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Biomedical subjects

K Bacon

Publications and source records attributed to K Bacon.

At least 19 recordsLinked to original sources
PubMed2001

Discovery and evaluation of piperidinyl carboxylic acid derivatives as potent alpha(4)beta(1) integrin antagonists.

Piperidinyl carboxylic acid-based derivatives were prepared as antagonists of the leukocyte cell adhesion process that is mediated through the interaction of the alpha(4)beta(1) integrin (VLA-4, very late antigen 4) and the vascular cell adhesion molecule 1 (VCAM-1). Compounds 2a-h inhibited the adhesion in a cell-based assay in the low and sub micromolar range, a pharmacokinetic study of 2d is reported.

Area Under Curve↗
PubMed2000

Alternative antigen receptor (TCR) signaling in T cells derived from ZAP-70-deficient patients expressing high levels of Syk.

ZAP-70-deficient patients present with nonfunctional CD4+ T cells in the periphery. We find that a subset of primary ZAP-70-deficient T cells, expressing high levels of the related protein-tyrosine kinase Syk, can proliferate in vitro. These cells (denoted herein as Syk(hi)/ZAP-70(-) T cells) provide a unique model in which the contribution of Syk to TCR-mediated responses can be explored in a nontransformed background. Importantly, CD3-induced responses, such as tyrosine phosphorylation of cellular substrates (LAT, SLP76, and PLC-gamma1), as well as calcium mobilization, which are defective in T cells expressing neither ZAP-70 nor Syk, are observed in Syk(hi)/ZAP-70(-) T cells. However, Syk(hi)/ZAP-70(-) T cells differ from control T cells with respect to the T cell antigen receptor (TCR)-mediated activation of the MAPK cascades: extracellular signal-regulated kinase activity and recruitment of the JNK and p38 stress-related MAPK pathways are diminished. This distinct phenotype of Syk(hi)/ZAP-70(-) T cells is associated with a profound decrease in CD3-mediated interleukin 2 secretion and proliferation relative to control T cells. Thus, ZAP-70 and Syk appear to play distinct roles in transducing a TCR-mediated signal.

Adaptor Proteins, Signal Transducing↗
PubMed1999

The role of interleukins 1, 6 and 8 as lymphocyte attractants in the photodermatoses polymorphic light eruption and chronic actinic dermatitis.

The two photodermatoses, polymorphic light eruption (PLE) and chronic actinic dermatitis (CAD), are characterized by lymphocyte-rich inflammatory infiltrates, the pathogeneses of which are not fully understood. We have therefore studied suction blister fluid (SBF) samples from patients with these conditions before and at two time points after the induction of experimental lesions by means of a solar simulator; this SBF was then tested for the presence of selected cytokines known to induce peripheral blood lymphocyte (PBL) migration in vitro. A specific EL-4 NOB-1 bioassay was used to detect interleukin (IL)-1 activity, which has already been noted in normal skin and this was found in pre-irradiation control samples as well as 1-3 h and 24 h post-irradiation in both patient groups, but at levels not significantly different from those of controls. Use of a B9 cell proliferation assay showed no detectable IL-6-like activity pre-irradiation, but there was substantial activity in samples at both post-irradiation time points in both patient groups. Further, in other experiments, retained SBF samples were tested in an in vitro PBL migration assay in the presence and absence of neutralizing antibodies against IL-1 alpha, IL-1 beta, IL-6 and IL-8; considerable PBL attractant activity was noted in the pre-irradiation SBF from both patient groups; a finding consistent with previous reports of such activity in samples from normal skin, and at least in CAD patients, a proportion of this activity appeared to be due to IL-1, pre-incubation of SBF with neutralizing antibodies against IL-1 alpha and IL-1 beta reducing the effect significantly. Substantial PBL attractant activity was present also in the SBF from 1-3 h and 24 h post-irradiation samples in both patient groups and again, IL-1 neutralizing antibodies reduced this in the 1-3 h and 24 h CAD samples. In addition, neutralizing antibodies against IL-6 and IL-8 reduced the activity in the 24 h PLE samples significantly and although not fully conclusive in the case of IL-1, these data suggest that IL-6, IL-8 and possibly IL-1 may be involved in the induction of PBL infiltrates, and perhaps other events, in both PLE and CAD.

