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PubMed2006

Vasoactive intestinal peptide generates human tolerogenic dendritic cells that induce CD4 and CD8 regulatory T cells.

Induction of antigen-specific tolerance is critical for autoimmunity prevention and immune tolerance maintenance. In addition to their classical role as sentinels of the immune response, dendritic cells (DCs) play important roles in maintaining peripheral tolerance through the induction/activation of regulatory T (T(reg)) cells. The possibility of generating tolerogenic DCs opens new therapeutic perspectives in autoimmune/inflammatory diseases. Characterizing endogenous factors that contribute to the development of tolerogenic DCs is highly relevant. We here report that the immunosuppressive neuropeptide vasoactive intestinal peptide (VIP) induces the generation of human tolerogenic DCs with the capacity to generate CD4 and CD8 T(reg) cells from their respective naive subsets. The presence of VIP during the early stages of DC differentiation from blood monocytes generates a population of IL-10-producing DCs unable to fully mature after the effects of inflammatory stimuli. CD4 T(reg) cells generated with VIP-differentiated DCs resemble the previously described Tr1 cells in terms of phenotype and cytokine profile. CD8 T(reg) cells generated with tolerogenic VIP DCs have increased numbers of IL-10-producing CD8(+)CD28(-)-CTLA4(+) T cells. CD4 and CD8 T(reg) cells primarily suppress antigen-specific T(H)1-mediated responses. Therefore, the possibility of generating or expanding ex vivo tolerogenic DC(VIPs) opens new therapeutic perspectives for treating autoimmune diseases and graft-versus-host disease after allogeneic transplantation in humans.

Autoimmunity↗

PubMed1990

[Aminopeptidase activity in populations of human blood mononuclear cells].

The aminopeptidase N (AP N, EC 3.4.11.2) is an ectoenzyme of the plasma membrane, playing presumably an important role in the regulation of immunological processes. The specific activities of Ala-pNA and Leu-pNA cleavage (per cell) are distributed in monocytes T- and non-T-lymphocytes in a proportion of 1:0.2:0.25 and 1:0.17:0.18, respectively. The capacities of Ala-pNA and Leu-pNA hydrolysis in the total fraction T- and non-T-cells are distributed as 1:0.8 and 1:0.7, respectively. The main part of Ala-pNA cleavage was shown to be caused by AP N on the basis of the KM-value (0.5 mmol/l), the activation by CO2+ ions and the pH optimum (7.0-7.5). The Leu-pNA cleavage is dependent on CO2+ and DTT and distinct from the classical cytosolic leucyl aminopeptidase.

Aminopeptidases↗

PubMed1999

Translocation (15;17)(q22;q21) as a secondary chromosomal abnormality in a case of acute monoblastic leukemia with tetrasomy 8.

We describe a case of acute monoblastic leukemia (AML M5a), originally presenting as granulocytic sarcoma of the testis, showing unusual cytogenetic abnormalities. Tetrasomy 8 (primary) and t(15;17)(q22;q21) (secondary) were detected in bone marrow cells 6 months post-diagnosis, both by routine karyotype analysis and by fluorescence in situ hybridization (FISH) studies on metaphases and interphase nuclei. Retrospectively, the same abnormalities were identified in the primary testicular lesion using interphase FISH. However, reverse transcriptase polymerase chain reaction (RT-PCR) did not reveal the presence of a classic PML/RAR alpha fusion transcript. To the best of our knowledge, this is the first case to be reported in the literature of AML showing tetrasomy 8 in combination with secondary t(15;17).

Aneuploidy↗

PubMed1998

Epidermal Langerhans cell development and differentiation.

