Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dendritic cells (DC) are the most efficient APC for T cells. The clinical use of DC as vectors for anti-tumor and infectious disease immunotherapy has been limited by their trace levels and accessibility in normal tissue and terminal state of differentiation. In the present study, daily injection of human Flt3 ligand (Flt3L) into mice results in a dramatic numerical increase in cells co-expressing the characteristic DC markers-class II MHC, CD11c, DEC205, and CD86. In contrast, in mice treated with either GM-CSF, GM-CSF plus IL-4, c-kit ligand (c-kitL), or G-CSF, class II+ CD11c+ cells were not significantly increased. Five distinct DC subpopulations were identified in the spleen of Flt3L-treated mice using CD8 alpha and CD11b expression. These cells exhibited veiled and dendritic processes and were as efficient as rare, mature DC isolated from the spleens of untreated mice at presenting allo-Ag or soluble Ag to T cells, or in priming an Ag-specific T cell response in vivo. Dramatic numerical increases in DC were detected in the bone marrow, gastro-intestinal lymphoid tissue (GALT), liver, lymph nodes, lung, peripheral blood, peritoneal cavity, spleen, and thymus. These results suggest that Flt3L could be used to expand the numbers of functionally mature DC in vivo for use in clinical immunotherapy.
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PMID:Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified. 892 Aug 82

Developments in the characterization of growth factors and the recognition of their potential for clinical use has advanced through a number of stages. The development of clonogenic haemopoietic colony assays in the 1960s led to the discovery of colony-stimulating activity in the conditioned medium produced by certain cell lines. This activity was then purified and the colony-stimulating factors were identified. With rapid progress in molecular biology techniques in the 1980s, many further growth factors were cloned and produced on an industrial scale. Although erythropoietin, interferons, G-CSF, GM-CSF and IL-2 were all introduced into clinical practice as single agents, cytokines have more recently been investigated for use either in combination, or sequentially. Clinical trials are currently in progress to examine the optimum combinations and timing of administration. Current clinical applications include optimization of methods for mobilization of peripheral blood progenitor cells and amelioration of cytopenias following chemotherapy and bone-marrow transplantation. In the future, cytokines will be employed to expand stem and progenitor cells ex vivo, to improve gene transduction strategies, possibly to protect the gastrointestinal epithelium and as immunomodulators, both in vivo and in vitro. This review will focus on recently characterized growth factors including c-kit ligand/stem cell factor, flt3 ligand, c-mpl ligand/thrombopoietin and interleukins-11, 4, 7, 10, 12 and 13.
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PMID:Cytokines at the research-clinical interface: potential applications. 893 32

The c-kit and flt-3 tyrosine kinase receptors are expressed on primitive hematopoietic cells, and ligands for both receptors have been cloned. In this study, the effects of c-kit ligand (KL) and flt-3 ligand (FL) were compared in the presence of IL-3, GM-CSF, and erythropoietin (3/GM/EPO), using frequent medium exchange cultures of human bone marrow mononuclear cells (BMMNC) and CD34-enriched cells. In MNC cultures, KL increased cell output by 1.7-fold (p < 10(-4), n = 13) and CFU-GM output by 2.4-fold (p < 10(-3)) as compared with control cultures containing only 3/GM/EPO. Analogously, FL increased cell output by 1.3-fold (p < 10(-3)) and CFU-GM output by 4.4-fold (p < 10(-6)). Therefore, FL was more potent on CFU-GM output than KL, but neither altered the lineage composition (granulocyte, monocyte, macrophage) of the colonies produced. Direct addition of KL or FL to colony assays resulted in only a 1.2-fold increase in CFU-GM outgrowth, suggesting that the effects on increased CFU-GM output were at the preprogenitor stage. In CD34-enriched cell cultures, the effects of KL and FL on CFU-GM output were similar (9-fold above control). Nevertheless, MNC cultures (containing an equivalent number of CD34+lin- cells) always generated more cells (2-fold to 4-fold) and CFU-GM (3-fold to 6-fold) than did parallel cultures of CD34-enriched cells. The greater effect of FL (over KL) in MNC cultures was probably due to synergy with endogenously produced growth factors that were absent in CD34-enriched cell cultures. FL-containing cultures (+/-KL) generated cells that formed larger colonies, and these cells had more proliferative potential on replating into secondary and tertiary cultures. Furthermore, FL increased the output of LTC-IC by 2.1-fold (p < 0.01) and CD34+lin- cells by 6-fold (p < 0.05) as compared with 3/GM/EPO cultures. In contrast, KL did not affect the output of LTC-IC and only slightly increased CD34+lin- cell output (by 1.4-fold). Erythrocytes were increased by KL (2.8-fold) and decreased by FL (0.6-fold), whereas granulocytes and monocytes were increased by both KL (1.4-fold) and FL (2.0-fold). When used together, KL and FL were completely additive with respect to cell, CFU-GM, and LTC-IC output, as well as lineage composition. The results indicate that FL is a more potent synergistic growth factor than KL for MNC expansion and that KL and FL act in an independent, direct, additive manner.
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PMID:flt-3 ligand is more potent than c-kit ligand for the synergistic stimulation of ex vivo hematopoietic cell expansion. 893 17

