29 results on '"Kindler V"'
Search Results
2. Fas engagement induces the maturation of dendritic cells (DCs), the release of interleukin (IL)-1beta, and the production of interferon gamma in the absence of IL-12 during DC-T cell cognate interaction: a new role for Fas ligand in inflammatory responses
- Author
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Rescigno, M., Piguet, V., Valzasina, B., Lens, S., Zubler, R., French, L., Kindler, V., Tschopp, J., and Ricciardi-Castagnoli, P.
- Subjects
Lipopolysaccharides ,Fas Ligand Protein ,FLIP ,T-Lymphocytes ,CASP8 and FADD-Like Apoptosis Regulating Protein ,chemical and pharmacologic phenomena ,Apoptosis ,Interferon-gamma ,Humans ,fas Receptor ,dendritic cells ,Cells, Cultured ,Inflammation ,Membrane Glycoproteins ,interferon γ ,Tumor Necrosis Factor-alpha ,Intracellular Signaling Peptides and Proteins ,Brief Definitive Report ,hemic and immune systems ,Cell Differentiation ,Fas ,Interleukin-12 ,Antigens, CD95/*immunology Apoptosis/drug effects CASP8 and FADD-Like Apoptosis Regulating Protein Carrier Proteins/biosynthesis Cell Differentiation Cells, Cultured Dendritic Cells/cytology/drug effects/*immunology Fas Ligand Protein Humans Inflammation/*immunology Interferon Type II/*biosynthesis Interleukin-1/*metabolism Interleukin-12/*immunology *Intracellular Signaling Peptides and Proteins Lipopolysaccharides/pharmacology Membrane Glycoproteins/*immunology Mitogens/pharmacology Phenotype T-Lymphocytes/*immunology Tumor Necrosis Factor-alpha/pharmacology Up-Regulation/drug effects ,Up-Regulation ,Phenotype ,interleukin 1β ,Mitogens ,Carrier Proteins ,Interleukin-1 - Abstract
Ligation of the Fas (CD95) receptor leads to an apoptotic death signal in T cells, B cells, and macrophages. However, human CD34(+)-derived dendritic cells (DCs) and mouse DCs, regardless of their maturation state, are not susceptible to Fas-induced cell death. This resistance correlates with the constitutive expression of the Fas-associated death domain-like IL-1beta-converting enzyme (FLICE)-inhibitory protein (FLIP) ligand. We demonstrate a new role of Fas in DC physiology. Engagement of Fas on immature DCs by Fas ligand (FasL) or by anti-Fas antibodies induces the phenotypical and functional maturation of primary DCs. Fas-activated DCs upregulate the expression of the major histocompatibility complex class II, B7, and DC-lysosome-associated membrane protein (DC-LAMP) molecules and secrete proinflammatory cytokines, in particular interleukin (IL)-1beta and tumor necrosis factor alpha. Mature DCs, if exposed to FasL, produce even higher amounts of IL-1beta. Importantly, it is possible to reduce the production of IL-1beta and interferon (IFN)-gamma during DC-T cell interaction by blocking the coupling of Fas-FasL with a Fas competitor. Finally, during cognate DC-T cell recognition, IL-12 (p70) could not be detected at early or late time points, indicating that Fas-induced, IFN-gamma secretion is independent of IL-12.
- Published
- 2000
3. Cytokine mRNA expression during an in vitro response of human B lymphocytes: kinetics of B cell tumor necrosis factor alpha, interleukin (IL)6, IL-10, and transforming growth factor beta 1 mRNAs.
- Author
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Matthes, T, primary, Werner-Favre, C, additional, Tang, H, additional, Zhang, X, additional, Kindler, V, additional, and Zubler, R H, additional
- Published
- 1993
- Full Text
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4. Murine autoimmune hemolytic anemia resulting from Fc gamma receptor- mediated erythrophagocytosis: protection by erythropoietin but not by interleukin-3, and aggravation by granulocyte-macrophage colony- stimulating factor
- Author
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Berney, T, primary, Shibata, T, additional, Merino, R, additional, Chicheportiche, Y, additional, Kindler, V, additional, Vassalli, P, additional, and Izui, S, additional
- Published
- 1992
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5. Interleukin 3 perfusion in W/Wv mice allows the development of macroscopic hematopoietic spleen colonies and restores cutaneous mast cell number.
- Author
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Ody, C, primary, Kindler, V, additional, and Vassalli, P, additional
- Published
- 1990
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6. Interleukin 3 perfusion prevents death due to acute anemia induced by monoclonal antierythrocyte autoantibody.
- Author
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Shibata, T, primary, Kindler, V, additional, Chicheportiche, Y, additional, Vassalli, P, additional, and Izui, S, additional
- Published
- 1990
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7. Presence of a very small population of Thy-1+ , L3T4+ cells producing large amounts of IL-3 in young athymic nude mice.
- Author
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Kimoto, M., de Kossodo, S., Kindler, V., Detraz, M., Vassalli, P., and Izui, S.
- Subjects
INTERLEUKIN-3 ,NUDE mouse ,PHORBOLS ,SPLEEN ,LYMPH nodes ,CELLS ,ANIMAL models in research ,IMMUNOLOGY - Abstract
A mixture of phorbol myristate acetate (PMA) and ionomycin was found to stimulate spleen and lymph node cells (LNC) from 6 to 8 week-old-athymic BALB/c nude mice, as well as from control +/+ mice, to secrete interleukin-3 (IL-3) in vitro. The specificity of the I L-3 bioassay was attested to by the use of rabbit anti-IL-3 antibodies, and by the detection of an accumulation of IL-3 mRNA. Cytotoxic treatment with relevant antibodies showed that the cells responsible for the IL-3 production in athymic nude mice was Thy-1
+ , L3T4+ , Ly 2- , while both L3T4+ and Ly 2+ cells produced IL-3 in control +/+ mice. Although the levels of IL-3 secreted by nude LNC varied among experiments, nude LNC were able to produce IL-3 at a level comparable to or higher than +/+ LNC. In addition, nude LNC consistently secreted two to three times more granulocyte-macrophage colony-stimulating factor (GM-CSF) than +/+ LNC, and the majority of GM-CSF secretion was dependent on the presence of L3T4+ cells. In contrast, IL-2 production by nude LNC was markedly limited. Since the flow microfluorometry analysis failed to demonstrate the presence of L3T4+ cells (<1%) in nude LNC, compared with 40–50% L3T4+ cells in +/+ LNC, our results suggest that athymic nude mice have a small population of Thy-1+ , L3T4+ cells characterized by its ability to secrete IL-3 and GM-CSF at a very high rate. [ABSTRACT FROM AUTHOR]- Published
- 1989
8. CD34+ cord blood cells expressing cutaneous lymphocyte-associated antigen are enriched in granulocyte-macrophage progenitors and support extensive amplification of dendritic cell progenitors
- Author
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Arrighi, J. F., Zubler, R., Hauser, C., Irion, O., Brouwers, N., Chapuis, B., and Kindler, V.
