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J R Dawson

Publications and source records attributed to J R Dawson.

At least 19 recordsLinked to original sources
PubMed1992

Peptide-induced modulation of target cell sensitivity to natural killing.

We have previously shown that the capacity of class I molecules to confer resistance to NK in transfected target cells maps to the Ag-binding site (ABS) of the HLA class I structure. Here we examine the effect of peptide (reagents specific for the ABS) pretreatment on the NK sensitivity of class I+ target cells. Synthetic peptides (10-17 amino acids in length) were used to pretreat C1R target cells expressing either no serologically detectable HLA-A, B class I molecules, or C1R transfectants expressing individual HLA-A or -B locus class I molecules. In each case in which the class I allele had previously been shown to directly bind a given peptide, peptide-pulsing of target cells resulted in increased sensitivity to NK-mediated conjugation and cytolysis. The NK susceptibility of C1R target cells expressing no HLA-A, B class I molecules or the nonprotective HLA-A2.1 or HLA-A2M70 mutant class I molecules was unaffected by pretreatment with HLA-A2-binding peptides. These results support the intimate involvement of the HLA class I ABS and potentially ABS-bound peptides in determining target cell sensitivity to NK. Furthermore, these findings form the basis of an effective screening procedure for discerning peptide class I allele-specific interactions.

Amino Acid Sequence↗
PubMed1992

Factors influencing left-ventricular stiffness.

The aim of the study was to investigate the relative contributions of geometrical and material factors to overall left-ventricular cavity stiffness. Left-ventricular cavity shapes were reconstructed using a computer and the variation of myocardial elastic modulus was calculated, by the finite element method, through the passive phase of diastole when rising volume coincided with rising pressure. Geometric data were obtained from biplane cineangiography, with micromanometer pressure measurements, for ten patients with left ventricular disease. Dimensional analysis was applied to the initial and derived data from which the influences of myocardial compliance, wall thickness-to-long dimension ratio, and aspect ratio (long-to-short axes) were determined. The ratio between the volume elasticity and the myocardial modulus of elasticity, the normalized stiffness ratio (NSR), is proposed as a useful index of left ventricular mechanical behaviour in diastole. The volume elasticity of the chamber is dependent not only upon the myocardium elastic modulus and the wall thickness ratio, but also on the shape of the chamber. Changes in the thickness/radius ratio of the ventricle have less effect upon its distention than those in the long dimension/radius ratio. The left ventricle becomes more spherical in shape through diastole and hence becomes stiffer by this geometric mechanism.

Cineangiography↗
PubMed1992

The profile of rat liver enzyme induction produced by prochloraz and its major metabolites.

1. The profile of the hepatic mixed-function oxidase system of male rats has been examined following treatment with prochloraz (I) and three of its major metabolites (II, III and IV). 2. The overall induction profile of prochloraz reflected the contribution of the individual metabolites. There was a slight increase of lauric acid hydroxylase, but by far the major induction was seen in the activity of aldrin epoxidase and 7-pentoxyresorufin-O-dealkylase (7- and 14-fold respectively). 3. N-Propyl-N-[2-(2,4,6-trichlorophenoxy)ethyl]urea (II), a primary intermediate in the metabolism of prochloraz, was a phenobarbitone-type inducer, increasing the activity of aldrin epoxidase and 7-pentoxyresorufin-O-dealkylase by 120% and 8-fold respectively. 4. The prochloraz metabolites, trichlorophenoxyethanol (III) and trichlorophenoxyacetic acid (IV) were both inducers of the clofibrate type, increasing the activity of lauric acid 12-hydroxylase. 5. The induction profile of prochloraz was of a mixed type, but the predominant characteristics were those of phenobarbitone induction.

Animals↗
PubMed1991

Characterization of a subset of human B lymphocytes interacting with natural killer cells.

