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Biomedical subjects

N Walters

Publications and source records attributed to N Walters.

14 recordsLinked to original sources
PubMed2001

Cutting edge: dichotomy of homing receptor dependence by mucosal effector B cells: alpha(E) versus L-selectin.

The common mucosal immune system may be compartmentalized because lymphocyte homing to the upper respiratory tract appears to be mediated by L-selectin interactions rather than alpha(4)beta(7) interactions, as is the case for gut-associated lymphoreticular tissue. To assess the role of L-selectin in effector B cell immunity, L-selectin-deficient mice were intranasally immunized with cholera toxin (CT), and mucosal immune responses were compared with C57BL/6 mice. The absence of L-selectin correlated with a reduction in CT-specific secretory-IgA responses in nasal passages and reproductive tract, but not intestinal lamina propria. Cell sorting experiments showed that an L-selectin-dependent subset was responsible for CT-specific responses in nasal passages and reproductive tract, whereas an alpha(E)beta(7)(+) B cell subset was responsible for L-selectin-independent intestinal immunity. This study provides evidence for compartmentalization of the common mucosal immune system into "intestinal" vs "nonintestinal" effector sites.

Animals↗
PubMed2001

M cell-targeted DNA vaccination.

DNA immunization, although attractive, is poor for inducing mucosal immunity, thus limiting its protective value against most infectious agents. To surmount this shortcoming, we devised a method for mucosal transgene vaccination by using an M cell ligand to direct the DNA vaccine to mucosal inductive tissues and the respiratory epithelium. This ligand, reovirus protein final sigma1, when conjugated to polylysine (PL), can bind the apical surface of M cells from nasal-associated lymphoid tissues. Intranasal immunizations with protein final sigma1-PL-DNA complexes produced antigen-specific serum IgG and prolonged mucosal IgA, as well as enhanced cell-mediated immunity, made evident by elevated pulmonary cytotoxic T lymphocyte responses. Therefore, targeted transgene vaccination represents an approach for enabling DNA vaccination of the mucosa.

Animals↗
PubMed2001

Comparison of apomorphine, amphetamine and dizocilpine disruptions of prepulse inhibition in inbred and outbred mice strains.

The dopamine agonist apomorphine robustly disrupts prepulse inhibition of the acoustic startle response in the rat, yet published studies have not demonstrated a robust disruption of prepulse inhibition with apomorphine in the mouse. The aim of these studies was to establish the optimal prepulse conditions (using manipulations to prepulse intensity and inter-stimulus interval) and mouse strain(s) for testing apomorphine, and also the prepulse inhibition disrupting drugs amphetamine, and dizocilpine (MK-801). The effects of these drugs on startle response and prepulse inhibition were tested in outbred CD-1 and Swiss Webster (CFW) strains, and the inbred C57BL/6, 129X1/SvJ, and A/J strains. There were strain differences with baseline startle and prepulse inhibition in that the CD-1, CFW, and C57BL/6 strains exhibited high levels of startle and prepulse inhibition, the 129X1/SvJ strain exhibited low levels of startle but high levels of prepulse inhibition, while the A/J strain exhibited low startle and no prepulse inhibition. Apomorphine disrupted prepulse inhibition in the CFW and C57BL/6 strains and the effect was only evident when using a short 30 ms inter-stimulus interval. Amphetamine disrupted prepulse inhibition in the CFW, C57BL/6, and 129X1/SvJ strains, and dizocilpine disrupted prepulse inhibition in the CD-1, CFW, C57BL/6, and 129X1/SvJ strains. The effects of amphetamine and dizocilpine were independent of the inter-stimulus interval. These studies demonstrated clear strain differences in the startle response and prepulse inhibition, and the pharmacological disruptions of prepulse inhibition, and suggest that inter-stimulus intervals less than 100 ms may be optimal for detecting the effects of apomorphine in mice.

Acoustic Stimulation↗
PubMed2001

Impaired mucosal immunity in L-selectin-deficient mice orally immunized with a Salmonella vaccine vector.

