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Glucocorticoid hormones are effective in inhibiting inflammatory responses, but the mechanisms that confer this action have not been completely elucidated. The prevailing view is that these compounds inhibit novel gene transcription regulated by the nuclear factor kappa B and/or activator protein-1 transcription factors. In the last few years, several reports have shown that glucocorticoids can also block signal transduction in lymphocytes at an early, postreceptor step, suggesting novel molecular targets for these hormones. These data will be briefly reviewed and the possible in vivo relevance of these findings discussed, with particular emphasis on T cell development. [ABSTRACT FROM AUTHOR]

Study Objectives: We sought to investigate the effect of lung volume reduction surgery (LVRS) on regional lung ventilation.Design: Retrospective analysis of routinely acquired data before and after LVRS.Setting: Large, urban, university medical center.Patients: Twenty-nine patients with severe emphysema.Intervention: Bilateral LVRS.Measurements and Results: (133)Xe washout curves during lung scintigraphy exhibit a biphasic pattern (the first component of the washout curve [m(r)] corresponds to an initial rapid phase in washout that reflects larger airways emptying, and the second component [m(s)] reflects a slower phase of washout that is attributed to gas elimination via smaller airways). We analyzed six standardized regions of the lung (upper, mid, and lower zones of the right and left lung), and calculated m(r) and m(s) for each lung region. The mean (+/- SE) baseline FEV(1) was 0.69+/-0.04 L, total lung capacity (TLC) was 139 +/-4% predicted, and the residual volume (RV)/TLC ratio was 65+/-2%. The mean improvement in FEV(1) 3 months post-LVRS was 38%. Post-LVRS, m(r) and m(s) increased in 79 and 74 lung regions, respectively, and there was no relationship with respect to lung regions that had or had not been operated on. The increase in m(s), however, significantly correlated with the increase in FEV(1) (r = 0.66; p<0.0001) and the decrease in RV/TLC (r = -0.67; p<0.0001). An increase in m(s) also correlated with a decrease in PaCO(2) (r = -0.39; p = 0.03), but m(r) showed no relationship with any parameter.Conclusions: Small airways ventilation in lung regions that had and had not been operated on is associated with a greater improvement in lung mechanics following LVRS. [ABSTRACT FROM AUTHOR]

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Unlabelled: The lactulose breath test (LBT) and gastroenterocolonic scintigraphy (GECS) can both be used to measure orocecal transit time (OCTT). The aims of this study were (1) to measure OCTT by LBT and GECS and (2) to determine whether lactulose alters orocecal transit.Methods: Eight normal subjects underwent simultaneous breath hydrogen testing, GECS, and duodenal manometry while receiving either 10 g lactulose or placebo with a radiolabeled solid/liquid test meal during two studies. There was a good correlation between OCTT by LBT and GECS when performed simultaneously (r = 0.95; P < 0.001). OCTT by GECS with lactulose was significantly faster (P = 0.004) than by GECS without lactulose, despite no change in gastric emptying of liquids and slowing of gastric emptying of solids (P = 0.02). The postprandial duodenal motility index was greater with lactulose than with placebo (P = 0.031). This study demonstrates that LBT and GECS (without lactulose) are not equivalent measures of OCTT. The standard LBT accelerates OCTT and slows gastric emptying. Therefore, lactulose has a direct accelerating effect on small intestinal transit. [ABSTRACT FROM AUTHOR]

Based on the specificity of the Watson-Crick base pairing formation, antisense deoxyoligonucleotides have been used to inhibit the expression of oncogenes in various cancer cells. Activation of an oncogene by means of amplification leads to an increased, detectable amount of the mRNA transcript in the cytoplasm. The aim of this study was to demonstrate that cells which are expressing a particular mRNA transcript do preferentially and specifically retain the antisense probe targeting that mRNA. Using a mouse plasmacytoma cell line (MOPC315) which produces high levels of IgA heavy chain mRNA, a control mouse pre B cell line (70ZJ3B), a human mammary cell line (MCF7) which expresses the erbB2 or neu oncogene, MOPC315 cells as neu-negative controls, and antisense DNA oligonucleotides complementary to the 5′ region of the mRNAs and the sense sequence, we have shown that there is a preferential, specific retention of the IgA and neu antisense sequence in MOPC315 and MCF7 cells, respectively. We have further demonstrated that this retention is time and concentration dependent with a maximum at 24 h. We conclude that cancer cells which express a particular oncogene are suitable targets for radiolabeled antisense deoxyoligonucleotides directed toward the oncogene transcript. This work and recent developments in the antisense field lead to the expectation of a new class of radiopharmaceuticals with unique specificity. [ABSTRACT FROM AUTHOR]

