Characteristics of deoxycholic acid-induced histamine release from mast cells of guinea-pig rectocolonic mucosa and rat peritoneal cavity

Deoxycholic acid (DA) caused a dose-related release of histamine (HR) from mast cells of rat peritoneum (RPMC) and mucosal cells of guinea pig rectocolon (RCMC). In both cell populations, DA-induced HR was: (1) accompared by a parallel release of lactate dehydrogenase (LDH), (2) not affected by metabolic inhibitors, (3) dependent on time of incubation, temperature and pH, and affected by Ca⁺⁺ concentration in RPMC but not in RCMC. DA-induced HR from RCMC may be involved in certain functional disorders of the colon.     

Ischaemia and mediator release: interrelationship in antigen-challenged sensitized guinea-pig kidney.

Renal vasoconstriction and ischaemia that follow in vitro antigen challenge of isolated perfused kidney of sensitized guinea-pig appears to be a self-perpetuating process, starting with a primary peak of release of vasoconstrictor mediators and followed by secondary peaks (particularly of arachidonic acid metabolites) which are probably initiated by ischaemia/reperfusion damage.     

Neural network models for the gaze shift system in the superior colliculus and cerebellum.

We investigate the role that the superior colliculus (SC) and the cerebellum might play in generating gaze shifts. The discharge of cells in the intermediate layers of the SC is tightly linked to the occurrence of saccades. Many studies have demonstrated that the cerebellum is involved in both eye and head movements. When the head is unrestrained, large amplitude gaze shifts are composed of coordinated eye and head movements. In this study, we propose that the gaze saccades system is controlled by a feedback loop between the SC and the cerebellum. The SC only encodes retinal coordinates and controls the eye displacement (to move the fovea to the target), while the cerebellum deals with the gaze programming and controls the head displacement. When a target appears in space, the buildup cells within the SC decode the target signal in the retina before the saccade onset, and input the signal of the gaze displacement to the cerebellum. The cells in the cerebellum vermis encode the initial position of the eye in the orbit. The gaze displacement is decomposed into the head amplitude and the eye amplitude within the cerebellum. There are two output signals from the cerebellum. One signal controls the head movement. The other is projected back to the SC, and forms a component of the saccade vector to control the eye movement. The sum of the vectors provided by the cerebellum and the vector provided by the burst cells in the SC indicates the direction and the amplitude of the desired movement of the eye during the saccade. We propose a cerebellum model to predict the displacements of the eye and head under the condition that the position of the target signal in the retina and the initial position of the eye in the orbit are known. The results from the model are close to that observed physiologically. We conclude that before gaze shift onset, the cerebellum may play an important role in decomposing the gaze displacement into an eye amplitude and head amplitude signal.     

Effects of leukotrienes C4 and D4 on guinea-pig heart and the participation of SRS-A in the manifestations of guinea-pig cardiac anaphylaxis

Synthetic leukotrienes C₄ and D₄ (LTC and LTD) were found to possess potent coronary vasoconstrictor and cardiac depressant actions on isolated guinea-pig hearts. We therefore went further to investigate the possibility that endogenously released slow-reacting substance of anaphylaxis (SRS-A) might be responsible for the coronary vasoconstriction and negative inotropism in guinea-pig cardiac anaphylaxis. Results using time-course analysis as well as the specific SRS antagonist FPL 55712 have shown that SRS-A released during cardiac anaphylaxis was unlikely to be responsible for the early and most dramatic phase of coronary vasoconstriction that usually occurred at the 2nd min after antigen challenge, but could possibly be responsible for the latter and more prolonged phase occurring between the 6th and 14th min. This is because SRS-A release was found to peak at the 4th min after antigen challenge, 2 min after vasoconstriction had already peaked. Moreover, this early component of coronary vasoconstriction could not be blocked by FPL 55712, whereas the latter component was significantly reduced by the antagonist. The negative inotropism following cardiac anaphylaxis was also found to be significantly reduced by FPL 55712, thus suggesting SRS-A involvement. However, our experiments did not show whether the two actions were direct effects of SRS-A or whether contractility failure was a consequence of coronary vasoconstriction.     