- Published
- 2001
- Full Text
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9. Stimulation of hematopoiesis in vivo by recombinant bacterial murine interleukin 3.
- Author
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Kindler, V, Thorens, B, de Kossodo, S, Allet, B, Eliason, J F, Thatcher, D, Farber, N, and Vassalli, P
- Abstract
Mouse interleukin 3 (IL-3) cDNA was cloned into a plasmid construction, allowing the synthesis of very high quantities of IL-3 in Escherichia coli. The recombinant (r) IL-3, purified to homogeneity, was active in vitro on the proliferation and differentiation of various hematopoietic progenitor cells at 1 pM. To maintain detectable blood levels of IL-3, osmotic pumps containing rIL-3 or control solutions were placed under the skin of normal and irradiated C3H/HeJ and (BALB X B10) F1 mice. The effect of IL-3 on hematopoietic progenitor cell numbers in spleen and bone marrow was evaluated 3 and 7 days later by using an in vitro clonal assay. The results demonstrated the following: (i) Doses of IL-3 infused at the rate of 2.5-5 ng per g of body weight per hr were sufficient to increase the numbers of hematopoietic progenitors in normal mice by at least 2-fold within 3 days. (ii) In mice with progenitor cell levels depressed by sublethal irradiation, 7-day treatment with IL-3 resulted in a 10-fold increase to near normal levels. (iii) The erythroid and myeloid lineages appeared to be enhanced to the same extent. (iv) Enhancement of hematopoiesis occurred primarily in spleen, but hematopoietic foci were also evident in the liver; in contrast, total cell and progenitor cell numbers were decreased in the bone marrow.
- Published
- 1986
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10. Prevention of experimental cerebral malaria by anticytokine antibodies. Interleukin 3 and granulocyte macrophage colony-stimulating factor are intermediates in increased tumor necrosis factor production and macrophage accumulation.
- Author
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Grau, G E, Kindler, V, Piguet, P F, Lambert, P H, and Vassalli, P
- Abstract
IL-3 and granulocyte/macrophage colony stimulating factor (GM-CSF) are two cytokines released by activated T lymphocytes that stimulate the growth and differentiation of various hematopoietic cell lines, among which are macrophages. It has been shown that TNF/cachectin, another cytokine that is released mostly by activated macrophages, plays a central role in experimental cerebral malaria (CM), an acute and lethal neurological syndrome induced by Plasmodium berghei ANKA infection in CBA mice. Since CM requires functional CD4+ T lymphocytes to occur, we explored, by injecting rabbit antibodies to murine rIL-3 and/or GM-CSF, whether these cytokines are intermediates in the marked TNF release leading to CM. Treatment of infected mice with each antibody separately had no protective effect. In contrast, when both anti-rGM-CSF and anti-rIL-3 antibodies were injected together; (a) the occurrence of neurological syndrome was prevented in 90% of the cases; (b) the rise in serum TNF was prevented; and (c) macrophage accumulation in the spleen was significantly reduced. Murine CM appears to involve a cytokine cascade in which IL-3 and GM-CSF lead to the accumulation of TNF-releasing macrophages in vivo.
- Published
- 1988
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11. A v-H-ras-dependent hemopoietic tumor model involving progression from a clonal stage of transformation competence to autocrine interleukin 3 production
- Author
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Nair, A P, Diamantis, I D, Conscience, J F, Kindler, V, Hofer, P, and Moroni, C
- Abstract
Autocrine interleukin 3 (IL-3)-secreting tumors were generated from an IL-3-dependent mouse mast cell line (PB-3c) after introduction of the v-H-ras oncogene. Tumor progression was characterized by four distinct phenotypes. The first corresponded to immortalized mast cells unresponsive to the oncogenic effect of v-H-ras. The second was expressed in a clonable subpopulation of PB-3c cells and was marked by the competence to form v-H-ras-dependent tumors (immortalized transformation competence). The third was a direct effect of v-H-ras expression on all PB-3c cells and was characterized in vitro by a reduced IL-3 requirement. Upon injection of v-H-ras-expressing, transformation-competent cells into mice, the final, fully malignant phenotype developed with a long latency period and was marked in vitro by independence of exogenous IL-3 and by autocrine IL-3 stimulation. Northern (RNA) blot analysis and an RNase A-T1 protection assay showed that IL-3 production was strictly associated with the tumor phenotype. Two of six tumors showed an alteration at the 5' region of the IL-3 gene. We conclude that v-H-ras required complementation by IL-3 gene rearrangement or an alternate event to generate autocrine mastocytomas.
