bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced cytotoxicity of allogeneic NK cells with killer immunoglobulin-like receptor ligand incompatibility against melanoma and renal cell carcinoma cells
Authors: Igarashi Takehito , Wynberg Jason , Srinivasan Ramprasad , Becknell Brian , McCoy J. Phillip , Takahashi Yoshiyuki , Suffredini Dante A. , Linehan W. Marston , Caligiuri Michael A. , Childs Richard W. 
Published: March 2004

AbstractCellular inactivation through killer immunoglobulin-like receptors (KIRs) may allow neoplastic cells to evade host natural killer (NK) cell–mediated immunity. Recently, alloreactive NK cells were shown to mediate antileukemic effects against acute myelogenous leukemia (AML) after mismatched transplantation, when KIR ligand incompatibility existed in the direction of graft-versus-host disease (GVHD). Therefore, we investigated whether solid tumor cells would have similar enhanced susceptibility to allogeneic KIR-incompatible NK cells compared with their KIR-matched autologous or allogeneic counterparts. NK populations enriched and cloned from the blood of cancer patients or healthy donors homozygous for HLA-C alleles in group 1 (C-G1) or group 2 (C-G2) were tested in vitro for cytotoxicity against Epstein-Barr virus–transformed lymphoblastic cell lines (EBV-LCLs), renal cell carcinoma (RCC), and melanoma (MEL) cells with or without a matching KIR-inhibitory HLA-C ligand. Allogeneic NK cells were more cytotoxic to tumor targets mismatched for KIR ligands than their KIR ligand–matched counterparts. Bulk NK populations (CD3–/CD2+/CD56+) expanded 104-fold from patients homozygous for C-G1 or C-G2 had enhanced cytotoxicity against KIR ligand–mismatched tumor cells but only minimal cytotoxicity against KIR ligand–matched targets. Further, NK cell lines from C-G1 or C-G2 homozygous cancer patients or healthy donors expanded but failed to kill autologous or KIR-matched MEL and RCC cells yet had significant cytotoxicity (more than 50% lysis at 20:1 effector-target [E/T] ratio) against allogeneic KIR-mismatched tumor lines. These data suggest immunotherapeutic strategies that use KIR-incompatible allogeneic NK cells might have superior antineoplastic effects against solid tumors compared with approaches using autologous NK cells.
Deletion of the major GATA1 enhancer HS 1 does not affect eosinophil GATA1 expression and eosinophil differentiation
Authors: Guyot Boris , Valverde-Garduno Veronica , Porcher Catherine , Vyas Paresh 
Published: March 2004

AbstractExpression of the myeloid transcription factor GATA1 is required for early stages of eosinophil differentiation. Defining mechanisms regulating eosinophil GATA1 expression will be important to understand development of this lineage. However, the cis-elements required for eosinophil GATA1 expression are not fully characterized. Previous work identified HS 1 as a major GATA1 enhancer, but its role in eosinophil GATA1 expression is unclear. Here, we show that mouse HS 1 deletion leaves eosinophil GATA1 mRNA expression and eosinophil differentiation unaffected. Chromatin isolated from eosinophils and encompassing HS 1 is weakly enriched for acetylated histones H3/H4. HS 1 deletion does not alter eosinophil GATA1 locus histone acetylation. In eosinophils, GATA1 and CCAAT/enhancer binding protein ϵ (C/EBPϵ) do not bind HS 1 but bind selectively a cis-element in the first GATA1 intron. Thus, HS 1 is not required for eosinophil GATA1 expression. Instead, this study suggests a previously unsuspected role for the GATA1 intron element for this function.
Down syndrome critical region protein 1 (DSCR1), a novel VEGF target gene that regulates expression of inflammatory markers on activated endothelial cells
Authors: Hesser Boris A. , Liang Xiao Huan , Camenisch Gieri , Yang Suya , Lewin David A. , Scheller Richard , Ferrara Napoleone , Gerber Hans-Peter 
Published: March 2004