LcrV plague vaccine with altered immunomodulatory properties

Yersinia pestis, the causative agent of plague, secretes LcrV (low-calcium-response V or V antigen) during infection. LcrV triggers the release of interleukin 10 (IL-10) by host immune cells and suppresses proinflammatory cytokines such as tumor necrosis factor alpha and gamma interferon as well as innate defense mechanisms required to combat the pathogenesis of plague. Although immunization of animals with LcrV elicits protective immunity, the associated suppression of host defense mechanisms may preclude the use of LcrV as a human vaccine. Here we show that short deletions within LcrV can reduce its immune modulatory properties. An LcrV variant lacking amino acid residues 271 to 300 (rV10) elicited immune responses that protected mice against a lethal challenge with Y. pestis. Compared to full-length LcrV, rV10 displayed a reduced ability to release IL-10 from mouse and human macrophages. Furthermore, the lipopolysaccharide-stimulated release of proinflammatory cytokines by human or mouse macrophages was inhibited by full-length LcrV but not by the rV10 variant. Thus, it appears that LcrV variants with reduced immune modulatory properties could be used as a human vaccine to generate protective immunity against plague.     

Human CD8+ intraepithelial lymphocytes: a unique model to study the regulation of effector cytotoxic T lymphocytes in tissue

Summary:  The epithelium of the human small intestine contains a large population of intraepithelial cytolytic αβ T-cell receptor (TCR) CD8αβ T lymphocytes (IE-CTLs), whose main role is to sustain epithelial integrity by rapidly eliminating infected and damaged cells. In mouse, the recognition of inducible/modified self-molecules, i.e. non-classical major histocompatibility complex (MHC) class I molecules, is mediated by the TCR and natural killer receptors (NKRs) co-expressed on the cell surface of a non-conventional autoreactive CD8αααβTCR cell subset. In contrast, in humans, the recognition of non-classical MHC class I molecules induced by stress and inflammation on intestinal epithelial cells (IECs) is principally mediated by NKRs expressed on conventional CD8αβαβTCR cells. By sensing microenvironmental signals of inflammation and stress through NKRs, IE-CTLs fine tune their TCR activation threshold. Furthermore, IE-CTLs under particular conditions, involving interleukin-15 upregulation, acquire the capacity to kill distressed intestinal epithelial cells in an antigen non-specific manner. Adaptive IE-CTLs appear hence to have autoreactive properties and modulate their immune response based on innate signals, reflecting the fitness of the tissue.     

Effect of adenosine agonists on guinea-pig isolated trachea

Inflammation Research -     

Demonstration of IgE-sensitized mast cells in human heart and kidney

We report the direct demonstration of IgE-bearing mast cells in human heart and kidney, as shown by immunohistochemical methods. This finding lends further support to the role of mast cells and IgE in the direct involvement of these two organs in immediate-type allergic reactions.     

Expression of p21 WAF1/CIP1 protein in colorectal cancers: study of its relation to p53 mutation and Ki67 antigen expression

Mutations of the p53 gene are the most common genetic alteration in malignant human tumors. A cyclin-dependent kinase inhibitor, p21WAF1/CIP1, is thought to be an important mediator of p53-induced cell cycle arrest. Although numerous studies have reported p53 expression and mutation in colorectal cancer few of them have correlated p53 expression with that of its downstream effector p21 and with the proliferation index as measured by expression of the Ki67 nuclear antigen. We studied p53, p21 and Ki67 expression by immunohistochemistry and molecular biology in 35 colorectal carcinomas. We compared these findings with each other and with clinical factors. Sixty three percent of tumors expressed p53 whereas seventy one percent expressed p21WAF1/CIP1. In adenocarcinomas, p21 staining was heterogeneous: p21-reactive cells were seen in the most differentiated areas. There was no correlation between p21WAF1/CIP1 and p53 expression, p53 mutation, Ki67 expression or clinical factors such as sex or location of the tumor. On the other hand, there was a statistical relationship between p21 expression and survival: our results indicated an association between high p21 expression and lower stages p21WAF1/CIP1 appears to be induced independently of p53 in these tumors and may be associated with differentiation rather than proliferation.     

Inhibition of histamine release from human lung and rat peritoneal mast cells by cyclosporin-A

Cyclosporin A (CS-A) partly inhibited IgE-mediated histamine release from human lung tissuein vitro (chopped and collagenase-dispersed preparations). Inhibition started at concentrations within the clinical blood level of the drug, but the IC₅₀ was much higher (10–50 M; 50% inhibition reached only in some experiments). CS-A also inhibited histamine release from rat peritoneal mast cells (RPMC) induced by antigen, concanavalin-A (Con-A), compound 48/80 and ionophore A23187. The IC₅₀ values were 0.3, 23.0, and 33.0 M for Con-A, A23187 and ovalbumin respectively. Inhibition of 48/80-induced release did not reach 50%. By comparison with human basophils the human lung and RPMC were less sensitive to the inhibitory action of CS-A. The IgE-mediated Schultz-Dale reaction in human lung strips was slightly and inconsistently inhibited by CS-A, but IgG₁-mediated reaction in guinea-pig lung strips was potentiated by the drug.