Epidermal Langerhans cells (LC) play a critical role in host defense. Still we know rather little about the development and functional specialization of these bone marrow-derived dendritic cells (DC) located in the most peripheral ectodermal tissue of the mammalian organism. How LC develop from their primitive progenitors in bone marrow and to what extent LC are related in their development to other lineages of the hemopoietic system is still under debate. There are currently 3 major areas of debate: 1) which are the signals required for LC development and differentiation to occur, 2) what are the (molecular) characteristics of the intermediate stages of LC differentiation, and 3) how are LC related in their development and/or function to other cells of the hemopoietic system? A better understanding of LC development and answers to these questions can be expected from recently developed technologies which allow the in vitro generation of DC with the typical molecular, morphological and functional features of LC from purified CD34+ progenitor cells under defined serum-free culture conditions. TGF-beta 1 was found to be an absolute requirement for in vitro LC development under serum-free conditions upon stimulation with the classical DC growth and differentiation factors GM-CSF, TNF-alpha and SCF. The recently identified cytokine FLT3 ligand further dramatically enhanced in vitro LC development and even allowed efficient in vitro generation of LC colonies from serum-free single cell cultures of CD34+ hemopoietic progenitor cells.

Animals↗

PubMed2000

Flow cytometric evaluation of material-induced platelet and complement activation.

Flow cytometry is used to characterize the activation state of platelets and leukocytes within whole blood after contact for 4 h at 37 degrees C with various materials under conditions of low shear. The contact involved adding heparinized whole blood to small diameter tubes that were connected to two arms extending from a rocking platform. For all surfaces (polyethylene, polypropylene, Silastic, PVA hydrogel) tested there was strong evidence of platelet activation in the bulk blood: platelet-derived microparticles. P-selectin expression and platelet-leukocyte aggregates. Only contact with PVA hydrogel surfaces led to dramatic increases in CD11b up-regulation on monocytes and neutrophils that was inhibited by complement inhibition (sCRI). Flow cytometry was also used to evaluate the effectiveness of various agents to inhibit material-induced complement activation. The assay involved incubating 10 microm polystyrene beads for 1 h with serum at 37 degrees C before isolating the beads so as to label them with a monoclonal antibody against a neoantigen on SC5b-9. The beads were then identified by flow cytometry and the fluorescence associated with their SC5b-9 level recorded. The ability of C1-INH, pentamidine and benzamidine to moderately inhibit SC5b-9 levels suggests a role for classical complement activation in material-induced complement activation.

Biocompatible Materials↗

PubMed2004

Histological inflammatory changes after surgery at the epithelium of the distal esophagus in patients with Barrett's esophagus: a comparison of two surgical procedures.

There are many reports concerning the surgical treatment of patients with Barrett's esophagus, but very few focus on histological changes of inflammatory cells in squamous and columnar epithelium before and late after classic antireflux or acid suppression-duodenal diversion surgery. We evaluate the impact of these procedures in the presence of intestinal metaplasia, dysplasia and Helicobacter pylori in the columnar epithelium. Two groups of patients were studied, 37 subjected to classic antireflux and 96 to acid suppression-duodenal diversion operations. They were subjected to endoscopic and histological studies before and at 1, 3 and more than 5 years after surgery. Manometric evaluations and 24 h pH monitoring were performed before and at 1 year after surgery. The presence of inflammatory cells at both the squamous and columnar epithelium was significantly higher at the late follow up in patients subjected to classic antireflux surgery compared with patients subjected to acid suppression-duodenal diversion operations (P < 0.02 and P < 0.001, respectively). Intestinal metaplasia, present in 100% of patients before surgery, had decreased significantly at 3 years after surgery in patients subjected to acid suppression-duodenal diversion operations compared with classic antireflux procedures, 75% versus 53%, respectively (P < 0.001). The presence of Helicobacter pylori did not vary before or after surgery in either group. In conclusion, acid suppression-duodenal diversion operations are followed by a decreased presence of inflammatory cells in both squamous and columnar epithelium compared with classic antireflux surgery in patients with Barrett's esophagus. Intestinal metaplasia and dysplasia and inflammation findings were also less common after acid suppression-duodenal diversion operation.

Anastomosis, Roux-en-Y↗

PubMed2001

Lack of specific receptors for C-reactive protein on white blood cells.

