scholarly journals Efficacy and safety of CDX-301, recombinant human Flt3L, at expanding dendritic cells and hematopoietic stem cells in healthy human volunteers

2015 ◽  
Vol 50 (7) ◽  
pp. 924-930 ◽  
Author(s):  
N Anandasabapathy ◽  
G Breton ◽  
A Hurley ◽  
M Caskey ◽  
C Trumpfheller ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dendritic Cells ◽  
Hematopoietic Stem Cells ◽  
Efficacy And Safety ◽  
Healthy Human ◽  
Hematopoietic Stem ◽  
Human Volunteers

Endothelial stroma programs hematopoietic stem cells to differentiate into regulatory dendritic cells through IL-10

Blood ◽  
2006 ◽  
Vol 108 (4) ◽  
pp. 1189-1197 ◽  
Author(s):  
Hua Tang ◽  
Zhenhong Guo ◽  
Minghui Zhang ◽  
Jianli Wang ◽  
Guoyou Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Hematopoietic Stem Cells ◽  
Critical Role ◽  
Regulatory Function ◽  
Hematopoietic Stem ◽  
Regulatory Dendritic Cells

Abstract Regulatory dendritic cells (DCs) have been reported recently, but their origin is poorly understood. Our previous study demonstrated that splenic stroma can drive mature DCs to proliferate and differentiate into regulatory DCs, and their natural counterpart with similar regulatory function in normal spleens has been identified. Considering that the spleen microenvironment supports hematopoiesis and that hematopoietic stem cells (HSCs) are found in spleens of adult mice, we wondered whether splenic microenvironment could differentiate HSCs into regulatory DCs. In this report, we demonstrate that endothelial splenic stroma induce HSCs to differentiate into a distinct regulatory DC subset with high expression of CD11b but low expression of Ia. CD11bhiIalo DCs secreting high levels of TGF-β, IL-10, and NO can suppress T-cell proliferation both in vitro and in vivo. Furthermore, CD11bhiIalo DCs have the ability to potently suppress allo-DTH in vivo, indicating their preventive or therapeutic perspectives for some immunologic disorders. The inhibitory function of CD11bhiIalo DCs is mediated through NO but not through induction of regulatory T (Treg) cells or T-cell anergy. IL-10, which is secreted by endothelial splenic stroma, plays a critical role in the differentiation of the regulatory CD11bhiIalo DCs from HSCs. These results suggest that splenic microenvironment may physiologically induce regulatory DC differentiation in situ.

scholarly journals Mobilization of Hematopoietic Stem Cells with Lenograstim in Healthy Donors: Efficacy and Safety Analysis According to Donor Age

2015 ◽  
Vol 21 (5) ◽  
pp. 881-888 ◽  
Author(s):  
Massimo Martino ◽  
Erminio Bonizzoni ◽  
Tiziana Moscato ◽  
Anna Grazia Recchia ◽  
Roberta Fedele ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Safety Analysis ◽  
Efficacy And Safety ◽  
Donor Age ◽  
Hematopoietic Stem ◽  
Healthy Donors

Coordinated involvement of cathepsins S, D and cystatin C in the commitment of hematopoietic stem cells to dendritic cells

2011 ◽  
Vol 43 (5) ◽  
pp. 775-783 ◽  
Author(s):  
Sabata Martino ◽  
Roberto Tiribuzi ◽  
Elisa Ciraci ◽  
Georgia Makrypidi ◽  
Francesco D’Angelo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dendritic Cells ◽  
Hematopoietic Stem Cells ◽  
Cystatin C ◽  
Hematopoietic Stem

Lysosomal Glycohydrolase Activities in Dendritic Cells: Is It a Function of Hematopoietic Stem Cells Differentiation Process?.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4193-4193
Author(s):  
Anna C. Berardi ◽  
Pamela Manieri ◽  
Elisa Ciraci ◽  
Roberto Tribuzi ◽  
Ilaria Di Girolamo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dendritic Cells ◽  
Hematopoietic Stem Cells ◽  
Cellular Proliferation ◽  
Stem Cell Differentiation ◽  
Neoplastic Disease ◽  
Differentiation Process ◽  
Hematopoietic Stem ◽  
Wide Range

