal Transduction - Abstract
Objective Past studies are inconsistent with regard to the role of matrix metalloproteinase 12 in lung tumorigenesis. This is due, in part, to differential tumorigenesis based on tumor-derived versus immune-derived matrix metalloproteinase 12 expression. Our study aims to thoroughly dissect the role of matrix metalloproteinase 12 in lung tumorigenesis. Methods We tested matrix metalloproteinase 12 expression and the association with prognosis using a tissue array and a published non–small cell lung cancer gene expression database. In addition, we characterized the contribution of matrix metalloproteinase 12 to tumor propagation in the lung using a series of in vitro and in vivo studies. Results Tumor cells of a diverse set of human lung cancers stained positive for matrix metalloproteinase 12, and high matrix metalloproteinase 12 mRNA levels in the tumor were associated with reduced survival. The lung microenvironment stimulated endogenous production of matrix metalloproteinase 12 in lung cancer cells (human 460 lung cancer cell line, Lewis lung carcinoma). In vitro, matrix metalloproteinase 12 knockout Lewis lung carcinoma and Lewis lung carcinoma cells had the same proliferation rate, but Lewis lung carcinoma showed increased invasiveness. In vivo, deficiency of matrix metalloproteinase 12 in Lewis lung carcinoma cells, but not in the host, reduced tumor growth and invasiveness. Conclusions We suggest that tumor cell–derived matrix metalloproteinase 12 promotes tumor propagation in the lung and that in the context of pulmonary malignancies matrix metalloproteinase 12 should further be tested as a potential novel therapeutic target.
- Published
- 2018
45. Apograft, a Novel Stem Cell Selection Technology, Prevents Graft vs. Host Disease (GvHD) While Preserving Graft vs Leukemia (GvL) Effects
- Author
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Tsila Zuckerman, Jerry Stein, Liat Pinkas, Alex Saar, Amotz Nechushtan, Isaac Yaniv, Jacob M. Rowe, Yuval Baar, Inbal Mishalian, Tami Katz, Shai Yarkoni, Hilit Levy-Barazany, Amnon Peled, Yaron Pereg, Michal Abraham, and Hila Wildbaum
- Subjects
Transplantation ,Leukemia ,business.industry ,Immunology ,Medicine ,Hematology ,Stem cell ,business ,medicine.disease ,Host disease ,Selection (genetic algorithm) - Published
- 2018
46. The CXCR4 Antagonist BL-8040 Induces a Robust Mobilization of CD34+CD38−CD45RA−CD90+ CD49f+ HSCs with Long-Term and Secondary Myeloid and Lymphoid Repopulating Activity
- Author
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Reuven Or, Orly Eizenberg, Klein Shiri, Eyal Benami, Rotem Golan, Galia Oberkovitz, Eithan Galun, Arnon Nagler, Katia Beider, Baruch Bulvik, Abi Vainstein, Yoseph Caraco, Hanna Wald, Amnon Peled, and Michal Abraham
- Subjects
0301 basic medicine ,Myeloid ,Chemistry ,Immunology ,CD34 ,hemic and immune systems ,Cell Biology ,Hematology ,CD38 ,Biochemistry ,Molecular biology ,Transplantation ,03 medical and health sciences ,Haematopoiesis ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,medicine ,CD90 ,Progenitor cell ,Stem cell - Abstract
Introduction: Lifelong blood cell production is dependent on rare hematopoietic stem cells (HSCs) to perpetually replenish mature cells via a series of lineage-restricted intermediates. The bulk of HSCs are CD34+, however, most CD34+ cells are lineage-restricted progenitors and HSCs remain rare. HSCs can be enriched further based on CD45RA, Thy1 (CD90), and CD38 expression. Loss of CD90 expression was proposed to be sufficient to separate CD34+CD38−CD45RA− CD90+ HSCs from CD34+CD38−CD45RA− CD90- multipotent progenitors (MPPs). Recently, it was demonstrated that the expression CD49f is a specific HSC marker. Single CD49f(+) cells were highly efficient in generating long-term multilineage grafts, and the loss of CD49f expression identified transiently engrafting MPPs. Results: CD34+ cells were purified from BL-8040 and G-CSF mobilized grafts and stained for CD38, CD45RA, CD90, and CD49f. The percentage of CD34+CD38- hematopoietic stem and progenitors was similar in both grafts (Figure 1A). However, whereas 23.2 % of BL-8040 mobilized CD34+ CD38- cells did not express CD45RA; only 1.6% of G-CSF mobilized CD34+ CD38- cells did not express CD45RA (Figure 1B). The percentages of CD34+CD38−CD45RA−CD49f+CD90+/-, CD34+CD38−CD45RA−CD49f+ CD90+, and CD34+CD38−CD45RA− CD90+ HPCS were increased significantly by 45, 25 and 12 -fold in the BL-8040 graft compared to G-CSF graft derived CD34+CD38- cells (Figure 1C). To assess the long-term engraftment potential of the BL-8040 mobilized CD34+ cells, engraftment was allowed for 4, 8, and 22 weeks after transplantation. Successful and robust long-term human engraftment of CD45+ and CD45+CD34+ cells was observed at week 22 (Figure 2A, 2B). The % of human CD45 cells remained stable in the BM whereas the percentage of CD45 cells in the blood and spleen increased at week 22 (Figure 2C). At 4 weeks, human CD3+CD4+ T cells were only observed at a low percentage in the spleen but not in the BM, whereas no significant percentage of CD3+CD8+ cells were found neither in the BM nor in the spleen (Figure 2D, 2E). 22 weeks after transplantation, the percentage of human CD3+CD4+ and CD3+CD8+ T cells was significantly increased in the spleen (30% vs. 5%, respectively) and to much lower levels in the BM (Figure 2D, 2E). Furthermore, successful and robust long-term human engraftment of secondary recipient was observed 14 weeks following the second transplantation (Figure 2A and 2B). Conclusion: In association with the high percentage of HPCs in the BL-8040-derived graft, we found a robust myeloid and lymphoid long-term engraftment (week 22) of BL-8040 mobilized human CD34+ cells in NSG mice. The ability of BL-8040 to collect high numbers of HPCs may be beneficial for a variety of HPCs dependent therapeutics. Disclosures Abraham: Biokine: Employment. Oberkovitz: BiolineRx: Employment. Eizenberg: Biokine: Employment. Vainstein: BiolineRx: Employment. Benami: BiolineRx: Employment. Golan: BiolineRx: Employment. Or: Bioline: Consultancy. Peled: Biokine: Consultancy; Biosight: Consultancy.
- Published
- 2017
47. The CXCR4 antagonist 4F-benzoyl-TN14003 stimulates the recovery of the bone marrow after transplantation
- Author
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Ido D. Weiss, Peled A, Dov Zipori, O. Eizenberg, Eithan Galun, Hanna Wald, Katia Beider, Michal Abraham, and Arnon Nagler
- Subjects
Benzylamines ,Receptors, CXCR4 ,Cancer Research ,medicine.medical_specialty ,Neutropenia ,Stromal cell ,Drug Evaluation, Preclinical ,Integrin alpha4beta1 ,Biology ,Cyclams ,Colony-Forming Units Assay ,Mice ,Bone Marrow ,Heterocyclic Compounds ,Internal medicine ,medicine ,Animals ,Progenitor cell ,Cyclophosphamide ,Cytopenia ,Hematology ,Plerixafor ,Graft Survival ,Recovery of Function ,Hematopoietic Stem Cells ,medicine.disease ,Coculture Techniques ,Hematopoietic Stem Cell Mobilization ,Specific Pathogen-Free Organisms ,Mice, Inbred C57BL ,Transplantation ,medicine.anatomical_structure ,Matrix Metalloproteinase 9 ,Oncology ,Radiation Chimera ,Immunology ,Cancer research ,Female ,Bone marrow ,Stromal Cells ,Stem cell ,Peptides ,Cell Division ,medicine.drug - Abstract
Cytopenia represents a significant complication after chemotherapy, irradiation before bone marrow (BM) transplantation or as a therapy for cancer. The mechanisms that determine the pace of BM recovery are not fully understood. During the recovery phase after chemotherapy or irradiation, the signals for retention of white blood cells within the BM increase significantly. This leads to a delay in the release of WBC, which can be overcome by targeting the CXCR4 axis with the antagonist 4F-benzoyl-TN14003 (T140). The delay in the release of WBC is also accompanied by suppression in the production of progenitor cells and mature cells by the BM stroma. Administration of T140 to mice transplanted with BM cells stimulates the production of all types of progenitors and mature cells, and increases the exit of mature cells to the periphery. Moreover, addition of T140, but not AMD3100, to BM stromal cultures stimulates the production of mature cells and progenitors from all lineages. The unique ability of the CXCR4 antagonist, T140 to stimulate the production and exit of WBC cells may be used as a novel therapeutic approach to overcome cytopenia associated with treatments for cancer and BM transplantation.