Tonsil B cells were analyzed for their capacity to interact directly with NK cells in vitro. A specific, direct interaction between NK cells and B cells could be detected by direct conjugation and by cold target inhibition using the B lymphoblastoid cell line BJA.B as a labeled target. The data further suggest that the B cell interaction with NK cells specifically activates the NK effectors and induces their production of IFN-gamma. The NK-interactive population of tonsil B cells were characterized as low-buoyant density cells (by Percoll gradient fractionation) that stained more brightly with Hoechst 33342, both characteristics of activated B cells. Immunofluorescent staining of NK cell-B cell conjugates allowed determination of the cell-surface antigenic phenotype of conjugate-forming B cells. B cell targets were ICAM-1bri, 4F2+, TfR+, CD32+, BB1+, and CD77-. They tended to be CD38-, but overlapped the CD38+ population. No correlation was seen with CD37, CD44, CD75, CD76, HC2, or Ig kappa. This phenotype is most consistent with a late activation stage of differentiation, just before and overlapping the expression of CD38. These B cells do not appear significantly sensitive to NK-mediated cytolysis, suggesting that NK cell cytokine synthesis and secretion (e.g., IFN-gamma) may be more important in the NK cell regulation of the humoral response.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1991

Class I-induced resistance to natural killing: identification of nonpermissive residues in HLA-A2.

Structural characteristics of major histocompatibility complex class I antigens associated with natural killer (NK)-resistance phenomena were examined. Previous research has shown that transfection of class I genomic DNA clones into class I-deficient, NK-sensitive target cell lines results in transfectants exhibiting class I+, NK-resistant phenotypes. In contrast to the HLA-A3, -B7, -B27, and -Bw58 class I molecules, the HLA-A2 class I molecules were shown not to protect target cells from NK activity. Here we show that this nonprotective phenotype maps to the alpha 1 domain of the HLA-A2 molecule by examining the NK-protective capacity of the natural interdomain recombinant HLA-Aw69 molecule. HLA-Aw69, which consists of an alpha 1 domain exhibiting homology with HLA-Aw68, and alpha 2/alpha 3/transmembrane-cytoplasmic domains, exhibiting homologies with HLA-A2, mimics HLA-Aw68 and provides HLA-A,B null target cell (C1R) transfectants with increased resistance to NK. Further, the inability of transfected HLA-A2 to confer protection against NK activity can be completely attributed to the expression of a "nonpermissive" residue at position 74 in the alpha 1 domain. Site-directed mutation of the His-74 residue in HLA-A2 to the Asp-74 (HLA-A3, -Aw68, -Aw69, -B7) residue generates a mutant that provides C1R cell line transfectants an NK-resistant phenotype. As His-74 blocks access to a side pocket in the HLA-A2 antigen-binding cleft, these results support the critical involvement of residues within the peptide-binding groove of class I molecules in determining the NK susceptibility phenotype of class I+ target cells.

Alleles↗
PubMed1991

Target structures involved in natural killing (NK): characteristics, distribution, and candidate molecules.

Natural killer (NK) cells comprise an important immune effector population that has been implicated in surveillance against tumor metastases and virally infected host cells, suppression of the humoral immune response, and regulation of hematopoiesis. These diverse functions require an initial cognate interaction between the NK effector cell and the target cell of interest. This specific interaction triggers the secretion of NK factors (i.e., lymphokines, cytolytic substances) which mediate NK activity. The target structures (TS) that stimulate the NK response remain ill-defined. While apparent TS heterogeneity may contribute to the difficulty in isolating distinct NK-TS, the proposed multifactorial nature of the NK cell-target cell interaction may represent the major complexity in the search for specific TS. Adhesion molecules such as ICAM-1 and LFA-3 may strengthen, while MHC antigens may weaken, the NK cell-target cell interaction. The following article analyzes the molecular interactions currently held to be relevant in target cell recognition by NK cells.

Animals↗
PubMed1990

Induction of HLA-specific CTL to nonimmunogenic, heat-inactivated lymphocytes by interleukin 2.

