bluuebunny/crossref_metadata_2025_split huggingface dataset:
ISCOMs: an adjuvant with multiple functions
Authors: Sjölander Anders , Cox John C , Barr Ian G 
Published: January 2018

Abstract
Aluminum salts are currently the only widely used adjuvant for human vaccines. Over the past 10–15 years, a large research effort has attempted to find novel adjuvants with ability to induce abroad range of immune responses, including cell-mediated immunity. The immunostimulating complex or ISCOM is one adjuvant with multiple adjuvant properties. ISCOMs are open cage-like complexes typically with a diameter of about 40 nm that are built up by cholesterol, lipid, immunogen, and saponins from the bark of the tree Quillaia saponaria Molina. ISCOMs have been demonstrated to promote antibody responses and induce T helper cell as well as cytotoxic T lymphocyte responses in a variety of experimental animal models, and have now progressed to phase I and II human trials. This review describes recent developments in the understanding of the structure, composition, and preparation of ISCOMs and will cover important aspects of the understanding of the adjuvant functions of ISCOMs and how they act on the immune system. J. Leukoc. Biol. 64: 713–723; 1998.
Nordihydroguaiaretic acid blocks secretory and endocytic pathways in human dendritic cells
Authors: Ramoner Reinhold , Rieser Claudia , Bartsch Georg , Thurnher Martin 
Published: January 2018

Abstract
Nordihydroguaiaretic acid (NDGA), an antioxidant and inhibitor of the lipoxygenase arm of the arachidonic acid metabolism, was recently demonstrated to inhibit transport of secretory proteins to the Golgi complex. We have investigated the effects of NDGA on the secretory and endocytic activity of cultured human blood dendritic cells (DC). Treatment with NDGA strongly diminished cytokine secretion by DC. Moreover, NDGA reduced in a dose- and time-dependent fashion fluid phase as well as receptor-mediated endocytosis in DC. Zileuton and MK-886, specific inhibitors of 5-lipoxygenase and 5-lipoxygenase-activating protein, respectively, had no effect. Likewise, N-acetyl-l-cysteine, a thiol antioxidant precursor of glutathione, did not affect DC function. Finally, serum remarkably protected the cells from the inhibitory effects of NDGA. Our data demonstrate that NDGA not only disrupts vesicular transport along the secretory route but is also a potent inhibitor of the endocytic pathways in human DC and that NDGA has inhibitory properties different from those described. J. Leukoc. Biol. 64: 747–752; 1998.
During human thymic development, β1 integrins regulate adhesion, motility, and the outcome of RHAMM/hyaluronan engagement
Authors: Gares Sheryl L , Giannakopoulos Nadia , MacNeil Donna , Faull Randall J , Pilarski Linda M 
Published: January 2018

Abstract
During human thymic differentiation, interactions between fibronectin (Fn)/β1 integrins and hyaluronan (HA)/RHAMM control motility and Fn/β1 integrins mediate spontaneous Fn-dependent adhesion. Multinegative (MN, CD3–4–8–) thymocytes exhibit strong spontaneous adherence to Fn (75%) that was efficiently inhibited by anti-α5β1 and only weakly inhibited by anti-α4β1. The relatively weak adherence of unfractionated thymocytes to Fn required both α4β1 and α5β1. Video time-lapse microscopy indicates that a subset of thymocytes also undergo spontaneous Fn-dependent motility mediated by α5β1, α4β1, and the HA-receptor RHAMM, but not by CD44. The loss of motility after hyaluronidase treatment of thymocytes indicated that motility is strongly dependent on HA. Of motile cells, 55% were DP, 19% were DN, and 24% were CD4+SP, but only 1% were CD8+SP. Overall, for MN thymocytes, β1 integrin mediated Fn-adhesion, but after expression of CD4/CD8, β1 integrins mediated Fn-dependent motility. Treatment with the activating anti-β1 mAb QE.2E5 inhibited thymic motility and converted otherwise nonadherent thymocytes to an adherent state. High-avidity interactions via integrins appear to supercede the motogenicity of RHAMM and HA, suggesting that integrin avidity may regulate RHAMM. During thymic development, changes in adhesion or motility appear to be mediated by integrin avidity modulation. J. Leukoc. Biol. 64: 781–790; 1998.
Separation of integrin-dependent adhesion from morphological changes based on differential PLC specificities
Authors: Wooten David K , Teague T Kent , McIntyre Bradley W 
Published: January 2018