- Published
- 1989
- Full Text
- View/download PDF
12. Presence of a very small population of Thy-1+, L3T4+ cells producing large amounts of IL-3 in young athymic nude mice
- Author
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Kimoto, M., de Kossodo, S., Kindler, V., Detraz, M., Vassalli, Pierre, and Izui, Shozo
- Subjects
Antigens, Differentiation, T-Lymphocyte ,Antigens, Differentiation, T-Lymphocyte/ analysis ,Mice, Inbred BALB C ,Ionomycin ,Lymphocytes/immunology/ metabolism ,Mice, Nude ,ddc:616.07 ,Lymphocyte Activation ,Mice ,Interleukin-3/ metabolism ,Antigens, Surface ,Animals ,Tetradecanoylphorbol Acetate ,Thy-1 Antigens ,Interleukin-3 ,Lymphocytes ,Antigens, Surface/ analysis ,Antigens, Thy-1 ,Cells, Cultured ,Research Article - Abstract
A mixture of phorbol myristate acetate (PMA) and ionomycin was found to stimulate spleen and lymph node cells (LNC) from 6 to 8 week-old-athymic BALB/c nude mice, as well as from control +/+ mice, to secrete interleukin-3 (IL-3) in vitro. The specificity of the IL-3 bioassay was attested to by the use of rabbit anti-IL-3 antibodies, and by the detection of an accumulation of IL-3 mRNA. Cytotoxic treatment with relevant antibodies showed that the cells responsible for the IL-3 production in athymic nude mice was Thy-1+, L3T4+, Ly2-, while both L3T4+ and Ly 2+ cells produced IL-3 in control +/+ mice. Although the levels of IL-3 secreted by nude LNC varied among experiments, nude LNC were able to produce IL-3 at a level comparable to or higher than +/+ LNC. In addition, nude LNC consistently secreted two to three times more granulocyte-macrophage colony-stimulating factor (GM-CSF) than +/+ LNC, and the majority of GM-CSF secretion was dependent on the presence of L3T4+ cells. In contrast, IL-2 production by nude LNC was markedly limited. Since the flow microfluorometry analysis failed to demonstrate the presence of L3T4+ cells (less than 1%) in nude LNC, compared with 40-50% L3T4+ cells in +/+ LNC, our results suggest that athymic nude mice have a small population of Thy-1+, L3T4+ cells characterized by its ability to secrete IL-3 and GM-CSF at a very high rate.
- Published
- 1989
13. Statistical Mechanics of Non-Muscle Myosin IIA in Human Bone Marrow-Derived Mesenchymal Stromal Cells Seeded in a Collagen Scaffold: A Thermodynamic Near-Equilibrium Linear System Modified by the Tripeptide Arg-Gly-Asp (RGD).
- Author
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Lecarpentier Y, Kindler V, Krokidis X, Bochaton-Piallat ML, Claes V, Hébert JL, Vallée A, and Schussler O
- Subjects
- Cell Differentiation, Humans, Oligopeptides, Thermodynamics, Collagen metabolism, Mesenchymal Stem Cells metabolism, Nonmuscle Myosin Type IIA metabolism, Tissue Scaffolds chemistry
- Abstract
Mesenchymal stromal cells (MSCs) were obtained from human bone marrow and amplified in cultures supplemented with human platelet lysate. Once semi-confluent, cells were seeded in solid collagen scaffolds that were rapidly colonized by the cells generating a 3D cell scaffold. Here, they acquired a myofibroblast phenotype and when exposed to appropriate chemical stimulus, developed tension and cell shortening, similar to those of striated and smooth muscle cells. Myofibroblasts contained a molecular motor-the non-muscle myosin type IIA (NMMIIA) whose crossbridge (CB) kinetics are dramatically slow compared with striated and smooth muscle myosins. Huxley's equations were used to determine the molecular mechanical properties of NMMIIA. Thank to the great number of NMMIIA molecules, we determined the statistical mechanics (SM) of MSCs, using the grand canonical ensemble which made it possible to calculate various thermodynamic entities such as the chemical affinity, statistical entropy, internal energy, thermodynamic flow, thermodynamic force, and entropy production rate. The linear relationship observed between the thermodynamic force and the thermodynamic flow allowed to establish that MSC-laden in collagen scaffolds were in a near-equilibrium stationary state (affinity ≪ RT), MSCs were also seeded in solid collagen scaffolds functionalized with the tripeptide Arg-Gly-Asp (RGD). This induced major changes in NMMIIA SM particularly by increasing the rate of entropy production. In conclusion, collagen scaffolds laden with MSCs can be viewed as a non-muscle contractile bioengineered tissue operating in a near-equilibrium linear regime, whose SM could be substantially modified by the RGD peptide.
- Published
- 2020
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14. Tripeptide Arg-Gly-Asp (RGD) modifies the molecular mechanical properties of the non-muscle myosin IIA in human bone marrow-derived myofibroblasts seeded in a collagen scaffold.
- Author
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Lecarpentier Y, Kindler V, Bochaton-Piallat ML, Sakic A, Claes V, Hébert JL, Vallée A, and Schussler O
- Subjects
- Blood Platelets metabolism, Bone Marrow Cells metabolism, Cell Differentiation genetics, Collagen chemistry, Collagen metabolism, Humans, Kinetics, Mesenchymal Stem Cells metabolism, Muscle Contraction genetics, Myofibroblasts metabolism, Myosin Heavy Chains genetics, Myosins chemistry, Myosins metabolism, Oligopeptides chemistry, Peptides chemistry, Potassium Chloride pharmacology, Muscle, Smooth metabolism, Myosin Heavy Chains chemistry, Oligopeptides metabolism, Peptides metabolism
- Abstract
Mesenchymal stem cells (MSCs) were obtained from human bone marrow and amplified in cultures supplemented with human platelet lysate in order to generate myofibroblasts. When MSCs were seeded in solid collagen scaffolds, they differentiated into myofibroblasts that were observed to strongly bind to the substrate, forming a 3D cell scaffold network that developed tension and shortening after KCl stimulation. Moreover, MSC-laden scaffolds recapitulated the Frank-Starling mechanism so that active tension increased in response to increases in the initial length of the contractile system. This constituted a bioengineering tissue that exhibited the contractile properties observed in both striated and smooth muscles. By using the A. F. Huxley formalism, we determined the myosin crossbridge (CB) kinetics of attachment (f1) and detachment (g1 and g2), maximum myosin ATPase activity, molar myosin concentration, unitary CB force and maximum CB efficiency. CB kinetics were dramatically slow, characterizing the non-muscle myosin type IIA (NMMIIA) present in myofibroblasts. When MSCs were seeded in solid collagen scaffolds functionalized with Arg-Gly-Asp (RGD), contractility increased and CB kinetics were modified, whereas the unitary NMMIIA-CB force and maximum CB efficiency did not change. In conclusion, we provided a non-muscle bioengineering tissue whose molecular mechanical characteristics of NMMIIA were very close to those of a non-muscle contractile tissue such as the human placenta., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
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15. Human Bone Marrow Contains Mesenchymal Stromal Stem Cells That Differentiate In Vitro into Contractile Myofibroblasts Controlling T Lymphocyte Proliferation.