BALB/c mice made tolerant to A/J alloantigens by neonatal injection of (A/J × BALB/c)F1 spleen cells develop a host-versus-graft (HVG) disease due to the activation of donor B cells by a subset of host alloreactive helper T cells. We have investigated the effects of a single neonatal injection of the 145-2C11 anti-mouse CD3 monoclonal antibody (MoAb) on the establishment of allotolerance and on the development of the immunopathological features of HVG disease. First, this treatment did not modify the specific anti-donor cytotoxic T lymphocyte (CTL) unresponsiveness or the persistence of circulating immunoglobulins bearing donor allotype. Second, the hyper IgE, the hyper IgG 1 and the increased expression of Ia antigens on B cells found in untreated HVG mice were not observed after injection of the 145-2C11 MoAb. Likewise, treated mice displayed lower levels of anti-DNA IgG antibodies and less glomerular immune deposits as compared with untreated HVG mice. We conclude that the administration of the anti-CD3 MoAb did not interfere with the induction of allotolerance but exerts a pronounced inhibitory effect on the associated immunopathological syndrome. [ABSTRACT FROM AUTHOR]

Intravenous injection of 2 × 108 DBA/2 spleen cells into adult intact (C57BL/6 × DBA/2) Fl mice results in a stimulatory graft-versus-host reaction (GVHR) linked to the recognition by donor CD4+ T cells of Ia alloantigens on host B cells. In the experiments presented here, we found that this GVHR is associated with a major increase in IgE serum levels which was already present 7 days after the cell transfer. At 6 weeks, mean IgE levels were more than 200-fold above the control values. Host B cells were responsible for the hypersecretion of IgE in stimulatory GVHR since it was also observed when the DBA/2 donor inoculum was depleted of B cells but not when the Fl recipients were irradiated. The induction of IgE secretion required donor CD4+ T cells as treatment of the donor inoculum with lytic anti-CD4 monoclonal antibody (MoAb) completely prevented the occurrence of the hyper IgE whereas depletion of CD8+ cells had no influence on this parameter. The role played by interleukin-4 (IL-4) in this model was analysed in vivo by the administration of the 11B11 anti-IL-4 rat MoAb (total dose 36 mg) during the first 12 days following induction of stimulatory GVHR by 8 × 107 DBA/2 spleen cells. This treatment completely prevented the development of hyper IgE whereas the administration of a control rat MoAb had no significant effect. We conclude that stimulatory GVHR in mice is associated with a major increase in serum IgE which is mediated by IL-4. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the mechanisms by which B7-related costimulatory molecules (CD80, CD86) increase T-cell responsiveness to extracellular ligands. As a model study, the in vitro response of purified splenic CD4+ T cells to a bacterial superantigen, SEB, was characterized. Previous analysis of this experimental model led us to conclude that expression of B7-related molecules is strictly required in order to activate CD4+ T cells in the presence of bacterial superantigens. In the present report, we demonstrate that antigen-presenting cell-derived costimulatory signals regulate the kinetics of interleukin-2 (IL-2) production by SEB-activated splenic CD4+ T cells. Indeed, experiments performed with purified subpopulutions of antigen- presenting cells and using B7-transfected cell lines indicated that increased levels of CD80 and/or CD86 cell surface expression is associated with a faster kinetics of IL-2 production in response to SEB. Accordingly, blocking of CD80 or CD86-derived signals by specific monoclonal antibodies led to a slower kinetics of IL-2 production in response to SEB. Thus these data demonstrate that similar strength of signal through the T-cell receptor can lead to immune responses displaying distinct kinetics depending on the level of costimulatory ligands on APC. [ABSTRACT FROM AUTHOR]