- Published
- 2009
48. In vitro induction of regulatory T cells by anti-CD3 antibody in humans
- Author
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Adi Dembinsky, David E. Anderson, Roopali Gandhi, Howard L. Weiner, Arnon Karni, Ariel Miller, and Michal Abraham
- Subjects
CD4-Positive T-Lymphocytes ,CD3 Complex ,Immunology ,Antigen-Presenting Cells ,Apoptosis ,Biology ,Lymphocyte Activation ,T-Lymphocytes, Regulatory ,Antibodies ,Article ,Interferon-gamma ,Interleukin 21 ,T-Lymphocyte Subsets ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,IL-2 receptor ,Antigen-presenting cell ,CD28 ,hemic and immune systems ,Natural killer T cell ,Molecular biology ,Interleukin 12 ,Cytokines ,CD80 - Abstract
Therapy with anti-CD3 antibody is effective in controlling models of autoimmune diseases and can reverse or prevent rejection of grafts. We studied the in vitro immunomodulatory effect of anti-CD3 treated human T cells. CD4(+) T cells were stimulated with plate-bound anti-CD3 and cultured for 12 days after which they were cultured with autologous peripheral blood mononuclear cells (PBMCs) and stimulated with soluble anti-CD3. We found that CD4(+) T cells that were stimulated with anti-CD3 (T(alphaCD3)) markedly suppressed the proliferation and cytokine production of autologous PBMCs. These regulatory T cells were not induced by incubation with isotype control (T(control)) antibody or when anti-CD3 was combined with high doses of anti-CD28 (T(alphaCD3/CD28)). T(alphaCD3) regulatory cells were anergic and produced lower levels of IFN-gamma, TNF-alpha and IL-2, and higher levels of TGF-beta than T(control) or T(alphaCD3/CD28). There were no differences in the expression of CD25 or CTLA4 on T(alphaCD3) as compared to T(control) or T(alphaCD3/CD28), and CD4(+) CD25(-) T(alphaCD3) cells were identical to CD4(+) CD25(+) T(alphaCD3) cells in their in vitro suppressive properties. Recombinant IL-2 in vitro abrogated the suppressive effect of T(alphaCD3). The suppressive effect was not related to apoptosis, was independent of HLA since T(alphaCD3) also suppressed allogeneic PBMCs, and was not related to soluble factors. Finally, no suppression was observed when non-T cells were removed from culture or when cultures were stimulated with plate-bound anti-CD3, consistent with the ability of T(alphaCD3) to downregulate CD80 on dendritic cells in co-culture experiments. Thus, we have identified human T cells with strong in vitro regulatory properties induced in vitro by anti-CD3 which appear to act in a non-HLA restricted fashion by affecting antigen presenting cells.