The classic acute-phase reactant C-reactive protein (CRP) plays an important role in innate immunity. Specific CRP receptors have been described on white blood cells and were further characterized as Fcgamma receptors I and II. Here, we used biotinylated, highly purified natural CRP and recombinant human CRP from E. coli to investigate binding to white blood cells. The structural integrity of recombinant CRP was demonstrated by proof of pentamer assembly using non-denaturing gel electrophoresis. Furthermore, the functional capability was confirmed by calcium-dependent ligand binding (phosphorylcholine-coupled BSA and nuclear constituents), and by complement activation (C3 deposition). The monocytic cell line U937 expresses FcgammaRI and FcgammaRII--the proposed CRP receptors--in high density. Binding of biotinylated CRP was only detected by flow cytometry using a partially purified CRP preparation, that contained additional proteins, e.g. IgG as demonstrated by immunoblotting. Highly purified and recombinant CRP, free of IgG, were not bound. To exclude blocking of binding epitopes by labeling on recombinant CRP, biotinylation was performed at various biotin to protein ratios. In addition, competition assays demonstrated that binding of biotinylated, partially purified CRP was only inhibited by partially purified CRP and IgG, but not by highly purified and recombinant CRP. Recombinant CRP bound to U937 cells only after contamination with 0.5 microg IgG per 100 microg CRP before biotinylation. Therefore, we conclude that CRP itself is not bound to white blood cells and strongly suggest a reassessment of previous data.

Binding Sites↗

PubMed2005

Regulation by allergens of chemokine receptor expression on in vitro-generated dendritic cells.

Immature dendritic cells (DCs) derived from CD34+ progenitor cells or peripheral monocytes, are used as in vitro sensitization models in many chemical allergen treatment studies. During the sensitization, DCs follow maturation process and gain the capacity to migrate to lymph nodes where they stimulate T cells. Chemokine receptor allows DCs to migrate along chemotactic gradients. In this work, we used immature DCs from peripheral monocytes to evaluate the influence of allergens on chemokine receptor and surface-marker expression. We tested the sensitizers dinitrochlorobenzene, Bandrowski's base, and coumarin, as well as the tolerogen dichloronitrobenzene, the irritant sodium dodecyl sulfate and the solvent dimethyl sulfoxide. All skin sensitizers up-regulated the co-stimulatory molecule CD86 and increased the CD83+ cell population. No expression of the chemokine receptors CCR2, CCR3, CCR6, or CXCR5 was observed on DCs exposed to the tested chemicals. The strong allergen dinitrochlorobenzene slightly increased CCR7 expression on DCs but down-regulated CCR1 surface expression. CCR1 down-regulation was not mediated by a classical maturation pathway, as it was unaffected by the corticosteroid dexamethasone.

Allergens↗

PubMed1999

Interleukin-18 and interleukin-1 beta: two cytokine substrates for ICE (caspase-1).

This special article deals with the role of processing enzymes in the generation of bioactive cytokines, particularly IL-1 beta and the novel cytokine IL-18, which was formerly called IFN gamma-inducing factor (IGIF). The "classical" pathways of cytokine processing are described, as well as the importance of alternative cleavage enzymes. The topic of this review also concerns the biology of IL-18. The regulation of IL-18 production, the IL-18 receptor complex, and the biological effects of this novel cytokine are described.

Amino Acid Sequence↗

PubMed2002

HER-2/neu-derived peptide epitopes are also recognized by cytotoxic CD3(+)CD56(+) (natural killer T) lymphocytes.