Abstract A key mechanism responsible for processing of peptide-MHC class II complexes in mature Dendritic Cells (DCs) is the generalized activation of lysosomal function. Mechanisms underlie these developmental changes are controversial. Thus, it is unclear whether immature DCs can present self antigens, and which are the checkpoints that regulate antigen presentation in immature and mature DCs. Here we generated in-vitro human DCs from peripheral blood CD34+ hematopoietic stem cells (HSCs), by adding to the medium culture Flt-3, GM-CSF, IL-4, and TNF-a (cytokine cocktail, CC) at 37°C for 14 days, and analysed the lysosomal glycohydrolases production and function. Lysosomal enzymes, b-N-Acetyl-Hexosaminidase, a-Mannosidase, b-Galactosidase and b-Glucoronidase are highly increased in a wide range in DCs (14 days of culture) with respect to the CD34+HSCs. All the glycohydrolases activities measured at 3 and 7 days in-vitro culture, were similar and four times more than CD34+HSCs (day 0) respectively. Interestingly, no activities increase were observed, even when SCF, an early acting cytokine, promoting cellular proliferation, were added to the CC medium, indicating that this phenomenon is independent from the proliferation process. Moreover, LPS treatment, to induce DCs maturation, slightly enhance the specific activities of all enzymes that we tested as respect to the untreated cells. and support the evidence that the lysosomal glycohydrolases activation is up-stream to DCs maturation process. Furthermore, for the first time, this date indicated that lysosomal glycohydrolases are regulated during the stem cell differentiation process. Understanding the key mechanism leading this phenomenon is critical for therapeutic application in immunologic or neoplastic disease.

Plasmacytoid Dendritic Cells Derived from Chronic Myeloid Leukemia Induced by Low Dose Cytosine Arabinoside Combined with Flt-3L and TPO

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4918-4918
Author(s):  
Lijuan Li ◽  
Lian- Sheng Zhang
Keyword(s):  
Stem Cells ◽  
Dendritic Cells ◽  
Chronic Myeloid Leukemia ◽  
Influenza Vaccine ◽  
Hematopoietic Stem Cells ◽  
Cytosine Arabinoside ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Control Group ◽  
Hematopoietic Stem

Abstract Objective Plasmacytoid dendritic cells(pDC) as a subtype of dendritic cells, play an important immunological effects in the body.It is a focus in resent research. After stimulated by viruses or CpG ODNs, pDC produce large amounts of IFN-α rapidly, result in an strong non-specific immunological effect, and then become differentiation and maturation, and attained certain antigen presenting function in adaptive immune response, act as a bridge connecting innate immunity with adaptive immunity. In vitro, FLT-3L combination with TPO can successfully develop pDC from hematopoietic stem cells. Chronic myeloid leukemia(CML) is a hematopoietic stem cell malignant proliferation of the disease. There are series of immune abnormalities in patients with CML. It is well known that Interferon - α treatment of CML is effective, patients can be gained part of cytogenetic and molecular biology mitigation, and effective in patients with interferon therapy, the long-term prognosis is superior to other methods of treatment. Clinical experience also found that low dose cytosine arabinoside(LD-Ara-C) in combination with interferon is superior therapeutic effect of interferon treatment alone. We assumed that whether the LD-Ara-C in patients has an improvement in the immune dysfunction? Whether it will affect on CML-derived pDC differentiation, maturation and function? Therefore, we used LD-Ara-C joint FLT-3L, TPO cultivante CML-derived hematopoietic stem cells that make it differentiate into CML derived pDC to study LD-Ara-C for the treatment of CML may be immune mechanism for the clinical treatment theory. Method Bone marrow mononuclear cells (BMMNCs) were isolated from CML patients in chronic phase at diagnosis by density gradient centrifugation. BMMNCs were incubate with a cocktail of Flt-3 and TPO, Ara-C were added at the same time of 5ng/ml (A1), 10ng/ml (A2), 25ng/ml (A3), 50ng/ml (A4) and zero as the control, respectively. After 30 days of culture, the morphologic features were observed and CD4,CD11c, CD123, BDCA-2 were analyzed by flow cytometry, IFN-α concentration in supernate were detected by ELISA kits after added influenza vaccine. Results after 25d of culture, cells clustered with increased size and widespread cytoplasmic projection. Wright-Giemsa-stained cytospin preparation the pDC displays an eccentric kidney-shaped nucleus.The immunophenotype expression of CD4,CD123 and BDCA-2 on pDCs of group A1 and A2 were obviously higher than control group(p<0.05),and group A1 were higher than A2(p<0.05). The majority cells of group A3 and all cells of A4 were died. The group A1 had the highest level of the secretion of IFN-α than A2 and than control group(p<0.05) Conclusion LD-Ara-C in combination with Flt-3 and TPO can induce CML cells into pDCs which express the typical immunophenotype, Increase the production of IFN-α on stimulated by influenza vaccine. This study indicates that LD-Ara-C increase the quantity of pDC and IFN-α production, and this maybe explain why the therapy with LD-Ara-C in CML patients have better outcome.