- Author
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Lecarpentier Y, Schussler O, Sakic A, Rincon-Garriz JM, Soulie P, Bochaton-Piallat ML, and Kindler V
- Abstract
Mesenchymal stromal stem cells (MSC) that reside in the bone marrow (BM) can be amplified in vitro. In 2-dimension (D) cultures, MSC exhibit a morphology similar to fibroblasts, are able to inhibit T lymphocyte and natural killer cell proliferation, and can be differentiated into adipocytes, chondrocytes, or osteoblasts if exposed to specific media. Here we show that medullar MSC cultured in 2D formed an adherent stroma of cells expressing well-organized microfilaments containing α -smooth muscle actin and nonmuscle myosin heavy chain IIA. MSC could be grown in 3D in collagen membranes generating a structure which, upon exposition to 50 mM KCl or to an alternating electric current, developed a contractile strength that averaged 34 and 45 μ N/mm
2 , respectively. Such mechanical tension was similar in intensity and in duration to that of human placenta and was annihilated by isosorbide dinitrate or 2,3-butanedione monoxime. Membranes devoid of MSC did not exhibit a significant contractility. Moreover, MSC nested in collagen membranes were able to control T lymphocyte proliferation, and differentiated into adipocytes, chondrocytes, or osteoblasts. Our observations show that BM-derived MSC cultured in collagen membranes spontaneously differentiate into contractile myofibroblasts exhibiting unexpected properties in terms of cell differentiation potential and of immunomodulatory function.- Published
- 2018
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16. Human myogenic reserve cells are quiescent stem cells that contribute to muscle regeneration after intramuscular transplantation in immunodeficient mice.
- Author
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Laumonier T, Bermont F, Hoffmeyer P, Kindler V, and Menetrey J
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- Adult, Animals, Biomarkers, Cell Differentiation, Cell Survival, Cells, Cultured, Humans, Immunocompromised Host, Mice, Mice, Transgenic, Models, Animal, Myoblasts, Skeletal cytology, Myoblasts, Skeletal metabolism, Myoblasts, Skeletal transplantation, Young Adult, Muscle Development, Regeneration, Stem Cell Transplantation methods, Stem Cells cytology, Stem Cells metabolism
- Abstract
Satellite cells, localized within muscles in vivo, are Pax7
+ muscle stem cells supporting skeletal muscle growth and regeneration. Unfortunately, their amplification in vitro, required for their therapeutic use, is associated with reduced regenerative potential. In the present study, we investigated if human myogenic reserve cells (MRC) obtained in vitro, represented a reliable cell source for muscle repair. For this purpose, primary human myoblasts were freshly isolated and expanded. After 2 days of differentiation, 62 ± 2.9% of the nuclei were localized in myotubes and 38 ± 2.9% in the mononucleated non-fusing MRC. Eighty percent of freshly isolated human MRC expressed a phenotype similar to human quiescent satellite cells (CD56+ /Pax7+ /MyoD- /Ki67- cells). Fourteen days and 21 days after cell transplantation in immunodeficient mice, live human cells were significantly more numerous and the percentage of Pax7+ /human lamin A/C+ cells was 2 fold higher in muscles of animals injected with MRC compared to those injected with human myoblasts, despite that percentage of spectrin+ and lamin A/C+ human fibers in both groups MRC were similar. Taken together, these data provide evidence that MRC generated in vitro represent a promising source of cells for improving regeneration of injured skeletal muscles.- Published
- 2017
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17. Implication of indolamine 2,3 dioxygenase in the tolerance toward fetuses, tumors, and allografts.
- Author
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Dürr S and Kindler V
- Subjects
- Animals, Female, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase chemistry, Immune Tolerance, Indoleamine-Pyrrole 2,3,-Dioxygenase physiology, Neoplasms immunology, Pregnancy immunology, Transplantation, Homologous immunology
- Abstract
Mammalian IDO is a heme-containing enzyme whose main activity in mammals is to degrade the essential amino acid tryp into l-kynurenine. Although the link between its enzymatic activity and the immune response is not straightforward, several lines of evidence suggest that this enzyme is involved in fighting infections and paradoxically, also in the establishment of the immune tolerance associated with fetus implantation and with the development of oncogenic processes. IDO is associated with the successful development of the fetus. It participates early in pregnancy to the efficient invasion of the uterine mucosa by the nascent trophoblast and remains active throughout the whole process, as illustrated by the decrease in systemic tryp from the second trimester of gestation and the return to normal values after delivery. The short-term activation of IDO in response to invading pathogens and emerging tumors participates in the elimination of these threats, whereas the sustained activation of IDO often results in a state of immune tolerance that may favor chronic infections and the uncontrolled proliferation of malignant cells. However, despite these potential deleterious effects of IDO, the enzyme is instrumental in maintaining the peripheral tolerance that is required to avoid autoimmune diseases. Below, we review the implication of IDO activation upon the physiological development of the fetus and the pathological development of tumors and discuss whether such an enzyme could be used as a therapeutic tool to decrease the rate of allograft rejections via its potent immunomodulatory properties.
- Published
- 2013
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18. Impact of selection of cord blood units from the United States and swiss registries on the cost of banking operations.
- Author
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Bart T, Boo M, Balabanova S, Fischer Y, Nicoloso G, Foeken L, Oudshoorn M, Passweg J, Tichelli A, Kindler V, Kurtzberg J, Price T, Regan D, Shpall EJ, and Schwabe R
- Abstract
Background: Over the last 2 decades, cord blood (CB) has become an important source of blood stem cells. Clinical experience has shown that CB is a viable source for blood stem cells in the field of unrelated hematopoietic blood stem cell transplantation., Methods: Studies of CB units (CBUs) stored and ordered from the US (National Marrow Donor Program (NMDP) and Swiss (Swiss Blood Stem Cells (SBSQ)) CB registries were conducted to assess whether these CBUs met the needs of transplantation patients, as evidenced by units being selected for transplantation. These data were compared to international banking and selection data (Bone Marrow Donors Worldwide (BMDW), World Marrow Donor Association (WMDA)). Further analysis was conducted on whether current CB banking practices were economically viable given the units being selected from the registries for transplant. It should be mentioned that our analysis focused on usage, deliberately omitting any information about clinical outcomes of CB transplantation., Results: A disproportionate number of units with high total nucleated cell (TNC) counts are selected, compared to the distribution of units by TNC available. Therefore, the decision to use a low threshold for banking purposes cannot be supported by economic analysis and may limit the economic viability of future public CB banking., Conclusions: We suggest significantly raising the TNC level used to determine a bankable unit. A level of 125 × 10(7) TNCs, maybe even 150 × 10(7) TNCs, might be a viable banking threshold. This would improve the return on inventory investments while meeting transplantation needs based on current selection criteria.