The human HER-2/neu gene encodes a 185 kDa transmembrane glycoprotein recognized by MHC class I-restricted CTLs. Here, we report that HER-2/neu peptide CTL epitopes can also be recognized by cytotoxic NK-T lymphocytes. Unfractionated peptides derived from HLA-A2(+), HER-2/neu(+) tumor cells acid cell extract (ACE), collected from patients with metastatic ovarian cancer, were used as antigen to generate in vitro cytotoxic effectors. ACE was able to elicit from cancer patients' PBMCs both alphabetaTCR(+)CD3(+)CD56(-) and alphaTCR(+)CD3(+)CD56(+) (NK-T) CTLs that lysed ACE-sensitized T2 cells in an HLA-A2-restricted manner. The same CTL lines also recognized T2 cells pulsed with HER-2/neu-derived CTL peptide epitopes, a HER-2/neu-transfected HLA-A2(+) cell line and autologous tumor cells. alphaTCR(+)CD3(+)CD56(+) CTL lines also exhibited NK-like cytotoxicity against autologous tumor cells. CTL clones were isolated from alphaTCR(+)CD3(+)CD56(+) bulk cultures displaying both MHC- and non-MHC-restricted cytotoxicity, thus confirming the dual cytolytic function of such cells. Our data demonstrate that ACE from metastatic ovarian tumors can be used as multiepitope vaccines for generating in vitro, besides classical CTLs, NK-T cells exerting efficient MHC- and non-MHC-restricted cytotoxicity against autologous tumor targets. Such NK-T cells expressing dual cytotoxic activity may prove advantageous in cancer immunotherapy.

Adenocarcinoma↗

PubMed1991

Histological changes in the liver in experimental graft-versus-host disease across minor histocompatibility barriers. VI. A light and electron microscopic study of the periportal changes.

Periportal changes of the liver in experimental graft-versus-host disease (GVHD) across minor histocompatibility barriers were investigated electron-microscopically for up to 14 months after bone marrow transplantation (BMT). In GVHD mice, periportal changes affecting the limiting plate of hepatocytes were relatively mild and, in general, classical piecemeal necrosis was rarely observed. However, around 2 weeks after transplantation disruption of the limiting plate of hepatocytes was transiently observed. At that time, lymphocytes invaded directly into the hepatic parenchyma and were in close contact with hepatocytes mainly through a number of point-contacts of cell membranes. Hepatocytes in close contact with lymphocytes showed minor degenerative changes under electron microscopy. On the other hand, periportal bile ductules and canals of Hering were constantly injured by inflammatory cells during the entire observation period up to 14 months after BMT. They were abutted by lymphocytes, together with other inflammatory cells including eosinophils, neutrophils, plasma cells and monocytes. Infiltration of inflammatory cells into the epithelial layer of the bile ductules and canals of Hering through the basement membrane was frequently found. Inflammatory cells were in contact with duct epithelial cells mainly through a number of point-contacts of cell membranes. Epithelial cells in contact with inflammatory cells exhibited a number of degenerative changes, including condensation of cytoplasm, irregular contour of nucleus, dilatation of endoplasmic reticulum, formation of cytoplasmic vesicles, focal cytoplasmic degeneration, and so on.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Does HIV cause AIDS? An updated response to Duesberg's theories.

AIDS is an acquired immunodeficiency syndrome caused by the lentivirus HIV and characterized by a successive depletion of CD4 helper/inductor lymphocytes. The humoral and cellular immune deficiency is the basis for the development of opportunistic infections and tumors. Because of a multitude of different bacterial, viral, and parasitic opportunistic agents, AIDS is typified by a number of divergent clinical symptoms. As with many lentiviruses, HIV is difficult to demonstrate in the organism, especially in asymptomatic carriers. Although the rate of infection in peripheral lymphocytes appears to be low, there is an increasing amount of virological and immunological data which help to explain the slow but irreversible failure of the immune defense. We still know relatively little about the pathogenic mechanisms of HIV, although a number of the presently available experimental results provide useful starting points for subsequent investigations. Peter H. Duesberg recently published that HIV and AIDS may well be correlated, but stated that HIV is not the cause of AIDS. Duesberg bases his hypothesis on the fact that HIV fulfills neither Koch's classic postulates nor several more of his own postulates for viral pathogenesis. Following the summary of individual pathogenic mechanisms of HIV infection, the separate points of Duesberg's hypothesis are discussed in detail. It is made very clear that the magnitude of epidemiologic, clinical, and experimental observations and results argue for a causal role of HIV and AIDS.