AbstractWe conducted a genome-wide analysis of genes that are regulated by vascular endothelial growth factor (VEGF) in endothelial cells and identified DSCR1 to be most significantly induced. Consistent with an antagonistic function on calcineurin (CnA) signaling, expression of DSCR1 in endothelial cells blocked dephosphorylation, nuclear translocation, and activity of nuclear factor of activated T cell (NFAT), a transcription factor involved in mediating CnA signaling. DSCR1 was not only induced by VEGF, but also by other compounds activating CnA signaling, suggesting a more general role for DSCR1 in activated endothelial cells. Transient expression of DSCR1 attenuated inflammatory marker genes such as tissue factor (TF), E-selectin, and Cox-2, identifying a previously unknown regulatory role for DSCR1 in activated endothelial cells. In contrast, knock-down of endogenous DSCR1 increased NFAT activity and stimulated expression of inflammatory genes on activated endothelial cells. Thus, the negative regulatory feedback loop between DSCR1 and CnA signaling in endothelial cells identified may represent a potential molecular mechanism underlying the frequently transient expression of inflammatory genes following activation of endothelial cells.
Advanced glycation end-products increase monocyte adhesion to retinal endothelial cells through vascular endothelial growth factor-induced ICAM-1 expression: inhibitory effect of antioxidants
Authors: Mamputu J C , Renier G 
Published: March 2004

AbstractAccumulating evidence indicates a role for advanced glycation end-products (AGEs) in the development of diabetic retinopathy. In the present study, we examined the in vitro effect of AGEs on human monocyte adhesion to bovine retinal endothelial cells (BRECs) and the molecular mechanisms involved in this effect. Treatment of cultured BRECs with AGEs led to a significant increase in monocyte adhesion and intercellular cell adhesion molecule-1 (ICAM-1) expression. These effects were inhibited by antioxidants including gliclazide and vitamins C and E. On the basis of the stimulatory effect of AGEs on vascular endothelial growth factor (VEGF) secretion by retinal endothelial cells, the role of this growth factor as mediator of AGE-induced monocyte adhesion to BRECs was next investigated. Incubation of BRECs with VEGF increased monocyte adhesion to these cells and enhanced ICAM-1 expression. Treatment of BRECs with an anti-VEGF antibody abrogated AGE-induced monocyte adhesion and ICAM-1 expression. Finally, incubation of BRECs with protein kinase C (PKC) and nuclear factor (NF)-κB inhibitors suppressed monocyte adhesion and ICAM-1 expression elicited by AGEs and VEGF. Taken together, these data indicate that AGEs increase monocyte adhesion to BRECs and that this effect is mediated through VEGF-induced ICAM-1 expression. They also demonstrate that this effect is oxidative stress-sensitive and involves PKC and NF-κB-dependent signaling pathways.
CD38 low IgG-secreting cells are precursors of various CD38 high-expressing plasma cell populations
Authors: Arce Sergio , Luger Elke , Muehlinghaus Gwendolin , Cassese Giuliana , Hauser Anja , Horst Alexander , Lehnert Katja , Odendahl Marcus , Hönemann Dirk , Heller Karl-Dieter , Kleinschmidt Harald , Berek Claudia , Dörner Thomas , Krenn Veit , Hiepe Falk , Bargou Ralf , Radbruch Andreas , Manz Rudolf A 
Published: March 2004