Tanespimycin Reverses Bortezomib-Induced Inhibition of Granulopoiesis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3846-3846 ◽  
Author(s):  
Bruce D. Car ◽  
Oliver P. Flint ◽  
Jan Oberdoerster ◽  
Jennifer Price ◽  
William R. Foster ◽  
...  
Keyword(s):  
Stem Cells ◽  
Clinical Trials ◽  
Hematopoietic Stem Cells ◽  
Colony Formation ◽  
Mononuclear Cells ◽  
Cultured Cells ◽  
Healthy Human ◽  
Hematopoietic Stem ◽  
Drug Concentrations

Abstract Abstract 3846 Poster Board III-782 INTRODUCTION Tanespimycin, an Hsp90 inhibitor, is in phase 3 clinical trials with bortezomib for the treatment of multiple myeloma (MM). Neutropenia and thrombocytopenia are commonly observed during bortezomib treatment in patients with MM. However, in a phase 1/2 study of tanespimycin + bortezomib in patients with MM, the incidence and severity of neutropenia was low (Richardson ASCO 2009). Here we present the in vitro effects of tanespimycin and bortezomib on hematopoiesis and granulopoiesis in cell culture systems using mononuclear cells from healthy subjects and cryopreserved hematopoietic stem cells. METHODS: Mononuclear cells were separated from fresh whole healthy human bone marrow cells and cultured for up to 14 days in suspension in the presence of tanespimycin (1 pM–300 μM) and bortezomib (1 nM–300 μM). Committed hematopoietic progenitor growth (CFC-GEMM [granulocyte/erythroid/macrophage/megakaryocyte], BFU-E [erythroid], GM-CFC [granulocyte/macrophage], MkCFC [megakaryocyte]) of cultured cells was assessed using intracellular ATP bioluminescence in the HemoGenix HALO® system, which couples specific hematopoietic lineage growth conditions with a surrogate for cell count. In addition, cryopreserved healthy human hematopoietic stem cells were cultured in semisolid methylcellulose and colonies (CFC-GEMM, CFU-E, BFU-E) were microscopically enumerated. RESULTS: When bortezomib and tanespimycin were given alone in suspension cultures, IC50 values for bortezomib-induced cytotoxicity and tanespimycin-induced cytotoxicity were approximately 1 nM to 2 nM and 100 nM, respectively, for all hematopoietic lineages. In semisolid methylcellulose cultures, 1 nM to 10 nM bortezomib induced a concentration-dependent inhibition of granulocyte-macrophage colony formation from 2% to 46% and of erythroid colony formation from 8% to 35%. While tanespimycin alone at a concentration of 10 nM had little or no effect on erythropoiesis or granulocytopoiesis, when bortezomib (1 nM or 3 nM) and tanespimycin (10 nM) were cocultured, tanespimycin completely reversed bortezomib-induced inhibition of erythropoiesis and granulopoiesis. More severe erythropoietic inhibition at 10 nM bortezomib was not reversed by tanespimycin, while granulopoietic inhibition was mitigated approximately 23%. At concentrations of melphalan (1 μM) and camptothecin (3 nM) that inhibit in vitro hematopoiesis approximately 50% and 90%, respectively, 10 nM tanespimycin had no effect. CONCLUSION: At clinically relevant drug concentrations in hematopoietic cultures, tanespimycin reverses bortezomib-induced inhibition of granulopoiesis, consistent with the low frequency of neutropenia observed in clinical trials of tanespimycin + bortezomib. This suggests tanespimycin may prevent bortezomib-induced apoptosis of granulocyte-macrophage progenitors. Disclosures: Flint: Bristol-Myers Squibb: Employment, Equity Ownership. Oberdoerster:Bristol-Myers Squibb: Employment. Price:Bristol-Myers Squibb: Employment. Foster:Bristol-Myers Squibb: Employment. Gemzik:Bristol-Myers Squibb: Employment. Berman:Bristol-Myers Squibb: Employment.

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