Abstract
In normal lymphocytes an inside-out signal up-regulating integrin adhesion is followed by a ligand-mediated outside-in cell spreading signal. Protein kinase C (PKC) inhibition blocks lymphocyte adherence to and spreading on fibronectin. In contrast, putative PLC inhibitors yield distinct differences with respect to adhesion and morphology. The phosphatidylinositol-specific phospholipase C (PLC) inhibitor neomycin blocked spreading of CD3/CD28-activated T cells on fibronectin by disrupting adhesion. Furthermore, when an additional inside-out signal for fibronectin adhesion is unnecessary such as with HPB-ALL T leukemic or phorbol-myristate-acetate-treated normal T cells, neomycin treatment does not alter adhesion or morphology. However, the phosphatidylcholine-specific PLC inhibitor D609 abrogates cell spreading without affecting adhesion to fibronectin in these cells as well as the CD3/CD28-activated T cells. These results strongly suggest that inside-out signaling for the integrin α4β1 in lymphocytes proceeds through phosphatidylinositol-specific PLC and PKC, whereas the outside-in signal utilizes phosphatidylcholine-specific PLC and PKC. J. Leukoc. Biol. 65: 127–136; 1999.
Regulation of early peritoneal neutrophil migration by macrophage inflammatory protein-2 and mast cells in experimental peritonitis
Authors: Mercer-Jones Mark A , Shrotri Milind S , Heinzelmann Michael , Peyton James C , Cheadle William G 
Published: January 2018

Abstract
Neutrophil (PMN) migration into the peritoneal cavity in response to fecal peritonitis is an important mechanism of host defense against bacterial invasion. We show that the murine C-X-C (PMN-specific) chemokine, macrophage inflammatory protein-2 (MIP-2), on intraperitoneal injection in mice, causes PMN migration into the peritoneum. MIP-2 mRNA and protein were expressed by peritoneal leukocytes after cecal ligation and puncture (CLP) in mice and neutralization of MIP-2 reduced peritoneal PMN migration. A prerequisite for neutrophil-endothelial adhesion and subsequent migration from the circulation is selectin-mediated rolling. Pretreatment of mice with an anti-P-selectin antibody before intraperitoneal injection of MIP-2 significantly reduced peritoneal PMN migration. However, there are no reports that a C-X-C chemokine can up-regulate endothelial selectins. We postulated that MIP-2, when injected intraperitoneally, interacts with a cell that is known to release factors that up-regulate endothelial selectins. A likely candidate is the mast cell, which contains histamine and tumor necrosis factor α (TNF-α), and both of these factors induce selectins. Intraperitoneally injected MIP-2 caused an early significant increase in peritoneal TNF-α, whereas histamine levels were unaffected. In a subsequent experiment, mast cell-deficient mice and their normal controls were then injected intraperitoneally with MIP-2 or underwent CLP. Significantly fewer PMNs migrated into the peritoneal cavity in the mast cell-deficient mice after MIP-2 injection or CLP. Thus, our findings indicate that mast cells and MIP-2 are necessary for PMN migration into the peritoneum in response to intra-abdominal infection, and that MIP-2 appears to facilitate this through an increase in TNF-α release. J. Leukoc. Biol. 65: 249–255; 1999.
Multiple roles for PI 3-kinase in the regulation of PLCγ activity and Ca2+ mobilization in antigen-stimulated mast cells
Authors: Barker Sheryll A , Lujan Don , Wilson Bridget S 
Published: January 2018