Information on the anti-carcinogenic effect of EGCG, the main constituent of the polyphenols present in Japanese green tea leaves, has recently been accumulating. In this report, we evaluate the effect of EGCG on leukemic blast cells from AML patients. The results showed that EGCG inhibited the proliferation of AML cells in all cases examined. Since AML cells might proliferate by autocrine or paracrine growth mechanisms, we also examined the effect of EGCG on the production of GM-CSF from AML cells. Although EGCG did not directly inhibit the production of GM-CSF, it did inhibit the effect of TNF-alpha or TPA, both of which stimulated AML cells to produce GM-CSF. On the other hand, the modulation of receptors for growth factors might play a role in the proliferation or carcinogenesis of AML cells. We also found that EGCG inhibited the modulation of c-kit, a receptor for stem cell factor, on leukemic cells. These findings suggested that EGCG might be available as a new therapeutic tool for AML patients.
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PMID:Effect of (-)-epigallocatechin gallate on leukemic blast cells from patients with acute myeloblastic leukemia. 900 Jan 19

We have investigated the mechanisms by which hematopoiesis is suppressed in patients suffering from human cytomegalovirus (HCMV) infections. Mixed populations of human bone marrow stromal and hematopoietic progenitor cells were inoculated with the Towne strain of HCMV to determine whether these populations could be infected and support HCMV replication. We found that the Towne strain of HCMV was capable of infecting and replicating in a mixed population of bone marrow stromal cells. We observed no significant alterations in bone marrow stromal cell proliferation or the production of IL-6, GM-CSF, soluble c-kit ligand and TNF-alpha following HCMV replication in either stimulated lipopolysaccharide (LPS) or unstimulated conditions. In samples of culture supernatants from LPS-stimulated HCMV-infected stromal cells, significant elevations in MIP-1alpha were observed. TGF-beta1 levels on the other hand exhibited two patterns following HCMV exposure; either TGF-beta1 levels decreased regardless of LPS stimulation or there was no effect. In addition, we observed that exposure to the Towne strain of HCMV resulted in significant inhibition of both granulocytic and erythrocytic colony formation in methylcellulose progenitor assays. Thus, both the direct effect of HCMV on hematopoietic progenitors as well as altered cytokine production by bone marrow stromal cells (including MIP-1alpha and TGF-beta1, but not IL-6) could contribute to hematopoietic failure during HCMV infection.
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PMID:Infection and replication of human cytomegalovirus in bone marrow stromal cells: effects on the production of IL-6, MIP-1alpha, and TGF-beta1. 905 14