Acquired Immunodeficiency Syndrome↗

PubMed2001

Activated protein C induction of MCP-1 in human endothelial cells: a possible role for endothelial cell nitric oxide synthase.

Classically, activated protein C (APC) of the protein C/protein S anticoagulant pathway has functioned not only to inactivate the procoagulant factors Va and VIIIa but also to inhibit the activity of plasminogen activator inhibitor-1 (PAI-1). More recent data have suggested that the protein C/protein S pathway may serve as a physiological link between coagulation and inflammation. This APC pathway link was proposed because of observations showing that APC could both modulate the effects of cytokines and block neutrophil activation. As a further extension of the effect(s) of APC on cytokines, we found that APC, at the equivalent physiological protein C concentration of 4 microg/ml, significantly upregulated monocyte chemotactic protein-1 (MCP-1) RNA in human umbilical vein endothelial cells (HUVECs), as indicated by a ribonuclease protection assay (RPA) at 3 and 6 h with a return to near basal levels by 24 h. ELISA determinations demonstrated that 4 microg/ml of APC induced a significant (P=.0001) increase in MCP-1 protein production over basal levels within a 24-h period. At the same concentration, APC downregulated endothelial cell nitric oxide synthase (eNOS) RNA. Downregulation first became apparent at 6 h and continued through 48 h of culture. This downregulation was concentration dependent over a range of 1.3-12 microg/ml, and there was no effect on cell viability within this range. In support of other studies, we also found that exogenously added nitric oxide (NO) inhibited MCP-1 production. These data suggest that APC may induce MCP-1 through the inhibition of eNOS.

Chemokine CCL2↗

PubMed2005

Protein kinase C betaII plays an essential role in dendritic cell differentiation and autoregulates its own expression.

Dendritic cells (DC) arise from a diverse group of hematopoietic progenitors and have marked phenotypic and functional heterogeneity. The signal transduction pathways that regulate the ability of progenitors to undergo DC differentiation, as well as the specific characteristics of the resulting DC, are only beginning to be characterized. We have found previously that activation of protein kinase C (PKC) by cytokines or phorbol esters drives normal human CD34(+) hematopoietic progenitors and myeloid leukemic blasts (KG1, K562 cell lines, and primary patient blasts) to differentiate into DC. We now report that PKC activation is also required for cytokine-driven DC differentiation from monocytes. Of the cPKC isoforms, only PKC-betaII was consistently activated by DC differentiation-inducing stimuli in normal and leukemic progenitors. Transfection of PKC-betaII into the differentiation-resistant KG1a subline restored the ability to undergo DC differentiation in a signal strength-dependent fashion as follows: 1) by development of characteristic morphology; 2) the up-regulation of DC surface markers; 3) the induction of expression of the NFkappaB family member Rel B; and 4) the potent ability to stimulate allo-T cells. Most unexpectedly, the restoration of PKC-betaII signaling in KG1a was not directly due to overexpression of the transfected classical PKC (alpha, betaII, or gamma) but rather through induction of endogenous PKC-beta gene expression by the transfected classical PKC. The mechanism of this positive autoregulation involves up-regulation of PKC-beta promoter activity by constitutive PKC signaling. These findings indicate that the regulation of PKC-betaII expression and signaling play critical roles in mediating progenitor to DC differentiation.

Cell Differentiation↗

PubMed1990

[Langerhans cells in the physiopathology of atopic dermatitis].