AbstractDespite the important role immunoglobulin G (IgG)-secreting plasma cells play in memory immune responses, the differentiation and homeostasis of these cells are not completely understood. Here, we studied the differentiation of human IgG-secreting cells ex vivo and in vitro, identifying these cells by the cellular affinity matrix technology. Several subpopulations of IgG-secreting cells were identified among the cells isolated from tonsils and bone marrow, particularly differing in the expression levels of CD9, CD19, and CD38. CD38 low IgG-secreting cells were present exclusively in the tonsils. A major fraction of these cells appeared to be early plasma cell precursors, as upon activation of B cells in vitro, IgG secretion preceded up-regulation of CD38, and on tonsillar sections, IgG-containing, CD38 low cells with a plasmacytoid phenotype were found in follicles, where plasma cell differentiation starts. A unitary phenotype of migratory peripheral blood IgG-secreting cells suggests that all bone marrow plasma cell populations share a common precursor cell. These data are compatible with a multistep model for plasma cell differentiation and imply that a common CD38 low IgG-secreting precursor gives rise to a diverse plasma cell compartment.
Eosinophil degranulation in the allergic lung of mice primarily occurs in the airway lumen
Authors: Clark Kristopher , Simson Ljubov , Newcombe Nicole , Koskinen Aulikki M L , Mattes Joerg , Lee Nancy A , Lee James J , Dent Lindsay A , Matthaei Klaus I , Foster Paul S 
Published: March 2004

AbstractEosinophil degranulation is thought to play a pivotal role in the pathogenesis of allergic disorders. Although mouse models of allergic disorders have been used extensively to identify the contribution of eosinophils to disease, ultrastructural evidence of active granule disassembly has not been reported. In this investigation, we characterized the degree of eosinophil activation in the bone marrow, blood, lung tissue, and airways lumen [bronchoalveolar lavage fluid (BALF)] of ovalbumin-sensitized and aero-challenged wild-type and interleukin-5 transgenic mice. Degranulation was most prominent in and primarily compartmentalized to the airways lumen. Eosinophils released granule proteins by the process of piecemeal degranulation (PMD). Accordingly, recruitment and activation of eosinophils in the lung correlated with the detection of cell-free eosinophil peroxidase in BALF and with the induction of airways hyper-reactivity. As in previous studies with human eosinophils, degranulation of isolated mouse cells did not occur until after adherence to extracellular matrix. However, higher concentrations of exogenous stimuli appear to be required to trigger adherence and degranulation (piecemeal) of mouse eosinophils when compared with values reported for studies of human eosinophils. Thus, mouse eosinophils undergo PMD during allergic inflammation, and in turn, this process may contribute to pathogenesis. However, the degranulation process in the allergic lung of mice is primarily compartmentalized to the airway lumen. Understanding the mechanism of eosinophil degranulation in the airway lumen may provide important insights into how this process occurs in human respiratory diseases.
Expression of CD45RB functionally distinguishes intestinal T lymphocytes in inflammatory bowel disease
Authors: ten Hove Tessa , The F Olle , Berkhout Marloes , Bruggeman Joost P , Vyth-Dreese Florry A , Slors J Frederik M , van Deventer Sander J H , te Velde Anje A 
Published: March 2004

AbstractThe importance of CD45RB expression on T cells was already shown in mice where CD45RBhigh expression determines pathogenic potential. In this study, we analyzed the expression of CD45RA, CD45RB, and CD45RO on CD4+ T lymphocytes in the intestinal mucosa and in the circulation of patients with inflammatory bowel disease (IBD). In addition, we studied the cytokine profile of these cells. In the circulation, virtually all CD4+CD45RBhigh T cells expressed the naive marker CD45RA, and circulating CD4+CD45RBlow cells expressed the memory marker CD45RO in IBD patients and a control patient population. In contrast, the intestinal CD4+ CD45RBhigh T cells are in normal controls for 90% CD45RO+. However, in IBD, 27.7% [Crohn’s disease (CD)] and 49% [ulcerative colitis (UC)] of the intestinal CD4+ CD45RBhigh T cells are CD45RA+. This special CD4CD45RA+ T cell in IBD can be found in the lamina propria as well as in lymphoid follicles (confocal laser-scanning microscopy). The CD4+CD45RBhigh T lymphocytes produce significantly less interleukin (IL)-10 and IL-4 and produce more tumor necrosis factor α than CD45RBlow T lymphocytes in control patients. CD4+CD45RBlow T cells from IBD patients produced less IL-10 than CD4+CD45RBlow T lymphocytes of controls, and interferon-γ production by both T lymphocyte subsets was decreased in IBD. These data indicate that CD and UC are characterized by an influx of CD4+CD45RBhigh T lymphocytes. These CD4+CD45RBhigh T lymphocytes seem to be important in the pathogenesis of IBD, as they produce more proinflammatory cytokines and less anti-inflammatory cytokines compared with CD4+CD45RBlow T lymphocytes.
MCP-1-dependent signaling in CCR2−/− aortic smooth muscle cells
Authors: Schecter Alison D , Berman Adriane B , Yi Lin , Ma Harry , Daly Christine M , Soejima Kenzo , Rollins Barrett J , Charo Israel F , Taubman Mark B 
Published: March 2004