Adult↗
PubMed1997

In vitro Entamoeba histolytica adhesion to human endothelium: a comparison using two strains of different virulence.

Extraintestinal dissemination of Entamoeba histolytica is frequently manifested by the life-threatening amebic liver abscess (ALA). The hepatic establishment of amebas implies invasion of blood vessels and contact with the endothelium. By means of a fluorescence-based quantitative adhesion assay, we assessed the binding to human endothelial cells of two E. histolytica strains of different virulence. The highly virulent strain (L-A) adhered substantially more strongly to unstimulated endothelium than the non-virulent one (BG3). Attachment of L-A was increased by treatment of endothelial cells with interleukin-1 beta (IL1 beta). Other proinflammatory cytokines such as interferon-gamma (IFN gamma) and tumor necrosis factor-alpha (TNF alpha) did not modify the spontaneous adhesion capacity of amebas. For purposes of comparison we also performed adhesion of the parasites to skin fibroblasts. Adhesion to this cell type was quite low (< 10%). Parasite virulence, differential adhesive capacity to endothelial cells, and modulation of the latter phenomenon by proinflammatory factors (IL1 beta) may influence the evolution and outcome of extraintestinal amebiasis, especially hepatic abscesses.

Animals↗
PubMed1997

Structure and bioactivity of recombinant human CTAP-III and NAP-2.

Connective tissue-activating peptide III (CTAP-III) and neutrophil-activating peptide-2 (NAP-2) are both derived from a common precursor, platelet basic protein (PBP), which is stored in the alpha-granules of platelets and released upon their activation. CTAP-III is an 85-residue peptide which is converted to NAP-2 by enzymic removal of the 15 amino-terminal residues. Both peptides play a role in the early stages of wound healing and inflammation through different activities. We have cloned the cDNA for PBP and expressed constructs coding for the CTAP-III and NAP-2 polypeptides in Escherichia coli. We have purified and renatured these recombinant proteins. The integrity of the recombinant proteins has been ascertained by in vitro bioassays. CTAP-III causes 51% histamine release from the basophilic cell lin KU812 at 10(-7) M, whereas NAP-2 only causes 28% release at the same concentration. In assays on human neutrophils, NAP-2 had an EC50 of 2 x 10(-8) M in chemotaxis, an EC50 of 3 x 10(-8) M for shape change, and could displace IL-8 from neutrophils with a Kd of 7.5 x 10(-9) M. CTAP-III had no activity in these assays. The disulfide bonds have been identified by peptide mapping and sequence analysis, and are in the positions predicted by homology to interleukin-8 and platelet factor 4. Measurement of the molecular mass at physiologic concentrations by gel permeation chromatography has shown that CTAP-III forms predominantly tetramers and dimers, whereas NAP-2 is only dimetric. SDS/PAGE analysis of samples cross-linked with disuccinimidyl suberate support these topologies. We postulate a mechanism for tetramer formation based on the interaction of the amino-terminal extension in CTAP-III involving a helix-helix interaction that could stabilize the association of two CTAP-III dimers.

Amino Acid Sequence↗
PubMed1996

Overexpression of RANTES using a recombinant adenovirus vector induces the tissue-directed recruitment of monocytes to the lung.