Abstract
Cross-linking the IgE-bound Fc∊RI with polyvalent antigen leads to Ca2+-dependent degranulation from mast cells and basophils, initiating the allergic response. This overview addresses novel roles for PI 3-kinase in the regulation of signaling events that lie downstream of Fc∊RI-mediated tyrosine kinase activation. The first novel role for PI 3-kinase is in the regulation of PLCγ activity and is demonstrated by a dramatic inhibition of Fc∊RI-induced Ins(1,4,5)P3 production after treatment of RBL-2H3 cells with wortmannin, a PI 3-kinase inhibitor. We show that PI 3-kinase lipid products support Ins(1,4,5)P3 production in at least two ways: by promoting translocation and phosphorylation of PLCγ1 and by direct stimulation of both PLCγ isoforms. In vitro stimulation of PLCγ activity by PtdIns(3,4,5)P3 synergizes with activation by in vivo tyrosine phosphorylation for maximal enzymatic activity. A second novel role for PI 3-kinase is in the regulation of antigen-stimulated Ca2+ influx. Compared with control cells, Ca2+ responses are markedly diminished in antigen-stimulated cells after wortmannin pretreatment. Differences include both a longer lag time to the initial elevation in Ca2+ after antigen and an inhibition of the sustained Ca2+ influx phase. However, thapsigargin challenge during the sustained phase demonstrates no difference in the state of the Ca2+ stores in antigen-stimulated cells in the presence or absence of wortmannin. These data suggest that sufficient Ins(1,4,5)P3 is synthesized in wortmannin-treated cells to mobilize intracellular calcium stores and, furthermore, that the affected phase of Ca2+ influx is unlikely to be attributed to capacitative mechanisms. These data are consistent with a model where at least two pathways mediate Ca2+ influx in antigen-stimulated RBL-2H3 cells, one that is dependent on signals from empty stores (capacitive influx) and another that is downstream of PI 3-kinase. J. Leukoc. Biol. 65: 321–329; 1999.
Signal transduction by reactive oxygen species in non-phagocytic cells
Authors: Finkel Toren 
Published: January 2018

Abstract
A growing body of evidence suggests a potential role for oxygen-derived radicals such as superoxide anions and hydrogen peroxide as intracellular signaling molecules. Recently, progress has been made regarding the regulation of oxidant production in non-phagocytic cells. Significant gaps in understanding persist, however, especially in regard to the source(s) of oxidant production and the direct intracellular target(s) of oxygen radicals. Nonetheless, numerous recent studies have implicated a dynamic change in the intracellular redox state as an important determinant in a host of cellular decisions ranging from growth, to apoptosis, to cellular senescence. J. Leukoc. Biol. 65: 337–340; 1999.
Involvement of JAK2, but not PI 3-kinase/Akt and MAP kinase pathways, in anti-apoptotic signals of GM-CSF in human eosinophils
Authors: Miike Satoshi , Nakao Atsuhito , Hiraguri Masaki , Kurasawa Kazuhiro , Saito Yasushi , Iwamoto Itsuo 
Published: January 2018