AbstractMonocyte chemoattractant protein-1 (MCP-1, CCL2) is a mediator of inflammation that has been implicated in the pathogenesis of a wide variety of human diseases. CCR2, a heterotrimeric G-coupled receptor, is the only known receptor that functions at physiologic concentrations of MCP-1. Despite the importance of CCR2 in mediating MCP-1 responses, several recent studies have suggested that there may be another functional MCP-1 receptor. Using arterial smooth muscle cells (SMC) from CCR2−/− mice, we demonstrate that MCP-1 induces tissue-factor activity at physiologic concentrations. The induction of tissue factor by MCP-1 is blocked by pertussis toxin and 1,2-bis(O-aminophenyl-ethane-ethan)-N,N,N′,N′-tetraacetic acid-acetoxymethyl ester, suggesting that signal transduction through the alternative receptor is Gαi-coupled and dependent on mobilization of intracellular Ca2+. MCP-1 induces a time- and concentration-dependent phosphorylation of the mitogen-activated protein kinases p42/44. The induction of tissue factor activity by MCP-1 is blocked by PD98059, an inhibitor of p42/44 activation, but not by SB203580, a selective p38 inhibitor. These data establish that SMC possess an alternative MCP-1 receptor that signals at concentrations of MCP-1 that are similar to those that activate CCR2. This alternative receptor may be important in mediating some of the effects of MCP-1 in atherosclerotic arteries and in other inflammatory processes.
Estrogen receptor-α deficiency promotes increased TNF-α secretion and bacterial killing by murine macrophages in response to microbial stimuli in vitro
Authors: Lambert K Chad , Curran Edward M , Judy Barbara M , Lubahn Dennis B , Estes D Mark 
Published: March 2004

AbstractIn this series of studies, we determined the potential role of intracellular estrogen receptors (ER), ERα and ERβ, on macrophage function in response to bacterial stimuli. The sex hormone 17β-estradiol (E2) and ER have been shown to modulate inflammatory responses as well as T helper cell type 1 (TH1)/TH2 responses. The mechanisms E2 and its receptors use to alter these immune functions remain largely unknown. ERα and ERβ possess complex actions in tissues where they are expressed. We have characterized the receptor repertoire of murine dendritic cells and thioglycollate-elicited peritoneal macrophages (PM). Both cell types express mRNA for ERα. Neither cell type expressed detectable amounts of ERβ mRNA, as determined by reverse transcriptase-polymerase chain reaction using exon-specific primers spanning each of the seven intron/exon junctions. Primary macrophages from ERα- and ERβ-deficient severe combined immunodeficiency mice [ERα knockout (KO) and ERßKO, respectively] were used to delineate the effects and potential mechanisms via which steroid receptors modulate macrophage function. ERα-deficient PM exposed ex vivo to lipopolysaccharide or Mycobacterium avium exhibited significant increases in tumor necrosis factor α (TNF-α) secretion as well as reduction in bacterial load when compared with wild-type (WT) PM. In contrast, ERβ-deficient PM possessed no significant difference in TNF-α secretion or in bacterial load when compared with WT littermates. These studies suggest that ERα, but not ERβ, modulates murine PM function.
Antagonism of the α4 integrin subunit attenuates the acute inflammatory response to stent implantation yet is insufficient to prevent late intimal formation
Authors: Ma Xiaoli , O’Brien Edward R 
Published: March 2004