Human lymphocytes that have been heat-inactivated (1 hr, 45 degrees C) were used as stimulator cells in a model system to study the requirements of allogeneic T cell activation in vitro. Cytotoxic T lymphocytes were not generated in either primary or secondary mixed lymphocyte cultures after exposure to heated stimulator cells. Successful reconstitution of cytolytic activity in primary cultures was achieved by the addition of rIL-2. Further, cytotoxic T cell lines could be maintained in culture for several weeks by stimulation with heated allogeneic cells and periodic addition of exogenous IL-2. The cytotoxic T cells generated in primary cultures or in the T cell lines were specific for the HLA class I antigens of the stimulating cells. Thus, the combination of heated cells and IL-2 stimulated antigen-specific cytotoxic cells, and not merely lymphokine-activated killers. Although IL-2 production appeared to be a crucial missing component of MLCs with heated lymphocytes, the addition of IL-1, a factor known to act as a second signal for stimulating IL-2 production, did not reconstitute cytolytic activity. These results indicate that (1) heat treatment does not appreciably affect class I structure; (2) HLA class I/T cell receptor interactions are intact, resulting in responsiveness to IL-2 but not IL-1; and (3) heating creates a defect that has a minimal effect on CTL precursor activation but does disrupt a T helper cell/stimulator cell interaction critical for IL-2 production.

Histocompatibility Antigens Class I↗
PubMed1990

Tip-oriented adherence of Treponema denticola to fibronectin.

The adherence of Treponema denticola to ligands on cell surfaces or in basement membranes of periodontal tissues might play an important role in its pathogenicity. A direct microscopic assay was used to examine the binding of T. denticola to fibronectin and other protein substrates adsorbed on plastic cover slips. All strains of T. denticola that were tested adhered to fibronectin but to different degrees. The strains which bound in high numbers frequently bound by their tips. Type strain ATCC 33520 bound to fibronectin in high numbers (149 +/- 11.3 bacteria per microscopic field), with 60% bound by the tips. Strain e' bound in high numbers (140 +/- 10.2) and had the highest percentage of tip binding (98%); strain e bound in lowest numbers (39 +/- 8.2) and had the lowest percentage of tip binding (15%). Laminin supported binding at a level similar to that of fibronectin, as did fibronectin fragments which contained the cell binding domain peptides, RGDS. Type IV collagen and non-RGDS peptides did not support binding. Binding to fibronectin and laminin was inhibited by the addition of antifibronectin and antilaminin antibodies. By lowering the incubation temperature from 37 to 4 degrees C, the number of cells that attached decreased by 60% and tip binding was reduced by 50%. Pretreatment of the cells with collagen did not affect binding, whereas fibronectin pretreatment enhanced binding by 50% and laminin pretreatment resulted in a decrease of 60%. T. denticola adheres by its tips to fibronectin-coated surfaces, which suggests that fibronectin-specific adhesins cluster at the tips.

Bacterial Adhesion↗
PubMed1990

Human natural killer cells do not inhibit growth of Cryptococcus neoformans in the absence of antibody.

The interaction between human natural killer (NK) cells and yeast cells of Cryptococcus neoformans was investigated because experiments in mice indicated that NK cells inhibited the growth of C. neoformans. Strains of C. neoformans serotype A that differed in both resistance to alveolar macrophages and the size and composition of their capsules were evaluated. Human NK cells, which were isolated from normal peripheral blood, were activated by preincubation with interleukin-2 and alpha interferon to generate lymphokine-activated killer (LAK) cells. Yeast cells of C. neoformans were incubated with effector cells (NK or LAK cells); and inhibition of yeast cell growth was measured at 4, 8, and 24 h by comparing quantitative plate counts with controls consisting of yeasts in the absence of effector cells. The cytolytic activity of effector cells against target cells was confirmed by the release of radiolabel from 51Cr-labeled K-562 tumor cells. Neither NK nor LAK cells inhibited the growth of 13 strains of C. neoformans at effector to target cell ratios of as high as 500:1. Monocytes, which were isolated from the same populations of leukocytes as the NK cells, inhibited the growth of two strains of C. neoformans at effector to target cell ratios of 100:1 (92 and 46% inhibition), 50:1 (87 and 17%), and 1:1 (49 and 0%). NK cells could inhibit the growth of C. neoformans by an antibody-dependent cellular cytotoxicity mechanism in the presence of rabbit anticryptococcal antiserum at dilutions up to 1:4,000. Purified capsular polysaccharide of C. neoformans had no effect on the viability or tumoricidal activity of NK or LAK cells. These data suggest that human NK and LAK cells are not impaired by C. neoformans, and in the absence of antibody, which is rarely detectable in patients, they afford much less protection against C. neoformans than monocytes do.

Animals↗
PubMed1990

Relation between intraventricular pressure and volume in diastole.