The alpha 4 beta 1 integrin very late activation antigen-4 (VLA-4) has been implicated to play a role in the adhesive interactions between hematopoietic progenitor cells (HPC) and bone marrow stromal cells which express the vascular cell adhesion molecule-1 (VCAM-1) or produce fibronectin (FN). Here, we summarize some of the recent advances made in the elucidation of the role of these particular adhesive interactions for the regulation of normal hematopoiesis. HPC bind to stroma mainly through VLA-4/VCAM-1 interactions. There is evidence which suggests that more primitive HPC constitutively express VLA-4 in a high-affinity state. In vitro studies in the mouse have shown that monoclonal antibodies (mAb) against VLA-4 partly block the development of lymphocytes, myelopoietic cells, and erythropoiesis, whereas in the human system outgrowth of TdT+ B cells is severely retarded by such mAb. In vivo studies revealed that VLA-4 is involved in erythropoietic development, and is particularly important for homing and lodgement of HPC in the bone marrow. Hematopoiesis in mice with deficient expression of alpha 4 integrin or VLA-4's ligand VCAM-1 appears to develop normally. However, chimeras developed from wild-type blastocysts and beta 1 -/- embryonic stem cells do not contain beta 1 -/- hematopoietic cells, although these are present as blood islands in the yolk sac. These beta 1 -/- hematopoietic cells are capable of forming colonies, indicating that beta 1-integrin is not involved in hematopoietic differentiation, but is primarily important for migration of hematopoietic cells into the fetal hematopoietic organs. In addition to the role of VLA-4 in migration, it may also have other regulatory functions. It has been demonstrated that ligation of VLA-4 induces phosphorylation of the protein tyrosine kinase (PTK) pp125FAK as well as other proteins which may be involved in the regulation of ligand affinity. Indeed, it has been shown that tyrosine kinase-dependent stimulation of CD34+ hematopoietic cell lines with c-kit ligand (KL), IL-3 or GM-CSF transiently activates the ability of VLA-4 to bind to VCAM-1 or FN. These events are most probably involved in the induction of quiescence in HPC which adhere to stromal cells. This claim was recently substantiated: when HPC were treated with Fab fragments of an anti-VLA-4 mAb, entry into S-phase of the cell cycle was prevented. Taken together, the present data point to a role for VLA-4 in HPC migration, cell cycle regulation, erythropoiesis and B-lymphopoiesis. Moreover, these insights may explain how defects in adhesive behavior of leukemic HPC through VLA-4 contribute to their dysregulated growth and provide a rationale for therapeutically correcting those defects.
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PMID:VLA-4-mediated interactions between normal human hematopoietic progenitors and stromal cells. 908 34

The kinetics of colony formation by granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cells (PBPCs) were monitored using clone-mapping experiments. Compared with normal resting bone marrow (BM), where the ratio of Day 7:Day 14 granulocyte-macrophage colony-forming cells (GM-CFCs) was 1:0.76-1.9, PB was found to be relatively deficient in progenitor cells with the capacity to form colonies by Day 7 (median ratio Day 7:Day 14 1:21). The most mature Day 7 GM-CFCs, those dispersing or extinguishing before Day 14, were almost absent in PB (< 1% of all GM-CFCs) but comprised 77% of Day 7 GM-CFCs and 32% of all GM-CFCs in BM. The expression patterns of high affinity receptors for G-CSF, GM-CSF, stem cell factor (SCF), and the ligand for flk-2 on CD38hi and CD38-/dim PB CD34+ cells were determined by binding of 125I-labeled ligand and autoradiography. G-CSF receptor (G-CSFR) expression was detected on approximately 25% of CD38-/dim cells (estimated mean 105 receptors per positive cell) and was higher in CD38hi cells (approximately 50% positive, with a mean of 227 receptors per cell). GM-CSFR expression was low (approximately 25% of cells positive, mean of 120 receptor per cell) and did not vary with CD38 expression. c-kit (SCFR) and flk-2 were expressed by > or = 90% and > or = 80% of CD34+ cells, respectively. SCF binding per cell was greater in the CD38hi population, while flk-2 expression did not vary with CD38 expression. These results confirm the heterogeneity of receptor expression by progenitor cells and imply differential regulation of receptor expression during maturation.
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PMID:G-CSF-mobilized peripheral blood progenitor cells: in vitro growth pattern and hematopoietic growth factor receptor profile. 913 Oct 4

We studied the effect of human flt3/flk2 ligand (FL) on the proliferation and differentiation of purified CD34+ blood progenitors which express different levels of c-kit protein in clonal cell culture in comparison with that of stem cell factor (SCF). FL alone did not support significant colony formation. However, FL significantly enhanced neutrophil colony (CFU-G) formation in the presence of granulocyte-colony stimulating factor (G-CSF) by peripheral blood (PB)-derived CD34+c-kit- cells which contained a large number of CFU-G. In addition, FL could synergistically increase the number of CFU-G supported by a combination of interleukin (IL)-3 and G-CSF, as did SCF. As we reported previously, SCF showed a significant burst-promoting activity (BPA). In contrast, FL did not exhibit any BPA on PB-derived CD34+c-kithigh cells in which erythroid-burst (BFU-E) was highly enriched. However, FL could synergize with IL-3 or GM-CSF in support of erythrocyte-containing mixed (E-Mix) colony by PB-derived CD34+c-kithigh or low cells in the presence of Epo. Replating of E-Mix colonies derived from CD34+c-kithigh cells supported by IL-3+Epo+SCF yielded more secondary colonies than those supported by IL-3+Epo or IL-3+Epo+FL. When PB-derived CD34+c-kitlow cells which represent a more immature population than CD34+c-kithigh cells were used as the target, number of secondary colonies supported by IL-3+Epo, IL-3+Epo+SCF or IL-3+Epo+FL was comparable. However, the number of lineages expressed in the secondary culture was significantly larger in the primary culture containing IL-3+Epo+FL than in that containing IL-3+Epo. These results suggest that FL not only acts on neutrophilic progenitors, but also on more immature multipotential progenitors.
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PMID:Human FLT3 ligand acts on myeloid as well as multipotential progenitors derived from purified CD34+ blood progenitors expressing different levels of c-kit protein. 918 37