Abstract
Granulocyte-macrophage colony-stimulating factor (GM-CSF) transmits anti-apoptotic signals in eosinophils and is involved in tissue eosinophilia at the site of allergic inflammation. We determined whether phosphatidylinositol 3-kinase (PI 3-kinase) and mitogen-activated protein kinase (MAP kinase) are involved in anti-apoptotic signals of GM-CSF in eosinophils. GM-CSF phosphorylated Akt, a downstream component of PI 3-kinase, and MAP kinases (ERK1 and ERK2) at 10 min after stimulation in eosinophils. GM-CSF prevented eosinophil apoptosis and sustained its survival during the 5-day culture. However, neither two PI-3 kinase inhibitors, wortmannin and LY294002, nor MEK inhibitor PD98059 inhibited GM-CSF-induced survival of eosinophils, although wortmannin and PD98059 inhibited GM-CSF-induced Akt phosphorylation and MAP kinase activation in eosinophils, respectively. In contrast, JAK2 inhibitor AG-490 inhibited both GM-CSF-induced JAK2 phosphorylation and cell survival in eosinophils. These results indicate that activation of JAK2, but not activation of PI 3-kinase/Akt and MAP kinase pathways, is critical for anti-apoptotic signals of GM-CSF in human eosinophils. Our findings suggest that manipulation of JAK2 activation would be useful for the treatment of allergic disorders. J. Leukoc. Biol. 65: 700–706; 1999.
Regulation of delta opioid receptor expression by anti-CD3-ε, PMA, and ionomycin in murine splenocytes and T cells
Authors: Li Ming D , McAllen Kathy , Sharp Burt M 
Published: January 2018

Abstract
Previous studies have shown that low levels of delta opioid receptor (DOR) mRNA were detectable by reverse transcription polymerase chain reaction (RT-PCR) in unstimulated splenocytes from BALB/c female mice. This study demonstrates that DOR transcripts can be detected in freshly obtained splenocytes from CD1 female mice as well. The results of studies using quantitative competitive RT-PCR showed that DOR transcripts in splenic T cells increased from &lt; 1 copy/cell to 22 and 42 copies/cell, respectively, after stimulation with anti-CD3-ε for 24 and 48 h compared to the level in freshly obtained T cells. In the presence of actinomycin D, anti-CD3-ε did not affect the rate of degradation of DOR mRNA, suggesting that its stability is not altered by anti-CD3-ε. After incubation with phorbol myristate acetate (PMA) and ionomycin, the expression of DOR mRNA in splenocytes and T cells was significantly reduced compared with unstimulated cells in culture. In addition, the inhibitory effect of PMA prevented anti-CD3-ε-stimulated DOR expression. These data suggest that signaling through the T cell receptor complex by anti-CD3-ε regulates DOR expression differently than PMA and ionomycin. J. Leukoc. Biol. 65: 707–714; 1999.
TRANCE is a TNF family member that regulates dendritic cell and osteoclast function
Authors: Wong Brian R , Josien Regis , Choi Yongwon 
Published: January 2018

Abstract
Tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE) is a new member of the TNF family emerging as a key regulator of the immune system and of bone development and homeostasis. TRANCE is expressed on activated T cells and activates mature dendritic cells (DC), suggesting that it plays a role in the T cell-DC interaction during an immune response. Furthermore, TRANCE is expressed on osteoblasts stimulated with vitamin D3, dexamethasone, and parathyroid hormone. TRANCE, when expressed on osteoblasts, induces osteoclastogenesis and osteoclast activation, suggesting that it links known calciotropic hormones to bone resorption. TRANCE mediates its effects via the TRANCE-receptor (TRANCE-R/RANK), whereas its activity can be inhibited by the soluble decoy receptor osteoprotegerin/osteoclast inhibitory factor (OPG/OCIF). OPG can be neutralized by another TNF-family member, the TNF-related apoptosis-inducing ligand (TRAIL), suggesting that TRANCE is part of a complex cytokine network that regulates a diverse set of functions. We will discuss the current literature describing TRANCE and its receptors and its role in controlling DC and osteoclast function. J. Leukoc. Biol. 65: 715–724; 1999.
Role of CD8α+ and CD8α− dendritic cells in the induction of primary immune responses in vivo
Authors: Maldonado-López Roberto , De Smedt Thibaut , Pajak Bernard , Heirman Carlo , Thielemans Kris , Leo Oberdan , Urbain Jacques , Maliszewski Charlie R , Moser Muriel 
Published: January 2018