Lymphocyte trafficking in the gastrointestinal tract is primarily mediated by interactions with the mucosal addressin cell adhesion molecule 1 and its lymphocyte ligand, alpha(4)beta(7), and partly by L-selectin (L-Sel) interactions with peripheral node addressin coexpressed on some mucosal addressin cell adhesion molecule 1. We inquired whether intestinal responses in mice lacking L-Sel would be enhanced. L-Sel-deficient (L-Sel(-/-)) mice were orally immunized with either Salmonella vaccine vector or Salmonella vector-expressing colonization factor Ag I (CFA/I) from enterotoxigenic Escherichia coli. In L-Sel(-/-) mice, mucosal IgA anti-CFA/I fimbrial responses were greatly reduced, and systemic IgG2a anti-CFA/I fimbrial responses were 26-fold greater compared with C57BL/6 (L-Sel(+/+)) mice. L-Sel(-/-) Peyer's patch (PP) CD4(+) Th cells revealed IFN-gamma-dominated responses and an unprecedented absence of IL-4, whereas the expected mixed Th cell phenotype developed in L-Sel(+/+) mice. PP CD4(+) Th cell anti-Salmonella responses were nearly nonexistent in L-Sel(-/-) mice immunized with either Salmonella vaccine. Splenic CD4(+) Th cell anti-Salmonella responses were reduced but did show cytokine production in Ag restimulation assays. Increased colonization of PP and spleen was noted only with the Salmonella vector in L-Sel(-/-) mice, resulting in increased splenomegaly, suggesting that the Salmonella-CFA/I vaccine was not as infectious or that the presence of the fimbriae improved clearance, possibly because of reduced neutrophil recruitment. However, sufficient anti-Salmonella immunity was induced, because Salmonella vector-immunized L-Sel(-/-) mice showed complete protection against wild-type Salmonella challenge, unlike L-Sel(+/+) mice. This evidence shows that L-Sel is important for development of mucosal immunity, and absence of L-Sel is protective against salmonellosis.

Administration, Oral↗
PubMed1999

Role of endogenous interleukin-18 in resolving wild-type and attenuated Salmonella typhimurium infections.

The stimulation of gamma interferon (IFN-gamma) has been shown to be essential in resolving infections by intracellular pathogens. As such, several different cytokines including, interleukin-12 (IL-12) and IL-18, can induce IFN-gamma. To resolve Salmonella infections, the stimulation of IL-12 and IFN-gamma are important for mediating its clearance. In this present study, the relevance of IL-18 in protection against oral challenge with Salmonella typhimurium was investigated to determine the role of this IFN-gamma-promoting cytokine. Rabbit anti-murine IL-18 antisera was generated and administered prior to the oral challenge of BALB/c and IL-12p40-deficient knockout (IL-12KO) mice with a wild-type S. typhimurium strain. The median survival time was reduced by 2 days for the anti-IL-18-treated BALB/c mice, while no significant reduction in survival rate for the anti-IL-18-treated IL-12KO mice was observed compared to vehicle-treated mice. To investigate the contribution of IL-18 to resolving Salmonella infections, an attenuated aro-negative mutant (H647) was orally administered to BALB/c mice. This Salmonella infection induced both IL-12 and IFN-gamma in both the Peyer's patches and the spleens. In vehicle-treated mice, Peyer's patch IL-12 peaked by 24 h, while IL-18 levels peaked at 3 days, suggesting sequential support by these cytokines for IFN-gamma. Anti-IL-18 treatment exerted its greatest effect upon the mucosal compartment, limiting early IFN-gamma production. However, anti-IL-18 treatment had little effect upon splenic IFN-gamma levels until late in the response. Infection of IL-12KO mice with H647 strain induced IFN-gamma, but it was not supported by IL-18, although IL-18 levels were reduced by this treatment. These results suggest that IL-18 does contribute to the clearance of S. typhimurium and that endogenously induced IL-18 could not substitute for IL-12.

Animals↗
PubMed1999

Expression of recombinant enterotoxigenic Escherichia coli colonization factor antigen I by Salmonella typhimurium elicits a biphasic T helper cell response.