RANTES (regulated on activation, normal T cell expressed and secreted) is a member of the C-C superfamily of chemokines and is reported to function as a potent chemoattractant for monocytes, eosinophils, and a subpopulation of CD4+ T cells. Using a recombinant human type 5 adenovirus containing the murine RANTES cDNA (Ad5E3 mRANTES), which is capable of expressing biologically active cytokine upon infection, we initiated a study to characterize the biologic functions of RANTES cytokine in vivo. Intratracheal administration of Ad5E3 mRANTES targeted transient RANTES expression to the bronchial epithelium of the lung in Sprague-Dawley rats. Bronchoalveolar lavage fluids (BAL) collected at 24 h had increased chemotactic activity vs controls as measured in a murine CD4+ T cell Boyden chamber microchemotaxis assay. There was a dramatic increase in the number of cells (macrophage, monocytes, and neutrophils) recovered from BAL samples taken from Ad5E3 mRANTES-treated animals at 24 h, with a >50-fold increase in monocytes, indicating a proinflammatory effect for this cytokine in vivo. This effect on monocytes was transient, decreasing by 7 days, with evidence of increased eosinophils and lymphocytes at this time. Histologic examination of lung sections at 24 h revealed greatly increased numbers of mononuclear cells, primarily monocytes, within the lungs of Ad5E3 mRANTES-treated animals, with increased extravasation of monocytes around blood vessels, indicating an ongoing process of peripheral blood monocyte recruitment. This study provides further evidence for RANTES to be a monocyte chemoattractant in vivo.

Adenoviridae↗
PubMed1996

Combined chemokine and cytokine gene transfer enhances antitumor immunity.

The probability of producing a specific antitumor response should be increased by multiplying the number of T lymphocytes that encounter the malignant cells. We tested this prediction in a murine model, using a recently discovered T-cell chemokine, lymphotactin (Lptn). This chemokine increased tumor cell infiltration with CD4+ lymphocytes but generated little antitumor activity. Coexpression of the T-cell growth factor interleukin-2, however, greatly expanded the T lymphocytes attracted by Lptn, affording protection from the growth of established tumor in a CD4+ and CD8+ T cell-dependent manner. Lesser synergy was seen with GM-CSF. Hence coexpression of a T-cell chemokine and T-cell growth factor potentiates antitumor responses in vivo, suggesting a general strategy to improve cancer immunotherapy.

Animals↗
PubMed1993

Human macrophage inflammatory protein alpha (MIP-1 alpha) and MIP-1 beta chemokines attract distinct populations of lymphocytes.

Lymphocyte trafficking is an essential process in immune and inflammatory functions which can be thought to contain at least two main components: adhesion and migration. Whereas adhesion molecules such as the selections are known to mediate the homing of leukocytes from the blood to the endothelium, the chemoattractant substances responsible for the migration of specific subsets of lymphocytes to sites of infection or inflammation are largely unknown. Here we show that two molecules in the chemokine (for chemoattractant cytokine) superfamily, human macrophage inflammatory protein 1 alpha (MIP-1 alpha) and MIP-1 beta, do not share identical attractant activities for lymphocyte subpopulations. When analyzed in vitro in microchemotaxis experiments, HuMIP-1 beta tends to attract CD4+ T lymphocytes, with some preference for T cells of the naive (CD45RA) phenotype. HuMIP-1 alpha, when tested in parallel with HuMIP-1 beta, is a more potent lymphocyte chemoattractant with a broader range of concentration-dependent chemoattractant specificities. HuMIP-1 alpha at a concentration of 100 pg/ml attracts B cells and cytotoxic T cells, whereas at higher concentrations (10 ng/ml), the migration of these cells appears diminished, and the migration of CD4+ T cells is enhanced. Thus, in this assay system, HuMIP-1 alpha and -1 beta have differential attractant activities for subsets of immune effector cells, with HuMIP-1 alpha having greater effects than HuMIP-1 beta, particularly on B cells.

Chemokine CCL3↗
PubMed1993

CD21 expressed on basophilic cells is involved in histamine release triggered by CD23 and anti-CD21 antibodies.