The pressure-volume curves for 10 patients with various types of heart disease were studied throughout mid to late diastole when both pressure and volume were increasing. The results were used to test a currently held theory that the form of this relation is exponential. It was found that for the patients examined this hypothesis was not valid.

Adult↗
PubMed1989

The alpha 1/alpha 2 domains of class I HLA molecules confer resistance to natural killing.

The expression of transfected HLA class I Ag has previously been shown to protect human target cells from NK-mediated conjugation and cytolysis. In this same system, transfected H-2 class I Ag fail to impart resistance to NK. In this study, we have mapped the portion of the HLA class I molecule involved in this protective effect by exploiting this HLA/H-2 dichotomy. Hybrid class I genes were produced by exon-shuffling between the HLA-B7 and H-2Dp genes, and transfected into the class I Ag-deficient B-lymphoblastoid cell line (B-LCL) C1R. Only those transfectants expressing class I Ag containing the alpha 1 and alpha 2 domains of the HLA molecule are protected from NK, suggesting the "protective epitope" is located within these domains. Since a glycosylation difference exists between HLA and H-2 class I Ag within these domains (i.e., at amino acid residue 176), the role of carbohydrate in the class I protective effect was examined. HLA-B7 mutant genes encoding proteins which either lack the normal carbohydrate addition site at amino acid residue 86 (B7M86-) or possess an additional site at residue 176 (B7M176+) were transfected into C1R. Transfectants expressing either mutant HLA-B7 Ag were protected from NK. Thus, carbohydrate is probably not integral to a class I "protective epitope." The potential for allelic variation in the ability of HLA class I Ag to protect C1R target cells from NK was examined in HLA-A2, A3, B7, and Bw58 transfectants. Although no significant variation exists among the HLA-A3, B7, and Bw58 alleles, HLA-A2 appears unable to protect. Comparison of amino acid sequences suggests a restricted number of residues which may be relevant to the protective effect.

Amino Acid Sequence↗
PubMed1989

Low angle light scattering studies on whole, half, and quarter molecules of T2 bacteriophage DNA.

Static light scattering measurements have been made at angles as low as 8 degrees on whole, half, and quarter molecules of native, T2 bacteriophage DNA in 0.195 M Na+. The fragments were obtained by high-speed stirring of the native DNA, and fractionated on methylated-albumin-kieselguhr columns. Accompanying measurements of sedimentation coefficients and intrinsic viscosities were made. Because linear extrapolations of light scattering data above 8 degrees for these samples were suspect, the measurements were analyzed by fitting curves calculated from the theory of wormlike coils to experimental curves at c = 0. Results showed that the excluded volume parameter, epsilon, must be used in analyzing the scattering curves; a reasonable value of epsilon was 0.08, in agreement with that found for T7 DNA (Harpst, J. A. 1980. Biophys. Chem. 11:295-302). The persistence length of all three DNAs in this paper was 50 +/- 5 nm, showed no dependence on molecular weight, but was somewhat below that reported previously for T7 DNA (60 nm). Theoretical curves calculated with the preceding parameters had a clear upward curvature in scattering envelopes below 8 degrees for quarter and half molecules, but such curvature was minimal for whole T2 DNA, so that linear extrapolations of experimental data above 8 degrees gave a molecular weight and root-mean-square radius which were nearly the same as those from theory. The molecular weight and radius for whole T2, derived from the comparison of theory and experiment, were 115 X 10(6) and 1,224 nm, respectively. The measurements on T2 DNA were clearly at the upper limit of current techniques.

DNA, Viral↗
PubMed1989

Reversal of natural killing susceptibility in target cells expressing transfected class I HLA genes.

A number of studies have suggested that resistance of target cells to natural killing (NK) may be correlated with their level of expression of major histocompatibility complex (MHC) class I antigens. To examine this hypothesis directly, a NK-sensitive class I-deficient human B-cell line was transfected with MHC class I genes. The expression of transfected HLA, but not H-2, class I gene products resulted in loss of susceptibility to human NK-mediated conjugation and cytolysis. Furthermore, this protection did not extend to cytotoxicity mediated by interleukin 2-stimulated human NK effector cells.