Abstract
Data from adoptive transfer of mature dendritic cells (DC) indicate that they are responsible for the induction of primary immunity. Two subclasses of DC have been recently identified in spleen that differ in their phenotype and in certain regulatory features. In vitro, both subsets have the capacity to activate naive T cells, although CD8α+ DC have been shown to induce T cell apoptosis and to stimulate lower levels of cytokines compared with CD8α− DC. The objective of this study was to analyze the function of these distinct DC types in vivo. Our results show that both subsets, pulsed extracorporeally with antigen and injected in the footpads of syngeneic mice, sensitize an antigen-specific T cell primary response. However, CD8α+ cells trigger the development of Th1-type cells, whereas CD8α− DC induce a Th2-type response. These observations suggest that the Th1/Th2 balance in vivo is regulated by the antigen-presenting-cells of the primary immune responses. J. Leukoc. Biol. 66: 242–246; 1999.
Activation and interaction of CD44 and hyaluronan in immunological systems
Authors: Siegelman Mark H , DeGrendele Heather C , Estess Pila 
Published: January 2018

Abstract
Adhesive interactions between receptors on vascular endothelial cells (EC) and circulating leukocytes are pivotal in regulating leukocyte extravasation. Although primary adhesion of lymphocytes to EC has been primarily attributed to the selectin family of receptors, CD44 can also mediate this function when activated to bind its ligand hyaluronan (HA). Triggering through the T cell receptor induces activated CD44 and CD44-dependent primary adhesion in both human and mouse lymphocytes, and the interaction can mediate the extravasation of activated T cells into an inflamed site. Lymphocytes capable of CD44/HA-dependent primary adhesion are found in peripheral blood of some rheumatologic patients, and their presence is associated with concurrent symptomatic or active disease. Thus, circulating T cells bearing activated CD44 may represent a pathogenically important subpopulation of activated cells that is elevated under conditions of chronic inflammation. Together, these data add to the selectin and immunoglobulin gene families a new receptor/ligand pair and further our understanding of their potential physiological role; i.e., antigen-specific T cell activation together with local vascular inflammation permits the CD44/HA interaction and subsequent T cell extravasation. J. Leukoc. Biol. 66: 315–321; 1999.
Tumor's other immune targets: dendritic cells
Authors: Esche Clemens , Lokshin Anna , Shurin Galina V , Gastman Brian R , Rabinowich Hannah , Watkins Simon C , Lotze Michael T , Shurin Michael R 
Published: January 2018

Abstract
The induction of apoptosis in T cells is one of several mechanisms by which tumors escape immune recognition. We have investigated whether tumors induce apoptosis in dendritic cells (DC) by co-culture of murine or human DC with different tumor cell lines for 4–48 h. Analysis of DC morphological features, JAM assay, TUNEL, caspase-3-like and transglutaminase activity, Annexin V binding, and DNA fragmentation assays revealed a time- and dose-dependent induction of apoptosis in DC by tumor-derived factors. This finding is both effector and target specific. The mechanism of tumor-induced DC apoptosis involved regulation of Bcl-2 and Bax expression. Double staining of both murine and human tumor tissues confirmed that tumor-associated DC undergo apoptotic death in vivo. DC isolated from tumor tissue showed significantly higher levels of apoptosis as determined by TUNEL assay when compared with DC isolated from spleen. These findings demonstrate that tumors induce apoptosis in DC and suggest a new mechanism of tumor escape from immune recognition. DC protection from apoptosis will lead to improvement of DC-based immunotherapies for cancer and other immune diseases. J. Leukoc. Biol. 66: 336–344; 1999.
Fully human anti-interleukin-8 monoclonal antibodies: potential therapeutics for the treatment of inflammatory disease states
Authors: Yang Xiao-Dong , Corvalan Jose R F , Wang Ping , Roy Catherine M-N , Davis C Geoffrey 
Published: January 2018