- Published
- 2013
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19. Autologous bone marrow mononuclear cell transplantation in patients with decompensated alcoholic liver disease: a randomized controlled trial.
- Author
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Spahr L, Chalandon Y, Terraz S, Kindler V, Rubbia-Brandt L, Frossard JL, Breguet R, Lanthier N, Farina A, Passweg J, Becker CD, and Hadengue A
- Subjects
- Adolescent, Adult, Aged, Biomarkers blood, Cell Proliferation, Cytokines blood, Female, Hepatic Artery surgery, Hepatocytes pathology, Humans, Liver pathology, Liver physiopathology, Liver surgery, Liver Diseases, Alcoholic blood, Liver Diseases, Alcoholic pathology, Liver Diseases, Alcoholic physiopathology, Male, Middle Aged, Recovery of Function, Regeneration, Stem Cell Transplantation adverse effects, Time Factors, Transplantation, Autologous adverse effects, Young Adult, Bone Marrow Transplantation adverse effects, Liver Diseases, Alcoholic surgery
- Abstract
Objective: Impaired liver regeneration is associated with a poor outcome in patients with decompensated alcoholic liver disease (ALD). We assessed whether autologous bone marrow mononuclear cell transplantation (BMMCT) improved liver function in decompensated ALD., Design: 58 patients (mean age 54 yrs; mean MELD score 19, all with cirrhosis, 81% with alcoholic steatohepatitis at baseline liver biopsy) were randomized early after hospital admission to standard medical therapy (SMT) alone (n = 30), including steroids in patients with a Maddrey's score ≥32, or combined with G-CSF injections and autologous BMMCT into the hepatic artery (n = 28). Bone marrow cells were harvested, isolated and reinfused the same day. The primary endpoint was a ≥3 points decrease in the MELD score at 3 months, corresponding to a clinically relevant improvement in liver function. Liver biopsy was repeated at week 4 to assess changes in Ki67+/CK7+ hepatic progenitor cells (HPC) compartment., Results: Both study groups were comparable at baseline. After 3 months, 2 and 4 patients died in the BMMCT and SMT groups, respectively. Adverse events were equally distributed between groups. Moderate alcohol relapse occurred in 31% of patients. The MELD score improved in parallel in both groups during follow-up with 18 patients (64%) from the BMMCT group and 18 patients (53%) from the SMT group reaching the primary endpoint (p = 0.43 (OR 1.6, CI 0.49-5.4) in an intention to treat analysis. Comparing liver biopsy at 4 weeks to baseline, steatosis improved (p<0.001), and proliferating HPC tended to decrease in both groups (-35 and -33%, respectively)., Conclusion: Autologous BMMCT, compared to SMT is a safe procedure but did not result in an expanded HPC compartment or improved liver function. These data suggest either insufficient regenerative stimulation after BMMCT or resistance to liver regenerative drive in patients with decompensated alcoholic cirrhosis., Trial Registration: Controlled-Trials.com ISRCTN83972743.
- Published
- 2013
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20. Initial cord blood unit volume affects mononuclear cell and CD34+ cell-processing efficiency in a non-linear fashion.
- Author
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Meyer-Monard S, Tichelli A, Troeger C, Arber C, de Faveri GN, Gratwohl A, Roosnek E, Surbek D, Chalandon Y, Irion O, Castelli D, Passweg J, and Kindler V
- Subjects
- Antigens, CD34 immunology, Blood Sedimentation, Humans, Hydroxyethyl Starch Derivatives chemistry, T-Lymphocytes cytology, T-Lymphocytes immunology, Cell Culture Techniques methods, Fetal Blood cytology, Hematopoietic Stem Cells cytology, Leukocytes, Mononuclear cytology
- Abstract
Background Aims: Umbilical cord blood (UCB) is a source of hematopoietic stem cells that initially was used exclusively for the hematopoietic reconstitution of pediatric patients. It is now suggested for use for adults as well, a fact that increases the pressure to obtain units with high cellularity. Therefore, the optimization of UCB processing is a priority., Methods: The present study focused on parameters influencing total nucleated cell (TNC), mononucleated cell (MNC) and CD34+ cell (CD34C) recovery after routine volume reduction of 1553 UCB units using hydroxyethyl starch-induced sedimentation with an automated device, under routine laboratory conditions., Results: We show that the unit volume rather than the TNC count significantly affects TNC, MNC and CD34C processing efficiency (PEf), and this in a non-linear fashion: when units were sampled according to the collection volume, including pre-loaded anticoagulant (gross volume), PEf increased up to a unit volume of 110-150 mL and decreased thereafter. Thus units with initial gross volumes < 90 mL and > 170 mL similarly exhibited a poor PEf., Conclusions: These data identify unit gross volume as a major parameter influencing PEf and suggest that fractionation of large units should be contemplated only when the resulting volume of split units is > 90 mL.
- Published
- 2012
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21. Epigenetic features of human mesenchymal stem cells determine their permissiveness for induction of relevant transcriptional changes by SYT-SSX1.
- Author
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Cironi L, Provero P, Riggi N, Janiszewska M, Suva D, Suva ML, Kindler V, and Stamenkovic I
- Subjects
- Adolescent, Alleles, Child, Chromatin metabolism, CpG Islands, DNA genetics, Gene Expression Profiling, Humans, Sarcoma, Synovial metabolism, Transcription, Genetic, Translocation, Genetic, Epigenesis, Genetic, Gene Expression Regulation, Mesenchymal Stem Cells cytology, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion physiology
- Abstract
Background: A characteristic SYT-SSX fusion gene resulting from the chromosomal translocation t(X;18)(p11;q11) is detectable in almost all synovial sarcomas, a malignant soft tissue tumor widely believed to originate from as yet unidentified pluripotent stem cells. The resulting fusion protein has no DNA binding motifs but possesses protein-protein interaction domains that are believed to mediate association with chromatin remodeling complexes. Despite recent advances in the identification of molecules that interact with SYT-SSX and with the corresponding wild type SYT and SSX proteins, the mechanisms whereby the SYT-SSX might contribute to neoplastic transformation remain unclear. Epigenetic deregulation has been suggested to be one possible mechanism., Methodology/principal Findings: We addressed the effect of SYT/SSX expression on the transcriptome of four independent isolates of primary human bone marrow mesenchymal stem cells (hMSC). We observed transcriptional changes similar to the gene expression signature of synovial sarcoma, principally involving genes whose regulation is linked to epigenetic factors, including imprinted genes, genes with transcription start sites within a CpG island and chromatin related genes. Single population analysis revealed hMSC isolate-specific transcriptional changes involving genes that are important for biological functions of stem cells as well as genes that are considered to be molecular markers of synovial sarcoma including IGF2, EPHRINS, and BCL2. Methylation status analysis of sequences at the H19/IGF2 imprinted locus indicated that distinct epigenetic features characterize hMSC populations and condition the transcriptional effects of SYT-SSX expression., Conclusions/significance: Our observations suggest that epigenetic features may define the cellular microenvironment in which SYT-SSX displays its functional effects.