B-Lymphocytes↗
PubMed1989

Left ventricular filling and early diastolic function at rest and during angina in patients with coronary artery disease.

Left ventricular diastolic function was studied in 11 patients with coronary artery disease. Single plane ventriculography (30 degrees right anterior oblique projection) was performed at rest and during an episode of angina immediately after a period of rapid atrial pacing. Left ventricular pressure was recorded simultaneously by a micromanometer tipped catheter. The ventriculograms were digitised frame by frame to derive continuous plots of left ventricular shape, volume, and rate of change of volume. The time constant (tau) of the fall in left ventricular pressure was determined from the exponential portion of pressure decay during isovolumic relaxation. Ventricular pressure-volume loops were constructed to study the left ventricular diastolic pressure-volume relation. The time of minimum left ventricular pressure was used to divide diastole into an early phase and a late phase. Angina was associated with an increase in end systolic volume and a fall in ejection fraction with no significant change in end diastolic volume. Peak left ventricular pressure was unchanged but left ventricular minimum and end diastolic pressures were both increased and the diastolic pressure-volume relation was moved upwards. The time constant of left ventricular pressure fall was prolonged. At rest more than 50% of the stroke volume entered the left ventricle during the period of early diastole. This proportion was significantly reduced during angina and as a consequence a significantly greater proportion of the stroke volume entered the ventricle during late diastole. Despite this, and although the left ventricular diastolic pressure-volume relation was moved upwards with angina, the mean slope of the relation during late diastole--that is, chamber stiffness--was not significantly altered. The upward shift of the left ventricular diastolic pressure-volume relation seen during angina is thus already apparent in early diastole, and its extent does not change during the later phase of diastole, which alone shows the property of passive stiffness. A primary increase in the passive stiffness of the ventricle cannot therefore be the cause of the upward shift of the diastolic pressure-volume relation, and events occurring in early diastole have to be looked to for an explanation. The study findings show that left ventricular function in early diastole is profoundly disturbed during angina pectoris and it is suggested that loss of elastic recoil and dissipation of this restoring force by asynchronous onset of relaxation and abnormal changes in shape are important factors contributing to this disturbance of function.

Adult↗
PubMed1988

What stops the flow of blood from the heart?

The determinants of aortic pressure and flow are generally studied using impedance methods, the results of which indicate that reflected waves are important, particularly during aortic flow deceleration. An alternative analysis of measured aortic pressure and velocity, using the method of characteristics to calculate the energy flux per unit area of the waves, suggests a different conclusion. We suggest that aortic deceleration is caused by a discrete expansion wave propagating from the left ventricle, and that energy thus recovered by the ventricle may be coupled to early filling of the ventricle.

Aorta, Thoracic↗
PubMed1988

Left atrial myxoma infected with Streptococcus viridans.

A case is described of Streptococcus viridans endocarditis involving a left atrial myxoma. The diagnosis was made by echocardiography and the infected tumour was successfully treated by surgical removal. A review of the published literature about left atrial myxomas underlines the importance of performing echocardiography in all patients with suspected endocarditis.

Adult↗
PubMed1988

Cell-mediated cytotoxicity and the reorientation of effector cell granules towards the target cell are inhibited by the protonophore carbonylcyanide m-chlorophenylhydrazone.

Cell-mediated cytotoxicity involves a localized secretory process in which lytic agents stored in specialized granules of the effector cells are released upon contact with the appropriate target cell membrane and cause membrane damage. The protonophore carbonylcyanide m-chlorophenylhydrazone (CCCP) inhibits cytotoxicity of natural killer cells, cytotoxic T-lymphocytes and lymphokine-activated killer cells. This inhibition is due to an effect of CCCP on the cytolytic cells, rather than on their targets, and is reversible. Treatment with CCCP does not inhibit the formation of effector-target conjugates, but seems to affect the programming of the effector cells for lysis. CCCP only inhibits lysis if added during a certain period of the lytic cycle: it has an effect only if added before, or within 5 minutes of the initiation of killing by a pulse of Ca++. Effector cells treated with CCCP retain their characteristic beta-glucuronidase-positive granules, but in the presence of the drug, these are no longer oriented to face the contact area with the target cell membrane.

Carbonyl Cyanide m-Chlorophenyl Hydrazone↗