- Published
- 2008
49. Innate Immunity in Multiple Sclerosis: Myeloid Dendritic Cells in Secondary Progressive Multiple Sclerosis Are Activated and Drive a Proinflammatory Immune Response
- Author
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Howard L. Weiner, Samia J. Khoury, Arnon Karni, Michal Abraham, Gordon J. Freeman, Alon Monsonego, Guifang Cai, and David A. Hafler
- Subjects
Adult ,Male ,Myeloid ,Immunology ,chemical and pharmacologic phenomena ,Inflammation ,Leukocyte Count ,Immune system ,medicine ,Humans ,Immunology and Allergy ,CD40 Antigens ,Cells, Cultured ,Autoimmune disease ,Innate immune system ,CD40 ,biology ,Tumor Necrosis Factor-alpha ,Multiple sclerosis ,hemic and immune systems ,Dendritic Cells ,Middle Aged ,Multiple Sclerosis, Chronic Progressive ,medicine.disease ,Interleukin-12 ,Immunity, Innate ,CD11c Antigen ,Up-Regulation ,medicine.anatomical_structure ,biology.protein ,Female ,Inflammation Mediators ,medicine.symptom ,CD80 - Abstract
Multiple sclerosis (MS) is postulated to be a T cell-mediated autoimmune disease characterized clinically by a relapsing-remitting (RR) stage followed by a secondary progressive (SP) phase. The progressive phase is felt to be secondary to neuronal degenerative changes triggered by inflammation. The status of the innate immune system and its relationship to the stages of MS is not well understood. Dendritic cells (DCs) are professional APCs that are central cells of the innate immune system and have the unique capacity to induce primary immune responses. We investigated circulating myeloid DCs isolated directly from the blood to determine whether there were abnormalities in myeloid DCs in MS and whether they were related to disease stage. We found that SP-MS subjects had an increased percentage of DCs expressing CD80, a decreased percentage expressing PD-L1, and an increased percentage producing IL-12 and TNF-α compared with RR-MS or controls. A higher percentage of DCs from both RR and SP-MS patients expressed CD40 compared with controls. We then investigated the polarization effect of DCs from MS patients on naive T cells taken from cord blood using a MLR assay. Whereas DCs from RR-MS induced higher levels of Th1 (IFN-γ, TNF-α) and Th2 (IL-4, IL-13) cytokines compared with controls, DCs from SP-MS only induced a polarized Th1 response. These results demonstrate abnormalities of DCs in MS and may explain the immunologic basis for the different stages and clinical patterns of MS.
- Published
- 2006
50. Oral CD3-specific antibody suppresses autoimmune encephalomyelitis by inducing CD4+CD25−LAP+ T cells
- Author
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Alexandre S. Basso, Hiroki Ishikawa, Hirofumi Ochi, Howard L. Weiner, Michal Abraham, Mei-Ling Chen, Ariel Miller, Ruth Maron, Henry Wu, Dan Frenkel, Roopali Gandhi, and Kaiyong Yang
- Subjects
CD4-Positive T-Lymphocytes ,Adoptive cell transfer ,Encephalomyelitis, Autoimmune, Experimental ,CD3 Complex ,medicine.medical_treatment ,Administration, Oral ,General Biochemistry, Genetics and Molecular Biology ,Mice ,Immune system ,Antigen ,T-Lymphocyte Subsets ,Transforming Growth Factor beta ,Cricetinae ,Animals ,Humans ,Medicine ,IL-2 receptor ,Immunologic Tolerance ,Mice, Inbred BALB C ,biology ,business.industry ,Antibodies, Monoclonal ,Receptors, Interleukin-2 ,General Medicine ,Immunotherapy ,Adoptive Transfer ,Mice, Inbred C57BL ,Transplantation ,Immunology ,biology.protein ,Female ,Antibody ,Peptides ,business - Abstract
A major goal of immunotherapy for autoimmune diseases and transplantation is induction of regulatory T cells that mediate immunologic tolerance. The mucosal immune system is unique, as tolerance is preferentially induced after exposure to antigen, and induction of regulatory T cells is a primary mechanism of oral tolerance. Parenteral administration of CD3-specific monoclonal antibody is an approved therapy for transplantation in humans and is effective in autoimmune diabetes. We found that orally administered CD3-specific antibody is biologically active in the gut and suppresses autoimmune encephalomyelitis both before induction of disease and at the height of disease. Orally administered CD3-specific antibody induces CD4+ CD25- LAP+ regulatory T cells that contain latency-associated peptide (LAP) on their surface and that function in vitro and in vivo through a TGF-beta-dependent mechanism. These findings identify a new immunologic approach that is widely applicable for the treatment of human autoimmune conditions.
- Published
- 2006
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