INTRODUCTION. Atopic dermatitis (AD), allergic rhino-conjunctivities and allergic asthma constitute the classical triad of atopic diathesis attended, in many cases, by high serum IgE levels. While the pathophysiology of IgE-mediated allergic respiratory diseases is now better understood, the pathophysiological significance of atopic phenomena in the genesis and control of AD is still far from being clear. Numerous clinical and laboratory data point to a pathophysiological relation between IgE-mediated reactions and AD, but no one yet knows by which mechanism this interaction takes place. Some recent studies suggest that Langerhans cells might well be the missing link. THE LANGERHANS CELLS. Langerhans cells (LC) are dendritic epidermal cells originating in the bone marrow and supposedly belonging to the monocyte lineage. Their circulating precursors, the mechanism of their migration into the epidermis and their relationship with other dendritic cells, such as the interdigitating follicular cells, are controverted. LC express numerous surface markers, such as class I and II HLA, CD1a, CD4 and receptors for complement and IgE Fc fragments. Under normal conditions, LC do not express IgE receptors. Ultrastructurally, LC are characterized by the presence of Birbeck granules in their cytoplasm. Among the presumed functions of LC in the skin, the best documented is the presentation of antigens to T lymphocytes in allergic contact dermatitis. LANGERHANS CELLS IN ATOPIC DERMATITIS. Quantitative studies. Modern immunohistological methods based on the reactivity of monoclonal anti-CD1a antibodies have given results that are sometimes conflicting due to differences in the quantification techniques utilized. However, morphometric enumeration of LC on cryostat sections have shown that their number is about the same in AD and in normal skin. PRESENCE OF IgE BEARING LANGERHANS CELLS IN ATOPIC DERMATITIS. The presence of IgE molecules on the LC surface has been demonstrated in subjects with AD. It must be noted that in atopic subjects IgE bearing Lc are only found in patients with high serum IgE levels. They are absent in asthma patients without eczema, irrespective of their serum IgE levels. Daily applications of corticosteroids on AD lesions result in a decrease of anti-IgE markers on LC after one week and in their complete disappearance after 2 weeks. IN ATOPIC DERMATITIS LANGERHANS CELLS EXPRESS A RECEPTOR SPECIFIC TO Fc FRAGMENTS OF IgE. The exact nature of the receptor for IgE expressed in situ in AD patients is still conjectural. Some authors have been able to demonstrate that the binding of IgE molecules by LC isolated from the skin of atopic patients is inhibited by a monoclonal antibody directed against the low affinity receptor (Fc epsilon R2) of eosinophils and macrophages. This strongly suggests that certain factors induce the expression by LC of an Fc epsilon R2 receptor. IN VITRO INDUCTION OF IgE RECEPTORS ON NORMAL LANGERHANS CELLS...

Dermatitis, Atopic↗

PubMed2002

Microaerophilic conditions permit to mimic in vitro events occurring during in vivo Helicobacter pylori infection and to identify Rho/Ras-associated proteins in cellular signaling.

Molecular dissection of the mechanisms underlying Helicobacter pylori infection suffers from the lack of in vitro systems mimicking in vivo observations. A system was developed whereby human epithelial cells (Caco-2) grown as polarized monolayers and bacteria can communicate with each other under culture conditions optimal for each partner. Caco-2 cells grown on filter supports were inserted in a vertical position into diffusion chambers equilibrated with air and 5% CO(2) at their basolateral surface (aerophilic conditions) and 5% CO(2), 5% O(2), 90% N(2) (microaerophilic conditions) in the apical compartment. Remarkably, the epithelial polarized layer was stable under these asymmetric culture conditions for at least 24 h, and the presence of Caco-2 cells was necessary to maintain H. pylori growth. In contrast to previous studies conducted with non-polarized Caco-2 cells and other cell lines kept under aerophilic conditions, we found H. pylori-dependent stimulation of cytokine secretion (MCP-1 (monocyte chemoattractant protein-1), GRO-alpha (growth-regulated oncogene-alpha), RANTES (regulated on activation normal T cell expressed and secreted)). This correlated with nuclear translocation of NF-kappaB p50 and p65 subunits. Tyrosine phosphorylation of nine cellular proteins was induced or enhanced; we identified p120(RasGAP), p190(RhoGAP), p62dok (downstream of tyrosine kinases), and cortactin as H. pylori-inducible targets. Moreover, reduction of H. pylori urease expression was observed in adherent bacteria as compared with bacteria in suspension. In addition to mimicking several observations seen in the inflamed gastric mucosa, the novel in vitro system was allowed to underscore complex cellular events not seen in classical in vitro analyses of microaerophilic bacteria-epithelial cell cross-talk.