The reactivity and specificity of potyclonal and monoclonal anti-idiotypic antibodies raised against monoclonal anti-progesterone and anti-arsonate antibodies have been studied by solid phase radioimmunoassay (RIA) with immobilized idiotype and by passive haemagglutination with idiotype-coupled red cells. The sensitivity of the two methods was comparable, though some cross-reactions were only detected by RIA. Passive haemagglutination was found to be especially suitable in screening for monoclonal anti-idiotypes in hybridoma supernatants and ascites, and had advantages over RIA in detection of syngeneic anti-idiotypes. Demonstration of binding site-associated idiotopes was possible by haemagglutination inhibition. RIA and haemagglutination were used to investigate the idiotypic relationships between BALB/c antiprogesterone and anti-arsonate monoclonal antibodies which share heavy chains encoded by VHIX variable region genes. [ABSTRACT FROM AUTHOR]

The T-cell differentiation antigen, CD4, is expressed by major histocompatibility (MHC) class II restricted I lymphocytes. CD4+CD8+ T cells use their T-cell receptor to recognize foreign antigens in association with MHC class If products (Ia). The association between CD4 expression and restriction by MHC class II products has led to the hypothesis that CD4 may interact with monomorphic determinants of MHC class II molecules. A large body of experimental evidence suggests that CD4 interaction with MHC class II molecules leads to an increase in the binding avidity of T cell-stimulator cell interactions. A direct test for a functional CD4-MHC class II interaction in T-cell activation requires a separate evaluation of CD4-Ia interactions from T-cell receptor (TcR)-antigen (Ag)/Ia recognition. However, a separate evaluation proves difficult since the T-cell receptor and CD4 may interact with the same MHC class II molecule. In this report, we use a T-cell activation protocol where TcR-Ag/Ia recognition is replaced by TcR complex-anti-CD3 antibody interactions. Therefore, the affinity of the TcR complex for its ligand (the anti-CD3 mAb) is independent from MHC expression on target cells and allows a separate evaluation of the role of accessory molecules in T-cell activation. We have analysed the effects of monoclonal anti-MHC class II antibodies on the activation of a CD4 T-cell hybridoma in the absence of its TcR restricting MHC class II molecule (f!Ek) but in the presence of unrelated MHC class II molecules (I-Ed, I-Ad). The data obtained indicate a functional interaction between the CD4 molecule and a non-polymorphic region of the MHC class II product in T-cell triggering. [ABSTRACT FROM AUTHOR]

Lymphocytes are heterogeneous with respect to their life-span. Typical B cells, bearing on their membranes immunoglobulin receptors, easily detectable by immunofluorescence, belong mainly to the long-lived population: this can be observed using combined autoradiography and immunofluorescence. However, when primed mice receive [³H]thymidine before a boosting injection of tobacco mosaic virus (TMV), many plasma cells appearing in the spleen during the secondary response are labelled. In irradiated recipients repopulated with spleen cells from donors primed with TMV and injected with tritiated thymidine 2 hours before killing, the majority of plasma cells appearing in the spleen after antigen injection were labelled. If irradiated mice were repopulated simultaneously with spleen cells from donors primed with TMV and injected with [³H]thymidine, and from donors primed with haemocyanin, most of the anti-TMV plasma cells were labelled, while most of the anti-haemocyanin plasma cells were unlabelled. These results allowed us to exclude non-specific reutilization of labelled thymidine as the main reason of our observations. It is concluded that either plasma cells derive from shortlived precursors or they receive material from a labelled cell able to co-operate specifically with plasma cell precursors. [ABSTRACT FROM AUTHOR]