Abstract
Interleukin-8 (IL-8) is a potent chemotactic cytokine implicated in the pathogenesis of a number of inflammatory disease states. Agents that block the binding of IL-8 to its receptor have been shown to block inflammation in animal models of disease. This suggests that drugs specifically targeting IL-8 may prove efficacious in treating multiple human diseases. To this end, we developed a panel of fully human anti-IL-8 monoclonal antibodies (mAbs). These human antibodies were generated from XenoMouse™ strains, mice created by introducing megabase-size unrearranged human immunoglobulin heavy and κ light chain loci into a mouse genome in which the corresponding endogenous loci have been inactivated. From the panel of more than 50 mAbs, two antibodies, K4.3 and K2.2, were further characterized and evaluated for their specificity, productivity, affinity, and biological activity. Both K4.3 and K2.2 bind human IL-8 with high affinity (Kd of K4.3 = 2.1 × 10−10 M; Kd of K2.2 = 2.5 × 10−10 M). In vitro, in addition to blocking IL-8 binding to human neutrophils, K4.3 and K2.2 blocked a number of IL-8-dependent cellular functions including neutrophil activation, up-regulation of the cell adhesion receptor CD11b/ CD18, and neutrophil chemotaxis, suggesting that the fully human anti-IL-8 mAbs derived from XenoMouse strains are potent anti-inflammatory agents. This was further supported by in vivo studies in which K4.3 and K2.2 significantly inhibited IL-8-induced skin inflammation in rabbits. A pharmacokinetic study in Cynomolgus monkeys demonstrated that the α phase half-life is 9.4 h and the β phase 10.9 days, typical of human mAbs in monkeys. These data support advancing a fully human anti-IL-8 mAb into clinical trials to treat inflammatory diseases. J. Leukoc. Biol. 66: 401–410; 1999.`
Reactivity of monoclonal antibodies EG1 and EG2 with eosinophils and their granule proteins
Authors: Nakajima Hirokazu , Loegering David A , Kita Hirohito , Kephart Gail M , Gleich Gerald J 
Published: January 2018

Abstract
Use of the murine monoclonal antibodies EG1 and EG2 has been based on the assumption that EG2 recognizes activated eosinophils. We examined the reactivity of EG1 and EG2 with eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN), and stimulated and nonstimulated eosinophils from normal donors. By radioimmunoassay, EG1 recognized only ECP, whereas EG2 recognized both ECP and EDN. By Western blot, EG1 reacted with ECP, EG2 reacted with both ECP and EDN, but EG2 could not distinguish between lysates of stimulated and nonstimulated eosinophils. By immunofluorescence, EG1 and EG2 at 20 μg/mL stained 95–100% of nonstimulated eosinophils, regardless of fixative; EG1 and EG2 at 0.1 μg/mL stained 61–90% of acetone- and paraformaldehyde-fixed and only 5–21% of methanol-fixed nonstimulated eosinophils. Thus, the reactivity of EG1 and EG2 with eosinophils depends on the method of fixation and antibody concentration; and EG2, in contrast to previous reports, cannot reliably discriminate between resting and activated eosinophils. J. Leukoc. Biol. 66: 447–454; 1999.
The macrophage in atherosclerosis: modulation of cell function by sterols
Authors: van Reyk David M , Jessup Wendy 
Published: January 2018

Abstract
Lipid-laden macrophage foam cells are an early and persistent component of atherosclerotic lesions. As such they are likely to play a key role in disease progression, both as scavengers of lipid and as inflammatory mediators. The sterol content of macrophage foam cells is largely native cholesterol together with a small but significant proportion of oxidized cholesterol (oxysterols). Few in vitro investigations of the influence of sterol accumulation on macrophage function have used cells that contain physiologically or even pathologically representative amounts of cholesterol or, more particularly, oxysterols. However, recent studies, using macrophages with a sterol content much closer to that of authentic foam cells, show that the presence of oxysterols causes an impairment in macrophage cholesterol export, suggesting a key role for oxysterols in the maintenance of the foam cell phenotype. The implications of physiologically relevant levels of oxysterols on a wider range of macrophage function remain to be investigated. J. Leukoc. Biol. 66: 557–561; 1999.