Recombinant full-length human CD23 incorporated into fluorescent liposomes was used to detect a ligand for CD23 on the basophilic leukemia cell line, KU 812. Based on our recent finding that CD23 interacts with CD21 on subsets of B and T cells, we investigated if the same ligand was involved on KU 812 cells. An anti-CD21 monoclonal antibody (mAb) BU-33, was able to totally block CD23-liposome binding to KU 812 cells. Moreover, KU 812 cells express CD21 mRNA and have a cell surface molecule that reacts with anti-CD21 mAb. The CD23/CD21 interaction was not merely physical but was also associated with an increase in histamine release by KU 812 cells. Both recombinant soluble CD23 and an anti-CD21 mAb-mediated effect on histamine release was not restricted to and anti-CD21 mAb-mediated effect on histamine release was not restricted to the leukemic cell line, but was also observed with normal human blood basophils. These data demonstrate that CD21 is expressed on basophilic cells and that CD21 controls histamine production upon ligand-induced stimulation (CD23 or anti-CD21 mAb).

Antibodies, Monoclonal↗
PubMed1992

Topically applied verapamil hydrochloride inhibits tuberculin-induced delayed-type hypersensitivity reactions in human skin.

Calcium channel antagonists have been reported to possess inhibitory effects on lymphocyte migration and activation in vitro, and on cell-mediated immune reactions in the skin of experimental animals. We have therefore studied the effects of topically applied 8% (w/v) verapamil hydrochloride in propylene glycol on tuberculin-induced delayed-type hypersensitivity reactions in the skin of normal human volunteers. There was significant inhibition of the tuberculin reactions by the verapamil preparation compared to vehicle controls, as determined by forearm skin fold thickness measurement and assessment of the density of mononuclear cell infiltrates in skin biopsies. The precise mechanism of action of verapamil hydrochloride remains unclear, but could include effects on T-cell migration and activation, on antigen-presenting cells, and/or on other cells. The potential for the use of topical calcium channel antagonist preparations in inflammatory skin diseases warrants further study.

Administration, Topical↗
PubMed1990

Selective attraction of monocytes and T lymphocytes of the memory phenotype by cytokine RANTES.

An important process in the immune response is the migration of different populations of lymphocytes at the proper time to sites of antigenic challenge. Although several chemoattractants are known for broad classes of lymphocytes, such as T and B cells, the process by which lymphocytes of specific subsets, such as helper, cytotoxic or memory T cells, migrate to the appropriate sites remains obscure. Interleukin-8 is a chemoattractant for T cells and neutrophils and is a member of a superfamily of soluble molecules related by a conserved motif containing four cysteine residues. IL-8 and related molecules, including platelet factor 4, constitute the C-X-C class of the superfamily and a group of cytokines produced by haematopoietic cells constitute the RANTES/sis or C-C class. The roles of most of these molecules are not well known, although murine MIP-1 alpha of the C-C branch is a specific inhibitor of haematopoietic stem cell proliferation and some members of the C-X-C branch are neutrophil-targeted inflammatory agents. Here we report that the RANTES protein of the C-C class causes the selective migration of human blood monocytes and of T lymphocytes expressing the cell surface antigens CD4 and UCHL1. CD4+/UCHL1+T cells are thought to be prestimulated or primed helper T cells involved in memory T cell function. The preferential attraction of T-cell subsets by specific cytokines could in part explain how lymphocytes are targeted, and may provide insight into the workings of T cell memory.

Amino Acid Sequence↗
PubMed1990

Induction of in vitro human lymphocyte migration by interleukin 3, interleukin 4, and interleukin 6.