- Published
- 2009
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22. IGF1 is a common target gene of Ewing's sarcoma fusion proteins in mesenchymal progenitor cells.
- Author
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Cironi L, Riggi N, Provero P, Wolf N, Suvà ML, Suvà D, Kindler V, and Stamenkovic I
- Subjects
- Animals, Gene Expression Profiling, Humans, Mesenchymal Stem Cells metabolism, Mice, Mice, Inbred C57BL, Models, Biological, Phenotype, Promoter Regions, Genetic, Proto-Oncogene Protein c-fli-1 metabolism, RNA-Binding Protein EWS, Gene Expression Regulation, Insulin-Like Growth Factor I metabolism, Mesenchymal Stem Cells cytology, Oncogene Proteins, Fusion chemistry, Oncogene Proteins, Fusion metabolism, Proto-Oncogene Protein c-fli-1 chemistry, RNA-Binding Protein FUS metabolism, Transcription Factors metabolism
- Abstract
Background: The EWS-FLI-1 fusion protein is associated with 85-90% of Ewing's sarcoma family tumors (ESFT), the remaining 10-15% of cases expressing chimeric genes encoding EWS or FUS fused to one of several ets transcription factor family members, including ERG-1, FEV, ETV1 and ETV6. ESFT are dependent on insulin-like growth factor-1 (IGF-1) for growth and survival and recent evidence suggests that mesenchymal progenitor/stem cells constitute a candidate ESFT origin., Methodology/principal Findings: To address the functional relatedness between ESFT-associated fusion proteins, we compared mouse progenitor cell (MPC) permissiveness for EWS-FLI-1, EWS-ERG and FUS-ERG expression and assessed the corresponding expression profile changes. Whereas all MPC isolates tested could stably express EWS-FLI-1, only some sustained stable EWS-ERG expression and none could express FUS-ERG for more than 3-5 days. Only 14% and 4% of the total number of genes that were respectively induced and repressed in MPCs by the three fusion proteins were shared. However, all three fusion proteins, but neither FLI-1 nor ERG-1 alone, activated the IGF1 promoter and induced IGF1 expression., Conclusion/significance: Whereas expression of different ESFT-associated fusion proteins may require distinct cellular microenvironments and induce transcriptome changes of limited similarity, IGF1 induction may provide one common mechanism for their implication in ESFT pathogenesis.
- Published
- 2008
- Full Text
- View/download PDF
23. EWS-FLI-1 expression triggers a Ewing's sarcoma initiation program in primary human mesenchymal stem cells.
- Author
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Riggi N, Suvà ML, Suvà D, Cironi L, Provero P, Tercier S, Joseph JM, Stehle JC, Baumer K, Kindler V, and Stamenkovic I
- Subjects
- Animals, Bone Neoplasms genetics, Bone Neoplasms metabolism, Bone Neoplasms pathology, Cell Differentiation physiology, Enhancer of Zeste Homolog 2 Protein, Gene Expression Profiling, Gene Expression Regulation, Neoplastic genetics, Histone-Lysine N-Methyltransferase, Humans, Immunocompromised Host, Mice, Oncogene Proteins, Fusion genetics, Phenotype, Polycomb Repressive Complex 2, Proteins genetics, Proto-Oncogene Protein c-fli-1 genetics, RNA, Messenger biosynthesis, RNA, Messenger genetics, RNA-Binding Protein EWS, Sarcoma, Ewing genetics, Soft Tissue Neoplasms genetics, Soft Tissue Neoplasms metabolism, Soft Tissue Neoplasms pathology, Mesenchymal Stem Cells metabolism, Mesenchymal Stem Cells pathology, Oncogene Proteins, Fusion biosynthesis, Proto-Oncogene Protein c-fli-1 biosynthesis, Sarcoma, Ewing metabolism, Sarcoma, Ewing pathology
- Abstract
Ewing's sarcoma family tumors (ESFT) express the EWS-FLI-1 fusion gene generated by the chromosomal translocation t(11;22)(q24;q12). Expression of the EWS-FLI-1 fusion protein in a permissive cellular environment is believed to play a key role in ESFT pathogenesis. However, EWS-FLI-1 induces growth arrest or apoptosis in differentiated primary cells, and the identity of permissive primary human cells that can support its expression and function has until now remained elusive. Here we show that expression of EWS-FLI-1 in human mesenchymal stem cells (hMSC) is not only stably maintained without inhibiting proliferation but also induces a gene expression profile bearing striking similarity to that of ESFT, including genes that are among the highest ESFT discriminators. Expression of EWS-FLI-1 in hMSCs may recapitulate the initial steps of Ewing's sarcoma development, allowing identification of genes that play an important role early in its pathogenesis. Among relevant candidate transcripts induced by EWS-FLI-1 in hMSCs, we found the polycomb group gene EZH2, which we show to play a critical role in Ewing's sarcoma growth. These observations are consistent with our recent findings using mouse mesenchymal progenitor cells and provide compelling evidence that hMSCs are candidate cells of origin of ESFT.
- Published
- 2008
- Full Text
- View/download PDF
24. Human CD34+ CD11b- cord blood stem cells generate in vitro a CD34- CD11b+ subset that is enriched in langerin+ Langerhans dendritic cell precursors.