Caco-2 Cells↗

PubMed2001

Leukocyte attack in a 3D human coronary in-vitro model.

OBJECTIVE: The importance of peripheral blood leukocytes for the development of early atherosclerosis and restenosis has confronted cardiologists with classical hematologic issues. Three-dimensional human coronary in-vitro units of leukocyte attack (3DLA-units) open the field for exact studies of leukocyte attack and its subsequent effects on human medial coronary smooth muscle cells (HCMSMC). METHODS: Central part of 3DLA-units are polycarbonate membranes with a pore size of 5 microm that correspond to the internal elastic membrane. Human coronary endothelial cells (HCAEC) were cultured on one side of the membranes, HCMSMC on the other side. Before leukocyte attack expression of adhesion molecules was up-regulated by tumour necrosis factor-alpha (TNF-alpha). Leukocyte attack was mimicked by selective adding of human monocytes (MC), respectively human CD4+-lymphocytes (CD4+-LC) to the HCAEC side of the 3DLA-units. Three-dimensional leukocyte attack units were fixed and stained after a period of 30 min, 1, 2, 3, 4, 6, and 24 h. Cell divisions of HCMSMC were analysed by measuring the uptake of bromodeoxyuridine (BrdU). RESULTS: Monocytes were able to adhere to the endothelial surface, pass through the filter-pores, and penetrate the HCMSMC side of the 3DLA-units. Human CD4+-lymphocytes (CD4+-LC) only attached to the HCAEC side, and no chemotaxis to the HCMSMC side was detected. Proliferation of HCMSMC was increased 2.9-fold (P< 0.001) after selective MC-attack and 3.5-fold after selective MC-attack and TNF-alpha stimulus. No significant increase was found after selective CD4+-LC attack, a significant increase (2.1-fold; P < 0.001) was seen after selective CD4+-LC attack and TNF-alpha, stimulus. CONCLUSIONS: Within the given limitations of the model the study emphasizes a predominance of MC in comparison to CD4+-LC in the process of adhesion, chemotaxis, and triggered reactive proliferation of co-cultured HCMSMC within the first 24 h after leukocyte attack. 3DLA-units offer an elegant method to study directly the effects of intravascular and intramural treatment strategies.

CD4-Positive T-Lymphocytes↗

PubMed2000

Endotoxic activity of lipopolysaccharides isolated from emergent potential cystic fibrosis pathogens.

Improved antimicrobial therapies against the classical spectrum of pathogenic bacteria which colonise the lungs of cystic fibrosis (CF) patients has resulted in improved life expectancy and quality of life. Bacterial species that are resistant to a broad range of antibiotics including Stenotrophomonas maltophilia and Alcaligenes xylosoxidans have now emerged as potential new pathogens to fill the niche. At present, it is unclear from clinical data whether these microbes are commensal or pathogenic. In this study we have quantified the inflammatory potential of lipopolysaccharide (LPS) from eight species of Gram-negative organisms which have been cultured with increasing frequency from CF patients. Inflammatory responses induced by LPS from whole human blood and a human-derived monocyte cell line (THP-1) were assessed. Enzyme-linked immunosorbent assays were used to detect interleukin-6, interleukin-8, and tumour necrosis factor alpha (TNF). A bioassay was also used to assess TNF activity. With the exception of S. maltophilia, LPS extracted from all of the bacteria tested upregulated, by varying degrees, expression of each of the proinflammatory cytokines assayed. This study represents the first comprehensive report of the endotoxic potential of a new wave of microbes which are associated with CF.

Cell Line↗