The murine cell line SR-4987 was originated in our laboratory from adherent cells of a long term bone marrow culture. SR-4987 cells do not express p21-ras and c-fms products on membrane whereas secrete M-CSF, evidence a fibroblast-like morphology and are vimentine positive. This line shows a very poor "in vitro" agar clonogenicity which is not modulated by the addition of different cytokines and growth factors (M-CSF, GM-CSF, G-CSF, IL-3, IL-7, alpha-TNF, PDGF, and EGF). On the contrary, a dramatic increase in clonogenicity is observed in the presence of bFGF. The RT-PCR investigation evidences the mRNA encoding for bFGF, IL-7, GM-CSF, and SCF (c-kit ligand). The analysis of CD antigen expression on SR-4987 cell membrane indicates a phenotype (CD5+, CD44+, 45R(B220)+, sIg+, 5'-nucleotidase+) that is consistent with a B cell feature. Our observations suggest that exogenous bFGF might represent an appropriate stimulus for inducing the SR-4987 cells proliferation also in the absence of cell-substrate anchorage. Further, they indicate that SR-4987 cells could represent a particular differentiation stage in which characters of "stromal cell" and "B cell" are coexpressed in agreement with the hypothesis of a common stromal-hematopoietic differentiation.
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PMID:Expression of B cell markers on SR-4987 cells derived from murine bone marrow stroma. 919 33

We have been studying hematopoietic effects by the tachykinins, which like many other neuropeptides can be expressed in neural and nonneural tissues. Substance P (SP) and neurokinin-A (NK-A), members of the tachykinins are immune and hematopoietic modulators. SP and NK-A are derived from the preprotachykinin-I gene (PPT-I) through alternate splicing and posttranslational modification. In the bone marrow (BM), nerve fibers provide a source of neural SP and the stroma provides a source of nonneural SP. The tachykinins interact with each of three cloned neurokinin (NK) receptors (NK-1R, NK-2R, NK-3R) with SP and NK-A exhibiting binding preferences for NK-1R and NK-2R, respectively. Proliferation of myeloid progenitors (CFU-GM) is differentially regulated by SP and NK-A. The former enhances the proliferation whereas the latter is inhibitory. The BM stroma mediates most of the hematopoietic effects exerted by SP and NK-A partly through the induction of cytokines. The proliferative effects of SP correlate with the induction of positive hematopoietic growth factors such as IL-3, IL-6, GM-CSF and c-kit ligand and the inhibitory effects by NK-A correlate with the induction of two negative hematopoietic regulators, MIP-1 alpha and TGF-beta. Intracellular signals mediated by NK-1R and NK-2R are part of the mechanism responsible for tachykinin-mediated regulation of hematopoiesis. The stimulatory effects on BM progenitors mediated by NK-1R can be partly inhibited by NK-2R activation. IL-1 and other cytokines induced by SP in BM stroma modulate NK-1R induction. Furthermore, SP can induce IL-1 type I receptor in stroma. Together, these data suggest that the tachykinins and the cytokines interact to regulate hematopoiesis. These interactions contribute to hematopoietic regulation by mechanisms that involve induction of: (1) tachykinins and cytokines by each other; (2) NK-1R by cytokines and (3) cytokine receptor by the tachykinins. These studies emphasize that in terms of hematopoiesis, the cytokines and neuropeptides are not mutually exclusive factors and thus, the hematopoietic regulatory network would be incomplete without the role of neuropeptides being considered.
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PMID:Hematopoietic modulation by the tachykinins. 928


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