- Author
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Soulas C, Arrighi JF, Saeland S, Chapuis B, and Kindler V
- Subjects
- Antigens, CD34 biosynthesis, CD11b Antigen biosynthesis, Cell Differentiation drug effects, Cell Differentiation immunology, Cells, Cultured, Flow Cytometry, Granulocyte-Macrophage Colony-Stimulating Factor pharmacology, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells drug effects, Humans, Interleukin-4 pharmacology, Langerhans Cells cytology, Langerhans Cells drug effects, Lipopolysaccharides pharmacology, Membrane Proteins pharmacology, Stem Cell Factor pharmacology, Thrombopoietin pharmacology, Transforming Growth Factor beta1 pharmacology, Antigens, CD biosynthesis, Antigens, CD34 immunology, CD11b Antigen immunology, Fetal Blood cytology, Hematopoietic Stem Cells immunology, Langerhans Cells immunology, Lectins, C-Type biosynthesis, Mannose-Binding Lectins biosynthesis
- Abstract
Objective: We investigated whether the expression of CD11b on precursors derived in vitro from CD34+ hematopoietic stem cells was related to their ability to generate CD11b- and CD11b+ Langerhans dendritic cells (LC)., Methods: Human CD34+ cells purified from cord blood were cultured with FLT3 ligand, thrombopoietin, and stem cell factor (FTS) for 2 weeks, analyzed, and sorted by FACS. Sorted fractions were cultured as above, or differentiated into LC with GM-CSF, IL-4, and TGF-beta1 (G4-TGF) for 6 days. The capacity of LC to internalize langerin and dextran was assessed., Results: Ex vivo, human CD34+ cells were CD11b- and mostly CLA+. After 2 weeks of culture with FTS, CD34- CLA- CD11b- and CD34- CLA- CD11b+ cells emerged. CD11b- cells were the most ancestral because they were the only ones to proliferate with FTS, and constantly generated CD11b+ cells. Both CD11b- and CD11b+ sorted cells generated E-cadherin+ langerin+ LC after incubation with G4-TGF. The former fraction contained 46% +/- 15% of E-cadherin+ and 10% +/- 5% of langerin+ cells, whereas in the latter fraction these values reached respectively 66% +/- 23% and 30% +/- 16% (mean +/- SD, n = 7, p < 0.056). Looking at functional properties, CD11b- and CD11b+ LC were similar in terms of langerin and dextran endocytosis. By contrast, only CD11b+ LC internalized fluorescent LPS., Conclusion: Human CD34+ CD11b- cells differentiate in FTS culture into a CD34- CD11b- precursor that in turn generates CD34- CD11b+ cells. These cells are enriched in LC precursors compared to CD34- CD11b- cells. Both CD11b- and CD11b+ LC are generated in vitro, and each fraction may assume different functions in inflammatory situations.
- Published
- 2006
- Full Text
- View/download PDF
25. Haematopoietic stem cells and mesenchymal stem cells as tools for present and future cellular therapies.
- Author
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Kindler V, Suva D, Soulas C, and Chapuis B
- Subjects
- Animals, Antigen-Presenting Cells cytology, Cell Differentiation, Cells, Cultured, Child, Dendritic Cells immunology, Forecasting, Hematopoietic Stem Cell Transplantation, Humans, Leukemia therapy, Mesenchymal Stem Cell Transplantation, Mice, Osteogenesis Imperfecta therapy, Papio, Cell Transplantation trends, Hematopoietic Stem Cells cytology, Mesenchymal Stem Cells cytology
- Abstract
Postnatal stem cells are present in many adult tissues, and are thought to ensure homoeostasis by replacing functionally declining cells by newly differentiated ones. Postnatal stem cells used as such or after in vitro manipulation hold out strong hopes for reconstructive therapies. For instance, the grafting of native haematopoietic stem cells (HSC) restores haematopoiesis in genetically deficient individuals or in lethally conditioned leukaemic patients, and systemic injection of in vitro amplified mesenchymal stem cells (MSC) induces recovery of bone growth in patients with osteogenesis imperfecta. Moreover, cells differentiated in vitro from postnatal stem cells exhibiting a specific function can also be used for cell therapy. Myeloid dendritic cells (DC) derived from cultures of HSC may induce tumour-specific cytotoxic T lymphocytes to eradicate the tumour via antigen recognition. In addition, long-lived MSC has been engineered to secrete specific proteins coded by a transgene and used as a source of therapeutic molecules in vivo. All these approaches require large quantities of cells that cannot be obtained (with the exception of HSC) directly from the donor. In vitro procedures allowing the production of therapeutic cells from postnatal stem cells are needed and are at present under development. Below we discuss the rationale and methods currently available for generation of therapeutic cells derived from haematopoietic and mesenchymal stem cells.
- Published
- 2006
- Full Text
- View/download PDF
26. Postnatal stem cell survival: does the niche, a rare harbor where to resist the ebb tide of differentiation, also provide lineage-specific instructions?
- Author
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Kindler V
- Subjects
- Cell Differentiation physiology, Hematopoietic Stem Cell Transplantation adverse effects, Humans, Models, Immunological, Cell Lineage physiology, Stem Cells cytology, Stem Cells physiology
- Abstract
Postnatal stem cells regulate the homeostasis of the majority of our tissues. They continuously generate new progenitors and mature, functional cells to replace old cells, which cannot assume the tissue function anymore and are eliminated. Blood, skin, gut mucosa, muscle, cartilage, nerves, cornea, retina, liver, and many other structures are regulated by stem cells. As a result of their ability to produce large numbers of functionally mature cells, postnatal stem cells represent a promising tool for regenerative therapy. Indeed, unmanipulated stem cells or their progeny amplified in vitro are already used in some clinical applications to restore the function of injured or genetically deficient tissues. However, despite our cumulating understanding concerning postnatal stem cells, many aspects of their functionality remain unclear. For instance, in most tissues, we cannot reliably define the phenotype of the postnatal stem cells sustaining its survival. We do not know to which extent the environment surrounding the stem cell-the niche-which is a key actor insuring stem cell self-maintenance, is also implicated in the maintenance of stem cell lineage specificity. Moreover, we have to clarify whether postnatal stem cells are capable of undertaking "transdifferentiation", that is, the conversion of one cell type into another under physiological conditions. Answering these questions should help us to draw a more accurate picture of postnatal stem cell biology and should lead to the design of safe, effective therapies.