The effects of interleukin 3 (IL 3), IL 4, IL 6, and interferon-gamma (IFN-gamma) on lymphocyte migration have been investigated and compared with those of transforming growth factor-beta 1 (TGF-beta 1), granulocyte colony stimulating factor (GCSF), and macrophage colony stimulating factor (MCSF). Potent, temperature-dependent stimulation of lymphocyte migration was obtained in response to IL 3 and IL 4 (ED50 less than 10(-11) M and less than 10(-13) M, respectively) and this migration was abolished in the presence of 3 micrograms ml-1 cytochalasin B. IL 6 and IFN-gamma were less active (ED50 greater than or equal to 10(-9) M and greater than or equal to 10(-8) M, respectively), maximal migration in response to IFN-gamma being only 30% above background as compared with approximately 250% for IL 3 and IL 4. TGF-beta 1, GCSF, and MCSF failed to stimulate lymphocyte migration in doses similar to those used for IL 3, IL 4, and IL 6. The presence of antisera to IL 3, IL 4, and IL 6 specifically inhibited lymphocyte migration induced by the corresponding cytokines (IC50 values being 1/10,000, greater than 1/30,000, and greater than 1/30,000 dilution of antibody, respectively). Cross-desensitization experiments using IL 3 and IL 4 demonstrated that neither IL 3 nor IL 4 were able to stimulate dose-related lymphocyte migration in cells preincubated with IL 3. Cells preincubated with IL 4 were only stimulated by a supraoptimal concentration of IL 4 (10(-11) M). The induction of lymphocyte migration by IL 3, IL 4, and IL 6 therefore appears to be a specific and potentially important effect of these cytokines. Cross-desensitization of lymphocytes by IL 3 and IL 4 raises the possibility that the induction of lymphocyte migration by these cytokines may occur through a common postreceptor signal transduction mechanism.

Chemotaxis, Leukocyte↗
PubMed1986

Relationship between serum cortisol, liver function, and depression in detoxified alcoholics.

High levels of serum cortisol or abnormal dexamethasone suppression tests may be helpful in diagnosing major depressive disorder. However, a controversy exists as to whether abnormal liver function associated with alcohol abuse may negate the diagnostic value of the dexamethasone suppression test in alcoholics. We investigated the value of the dexamethasone suppression test in alcoholics by analyzing the liver function, cortisol levels, and psychiatric status of inpatients from an alcohol detoxification treatment center. The subjects met the DSM III criteria for alcohol dependence but took no chronic medication and had negative screening for substance abuse. They had routine blood screening to evaluate liver function, the afternoon cortisol test and dexamethasone suppression test to study glucocorticoid activity, and a structured evaluation to determine psychiatric diagnoses. The blood chemistry findings demonstrated a lack of significant liver synthetic dysfunction in this group, although 43% of the subjects had some elevation of their liver enzymes. We did not find differences in the liver function between patients with normal and abnormal cortisol levels. However, subjects with endogenous depression did have significantly elevated afternoon cortisol levels, and they tended to have more normal liver tests. These results indicate that modest liver dysfunction does not contaminate the validity of the plasma cortisol tests or the dexamethasone suppression test as diagnostic tools for assessing depression in this group of detoxified alcoholics. In addition, they demonstrate an association between depression and plasma cortisol levels and suggest a correlation between depression and better liver function in alcoholics who seek detoxification.

Adult↗
PubMed1975

Coats from Myxococcus xanthus: characterization and synthesis during myxospore differentiation.

An extracellular coat from glycerol-induced myxospores of Myxococcus xanthus has been isolated and characterized. Coats were examined chemically and by using both transmission and scanning electron microscopy. On a dry weight basis, approximately 75% of the coat is polysaccharide composed entirely of galactosamine and glucose. The remainder of the coat is protein (14%), glycine (8%), and organic phosphorus (less than 1%). Coats remained morphologically intact despite boiling in 10 M urea, sodium lauryl sulfate plus beta-mercaptoethanol, or extraction with warm phenol. Coats also resisted digestion with a variety of proteolytic and polysaccharide degrading enzymes. Synthesis of myxospore coat begins approximately 1 h after the addition of glycerol to a culture. One portion of the coat is complete by 5 to 6 h but additional material consisting primarily of glucose is added after 8 h.

Bacterial Proteins↗