AbstractMononuclear leukocytes infiltrate the artery wall via integrin-mediated mechanisms and play an integral role in intimal formation after stenting. We sought to determine if acute antagonism of the α4 subunit of very late antigen-4 is sufficient for the late attenuation of stent intimal area (IA). Twenty-four hypercholesterolemic rabbits underwent iliac artery balloon injury, followed 2 weeks later by stent implantation, and the animals were randomized to receive an anti-α4 antibody (HP1/2) or a nonspecific isotypic control immunoglobulin (1E6) intravenously 1 h before stenting. Compared with controls, HP1/2-treated rabbits showed 50%, 51%, and 44% reductions in the percentage on intimal cells that were macrophages on days 3, 7, and 28 after stenting and a 59% reduction in intimal proliferation on day 3. Although stent IA was reduced by 63% and 48% in the antibody-treated group compared with the control group on days 3 and 7, this difference was not present on day 28. These data highlight the need for sustained, anti-inflammatory therapies for the prevention of stent intimal formation.
VIP/PACAP oppositely affects immature and mature dendritic cell expression of CD80/CD86 and the stimulatory activity for CD4+ T cells
Authors: Delgado Mario , Reduta Allan , Sharma Vikas , Ganea Doina 
Published: March 2004

AbstractThe neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) released within lymphoid organs from nerve terminals and/or immune cells play a significant, anti-inflammatory role by inhibiting macrophage-induced inflammatory reactions and promoting T helper cell type 2 (Th2) responses. However, dendritic cells (DC) and not macrophages often are the major antigen-presenting cells and link between innate and adaptive immunity. The role of VIP/PACAP in DC development and function is mostly unknown. Here, we report that bone marrow-derived DC express VIP/PACAP receptors and that VIP and PACAP exert a differential effect on immature DC (iDC) and lipopolysaccharide (LPS)-treated DC. In iDC, VIP/PACAP up-regulates CD86 expression and enables them to stimulate T cell proliferation and differentiation into Th2 effectors in vivo and in vitro. In contrast, VIP/PACAP down-regulates CD80/CD86 expression in LPS-stimulated DC and strongly reduces their capacity to stimulate T cell proliferation and secretion of Th1 and Th2 cytokines. The VIP/PACAP effects on iDC and LPS-stimulated DC are mediated primarily through the VIP receptor 1. These results indicate that neuropeptides such as VIP and PACAP can differentially affect the function of iDC and mature DC. In the absence of an ongoing immune response, VIP/PACAP contributes to the initiation of Th2-type immunity, whereas in the presence of a full-blown, inflammatory reaction, VIP/PACAP act as anti-inflammatory agents.
Heparin-disaccharide affects T cells: inhibition of NF-κB activation, cell migration, and modulation of intracellular signaling
Authors: Hecht Iris , Hershkoviz Rami , Shivtiel Shoham , Lapidot Tzvi , Cohen Irun R , Lider Ofer , Cahalon Liora 
Published: March 2004

AbstractWe previously reported that disaccharides (DS), generated by enzymatic degradation of heparin or heparan sulfate, inhibit T cell-mediated immune reactions in rodents and regulate cytokine [tumor necrosis factor α (TNF-α), interleukin (IL)-8, and IL-1β] secretion by T cells, macrophages, or intestinal epithelial cells. Here, we investigated the effects of a trisulfated heparin DS (3S-DS) on two aspects of T cell function: secretion of proinflammatory cytokines and migration to an inflamed site. 3S-DS down-regulated nuclear factor-κB activity and reduced the secretion of TNF-α and interferon-γ (IFN-γ) by anti-CD3-activated T cells. In addition, 3S-DS inhibited CXC chemokine ligand 12 (CXCL12; stromal cell-derived factor-1α)-dependent migration in vitro and in vivo and decreased CXCL12-induced T cell adhesion to the extracellular matrix glycoprotein, fibronectin (FN). This inhibition was accompanied by attenuation of CXCL12-induced Pyk2 phosphorylation but did not involve internalization of the CXCL12 receptor, CXCR4, or phosphorylation of extracellular-regulated kinase. Despite inhibiting CXCL12-induced adhesion, 3S-DS, on its own, induced T cell adhesion to FN, which was accompanied by phosphorylation of Pyk2. A monosulfated DS showed no effect. Taken together, these data provide evidence that 3S-DS can regulate inflammation by inducing and modulating T cell-signaling events, desensitizing CXCR4, and modulating T cell receptor-induced responses.
Stage I and II Follicular Non-Hodgkin’s Lymphoma: Long-Term Follow-Up of No Initial Therapy
Authors: Advani Ranjana , Rosenberg Saul A. , Horning Sandra J. 
Published: March 2004