- Published
- 2005
- Full Text
- View/download PDF
27. BAFF production by antigen-presenting cells provides T cell co-stimulation.
- Author
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Huard B, Arlettaz L, Ambrose C, Kindler V, Mauri D, Roosnek E, Tschopp J, Schneider P, and French LE
- Subjects
- B-Cell Activating Factor, Cell Communication immunology, Gene Expression, Genes, MHC Class II genetics, Humans, Membrane Proteins genetics, RNA, Messenger metabolism, Receptor-CD3 Complex, Antigen, T-Cell genetics, Receptor-CD3 Complex, Antigen, T-Cell immunology, Receptor-CD3 Complex, Antigen, T-Cell metabolism, Recombinant Proteins genetics, Recombinant Proteins immunology, Recombinant Proteins metabolism, Tumor Necrosis Factor-alpha genetics, Up-Regulation genetics, Dendritic Cells immunology, Lymphocyte Activation, Membrane Proteins biosynthesis, T-Lymphocytes immunology, Tumor Necrosis Factor-alpha biosynthesis
- Abstract
The B cell-activating factor from the tumor necrosis factor family (BAFF) is an important regulator of B cell immunity. Recently, we demonstrated that recombinant BAFF also provides a co-stimulatory signal to T cells. Here, we studied expression of BAFF in peripheral blood leukocytes and correlated this expression with BAFF T cell co-stimulatory function. BAFF is produced by antigen-presenting cells (APC). Blood dendritic cells (DC) as well as DC differentiated in vitro from monocytes or CD34+ stem cells express BAFF mRNA. Exposure to bacterial products further up-regulates BAFF production in these cells. A low level of BAFF transcription, up-regulated upon TCR stimulation, was also detected in T cells. Functionally, blockade of endogenous BAFF produced by APC and, to a lesser extent, by T cells inhibits T cell activation. Altogether, this indicates that BAFF may regulate T cell immunity during APC-T cell interactions and as an autocrine factor once T cells have detached from the APC.
- Published
- 2004
- Full Text
- View/download PDF
28. High-level transgene expression in human hematopoietic progenitors and differentiated blood lineages after transduction with improved lentiviral vectors.
- Author
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Salmon P, Kindler V, Ducrey O, Chapuis B, Zubler RH, and Trono D
- Subjects
- Antigens, CD34 blood, Cell Differentiation genetics, DNA, Viral genetics, Dose-Response Relationship, Drug, Fetal Blood cytology, Fetal Blood metabolism, Flow Cytometry, Gene Expression Regulation, Viral, Gene Transfer Techniques, HIV genetics, Hepatitis B Virus, Woodchuck genetics, Humans, Moloney murine leukemia virus genetics, Peptide Elongation Factor 1 genetics, Phosphoglycerate Kinase genetics, Promoter Regions, Genetic, RNA Processing, Post-Transcriptional, T-Lymphocytes metabolism, Cell Lineage genetics, Genetic Vectors standards, Hematopoietic Stem Cells metabolism, Lentivirus genetics, Transduction, Genetic, Transgenes genetics
- Abstract
Recent experiments point to the great value of lentiviral vectors for the transduction of human hematopoietic stem cells (hHSCs). Vectors used so far, however, have been poorly satisfying in terms of either biosafety or efficiency of transgene expression. Herein is described the results obtained with human immunodeficiency virus-based vectors optimized in both of these aspects. It is thus shown that vectors containing the EF1alpha and, to a lesser extent, the phosphoglycerate kinase (PGK) promoter, govern high-level gene expression in human hematopoietic progenitors as well as derived hematopoietic lineages of therapeutic relevance, such as erythrocytes, granulocytes, monocytes, dendritic cells, and megakaryocytes. EF1alpha promoter-containing lentiviral vectors can also induce strong transgene expression in primary T lymphocytes isolated from peripheral blood. A self-inactivating design did not affect the performance of EF1alpha promoter-based vectors but significantly reduced expression from the PGK promoter. This negative effect could nevertheless be largely rescued by inserting the post-transcriptional regulatory element of woodchuck hepatitis virus upstream of the vector 3' long terminal repeat. These results have important practical implications for the genetic treatment of lymphohematologic disorders as well as for the study of hematopoiesis via the lentivector-mediated modification of hHSCs.
- Published
- 2000
29. Long-term culture of human CD34(+) progenitors with FLT3-ligand, thrombopoietin, and stem cell factor induces extensive amplification of a CD34(-)CD14(-) and a CD34(-)CD14(+) dendritic cell precursor.
- Author
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Arrighi JF, Hauser C, Chapuis B, Zubler RH, and Kindler V
- Subjects
- Animals, Antigens, CD1 analysis, Blood Physiological Phenomena, Cattle, Cell Count, Cell Differentiation drug effects, Culture Media pharmacology, Fetal Blood cytology, Granulocyte-Macrophage Colony-Stimulating Factor pharmacology, Humans, Interleukin-4 pharmacology, Lymphocyte Culture Test, Mixed, Tumor Necrosis Factor-alpha pharmacology, Antigens, CD34 analysis, Dendritic Cells cytology, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells drug effects, Lipopolysaccharide Receptors analysis, Membrane Proteins pharmacology, Stem Cell Factor pharmacology, Thrombopoietin pharmacology
- Abstract
Current in vitro culture systems allow the generation of human dendritic cells (DCs), but the output of mature cells remains modest. This contrasts with the extensive amplification of hematopoietic progenitors achieved when culturing CD34(+) cells with FLT3-ligand and thrombopoietin. To test whether such cultures contained DC precursors, CD34(+) cord blood cells were incubated with the above cytokines, inducing on the mean a 250-fold and a 16,600-fold increase in total cell number after 4 and 8 weeks, respectively. The addition of stem cell factor induced a further fivefold increase in proliferation. The majority of the cells produced were CD34(-)CD1a- CD14(+) (p14(+)) and CD34(-)CD1a-CD14(-) (p14(-)) and did not display the morphology, surface markers, or allostimulatory capacity of DC. When cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4), both subsets differentiated without further proliferation into immature (CD1a+, CD14(-), CD83(-)) macropinocytic DC. Mature (CD1a+, CD14(-), CD83(+)) DCs with high allostimulatory activity were generated if such cultures were supplemented with tumor necrosis factor-alpha (TNF). In addition, p14(-) cells generated CD14(+) cells with GM-CSF and TNF, which in turn, differentiated into DC when exposed to GM-CSF and IL-4. Similar results were obtained with frozen DC precursors and also when using pooled human serum AB+ instead of bovine serum, emphasizing that this system using CD34(+) cells may improve future prospects for immunotherapy.
- Published
- 1999
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