Accurate measurement of intragastric acidity has both clinical and investigational importance in studying gastric pathophysiology. Objectives: The aims of this study were fourfold: (I) to investigate whether regional differences in intragastric acidity exist: (2) to determine intragastric acidity after a standard antacid was administered in both the fasting and fed states; (3) to monitor gastric emptying of and anatomic distribution of radio-labeled antacid during fasting and postprandial periods; and (4) to determine whether the regional effects of ingested antacid correlated with the anatomic distribution of (he antacid. Methods: Eight normal male volunteers were studied after fluoroscopically guided nasogastric placement of a tube assembly containing four pH electrodes, with one electrode in each quartile of the stomach. Simultaneous pH readings were made from the four electrodes while fasting, after administration of fasting antacid (30 ml, 79 mEq buffering capacity), post-prandially, and after postprandial antacid ingestion. All subjects repeated the protocol on a separate day, five of them using radiolabeled antacid. Gastric emptying and gastric distribution over time of radiolabeled antacid were determined for comparison to regional intragastric acidity. Results: Intragastric acidity varied regionally over time in response to meals and to fasting and post-prandial antacid. In the fasting state, intragastric acidity returned to baseline after antacid ingestion in a proximal to distal (cardia to antrum) sequence, while post-prandial antacid resulted in a return to baseline acidity in a distal to proximal (antrum to cardia) sequence. Radiolabeled antacid distribution paralleled intragastric pH and hydrogen ion concentration in the fasting state, with 82% of the antacid localizing in the distance of the stomach within the first minute after antacid ingestion. Postprandially, the greatest initial and most prolonged antacid buffering... [ABSTRACT FROM AUTHOR]

The existence of a lag phase during the gastric emptying of solid foods is controversial. It has been hypothesised that among other early events, the stomach requires a period of time to process solid food to particles small enough to be handled as a liquid. At present no standardised curve fitting techniques exist for the characterisation and quantification of the lag phase or the emptying rate of solids and liquids. We have evaluated the ability of a modified power exponential function to define the emptying parameters of two different solid meals. Dual labelled meals were administered to 24 normal volunteers. The subjects received meals consisting of either Tc-99m in vivo labelled chicken liver or Tc-99m-egg, which have different densities, and In-111-DTPA in water. The emptying curves were biphasic in nature. For solids, this represented an initial delay in emptying or lag phase followed by an equilibrium emptying phase characterised by a constant rate of emptying. The curves were analysed using a modified power exponential function of the form y(t) = 1-(1-e-kt)beta, where y(t) is the fractional meal retention at time t, k is the gastric emptying rate in min-1, and beta is the extrapolated y-intercept from the terminal portion of the curve. The length of the lag phase and half-emptying time increased with solid food density (31 +/- 8 min and 77.6 +/- 11.2 min for egg and 62 +/- 16 min and 94.1 +/- 14.2 min for chicken liver, respectively). After the lag phase, both solids had similar emptying rates, and these rates were identical to those of the liquids. In vitro experiments indicated that the egg meal disintegrated much more rapidly than the chicken liver under mechanical agitation in gastric juice, lending further support to the hypothesis that the initial lag in emptying of solid food is due to the processing of food into particles small enough to pass the pylorus. We conclude that the modified power exponential model permits characterisation of the biphasic nature of gastric emptying allowing for quantification of the lag phase and the rate of emptying for both solids and liquids. [ABSTRACT FROM PUBLISHER]

Dendritic cells (DC) can be used as physiological adjuvant in vivo. Indeed, a single injection of DC, pulsed in vitro with antigen, induces activation of specific T and B lymphocytes in syngeneic mice. The unique capacity of DC to sensitize naive T lymphocytes correlates with elevated expression of MHC antigens as well as co-stimulatory molecules. The aim of this work was to evaluate the functional role of the individual CD28 ligands in the induction of primary humoral and cellular responses, and to characterize the nature of the immune response induced in the presence of selected co-stimulatory molecules. Our data show that the primary response is strictly B7 dependent, and that B7-1 and B7-2 mediate overlapping co-stimulatory functions, as either molecule alone is sufficient to initiate an immune reaction. Inhibition of B7-1 and B7-2, however, does not lead to tolerance as predicted by the two-signal hypothesis. Rather, recognition of antigen in the absence of B7 appears as a null event, since subsequent immunogenic stimulation results in a primary response. Blockade of B7-2 co-stimulatory molecules significantly inhibits antigen-specific IgG1 but not IgG2a production, suggesting that B7-2 may direct the development of Th2 cells. These data emphasize the critical role of the CD28/B7 pathway in the induction of the immune response by DC, which appear to be the initiating antigen-presenting cells in situ. [ABSTRACT FROM PUBLISHER]