PurposeTo analyze the outcome of no initial therapy in stage I and II follicular small-cleaved (FSC) and follicular mixed (FM) non-Hodgkin’s lymphoma (NHL) on overall survival, time to treatment, incidence and course of transformation, and cause of death.Patients and MethodsThis was a retrospective analysis. Criteria for selection were patients with stage I and IIA FSC and FM (grades 1 and 2) NHL with therapy deferred for at least 3 months after diagnosis and a minimum follow-up of 1 year.ResultsForty-three patients were identified (11 stage I, 32 stage II), with a median age of 58 years. Reasons for no initial therapy included: physician choice (n = 20), large abdominal radiation field required (n = 10), advanced age (n = 7), concern for xerostomia (n = 4), or patient refusal (n = 2). At a median follow-up of 86 months, 27 patients (63%) had not been treated. The median time to treatment in the remaining 16 patients was 22 months. Four of 16 patients transformed to a higher-grade lymphoma. Nine patients died—six due to progressive lymphoma. Estimated survivals at 5, 10, and 20 years were 97%, 85%, and 22%, respectively.ConclusionIn selected stage I and II follicular NHL patients, deferred therapy is an acceptable approach, as more than half of our patients remained untreated at a median of 6 or more years, and survival was comparable to that seen in reports with immediate treatment.
Effect of Ageing on Hormone Secretion and Follicular Dynamics in Sheep with and without the Booroola Gene
Authors: Gonzalez-Bulnes Antonio , Souza Carlos J. H. , Campbell Bruce K. , Baird David T. 
Published: March 2004

Abstract
It has been suggested that ewes carrying the Booroola gene (FecB) consistently ovulate more follicles because they recruit more primordial follicles and/or have a lower rate of atresia. If the former is correct, the pool of follicles would be depleted sooner in FecB animals. We have studied follicular dynamics and endocrine function during follicular and early luteal phases of the estrous cycle of older ewes with or without the fecundity gene and compared this data with data obtained 6 yr previously in the same animals. Older sheep carrying the Booroola gene maintained a significantly higher ovulation rate than noncarrier ewes [4.2 ± 0.8 vs. 2.2 ± 0.6 corpora lutea (CL), respectively; P &lt; 0.05], and in keeping with data from young animals, both ovulatory follicles and CL (4.7 ± 0.3 vs. 6.9 ± 0.7 mm and 12.8 ± 0.5 vs. 16.7 ± 0.8 mm, respectively) were smaller than those of noncarrier ewes (P &lt; 0.05). The interval from luteolysis to the onset of the LH surge increased with age in all the animals (from 52.0 ± 8.0 to 67.0 ± 7.5 h in gene carrier sheep and from 56.0 ± 2.0 to 79.5 ± 9.6 h in noncarrier sheep, P &lt; 0.05). The concentration of estradiol and inhibin A in the early luteal phase was lower in older noncarrier ewes (P = 0.08 and P &lt; 0.05, respectively), and the level of inhibin A was inversely related to the level of FSH in aged sheep of both genotypes (P &lt; 0.0001). In contrast, the number of developing follicles in older ewes of both genotypes was similar to the number found in younger ewes, suggesting that increased ovulation rate in sheep carrying the FecB mutation is related to a reduced rate of atresia.