Protective immunity to enterotoxigenic Escherichia coli (ETEC) is antibody (Ab) dependent; however, oral immunization with purified ETEC fimbriae fails to elicit protective immunity as a consequence of antigenic alteration by the gastrointestinal (GI) tract. Unless unaltered ETEC fimbriae can reach the inductive lymphoid tissues of the GI tract, immunity to ETEC cannot be induced. To produce immunity, live vectors, such as Salmonella typhimurium, can effectively target passenger antigens to the inductive lymphoid tissues of the GI tract. By convention, oral immunizations with Salmonella vectors induce CD4(+) T helper (Th) cell responses by gamma interferon (IFN-gamma)-dominated pathways both to the vector and passenger antigen, resulting in serum immunoglobulin G2a (IgG2a) and modest mucosal IgA Ab responses. In the present study, mice orally immunized with a Salmonella vector engineered to stably express ETEC colonization factor antigen I (CFA/I) showed initially elevated serum IgG1 and mucosal IgA anti-CFA/I Ab responses. As expected, mice orally immunized with an E. coli-CFA/I construct elicited poor anti-CFA/I Ab responses. In fact, the addition of cholera toxin during oral E. coli-CFA/I immunization failed to greatly enhance mucosal IgA Ab responses. Seven days after immunization with the Salmonella-CFA/I construct, cytokine-specific ELISPOT showed induction of predominant Th2-type responses in both mucosal and systemic immune compartments supporting the early IgG1 and IgA anti-CFA/I Abs. By 4 weeks, the Th cell response became Th1 cell dominant from the earlier Th2-type responses, as evidenced by increased mucosal and systemic IFN-gamma-producing T cells and a concomitant elevation of serum IgG2a Ab responses. This biphasic response offers an alternative strategy for directing Salmonella vector-induced host immunity along a Th2 cell-dependent pathway, allowing for early promotion of mucosal and systemic Abs.

Animals↗
PubMed1998

Repeated intratracheal instillations of nonreplicating adenovirus 2 vector attenuate CTL responses and IFN-gamma production.

The proposed usage of replication-deficient adenovirus (Ad) vectors for corrective gene therapy or for mucosal immunization has been limited in part by the host reactivity to the Ad vector, thus limiting repeated Ad instillations. We have recently shown that the reactivity to the Ad vector is in large part due to increased CD4+ Th1 and Th2 responses as well as elevated IgG and mucosal IgA responses. It has been recently proposed that the diminution of transgene expression in respiratory epithelia was due to increased CTL reactivity to expressed Ad proteins. Herein, we report that repeated intratracheal delivery of a second generation Ad2 vector into mice results in no detectable CTL activity in freshly isolated lymphoid cells from lungs, lower respiratory lymph nodes, or spleens or after in vitro restimulation. In contrast, a single dose of Ad2 vector did elicit a robust CTL response. This attenuation of CTL activity was long lived and was not affected by macrophage depletion or due to a reduction in CD4+ or CD8+ T cells. Examination of cytokine production via MHC class I or class II restimulation by lymphoid cells from three intratracheally treated mice showed an attenuation in the production of IFN-gamma by as much as 110-fold. This reduction in IFN-gamma could not be attributed to increased IL-4 or IL-10 production. Thus, this study shows that the CTL response to Ad vectors is attenuated upon repeated administration.

Adenoviridae↗
PubMed1998

Oral immunization with a Salmonella typhimurium vaccine vector expressing recombinant enterotoxigenic Escherichia coli K99 fimbriae elicits elevated antibody titers for protective immunity.

Bovine enterotoxigenic Escherichia coli (ETEC) continues to cause mortality in piglets and newborn calves. In an effort to develop a safe and effective vaccine for the prevention of F5(+) ETEC infections, a balanced lethal asd+ plasmid carrying the complete K99 operon was constructed and designated pMAK99-asd+. Introduction of this plasmid into an attenuated Salmonella typhimurium Deltaaro Deltaasd strain, H683, resulted in strain AP112, which stably expresses E. coli K99 fimbriae. A single oral immunization of BALB/c and CD-1 mice with strain AP112 elicited significant mucosal immunoglobulin A (IgA) titers that remained elevated for >11 weeks. IgA and IgG responses in serum specific for K99 fimbriae were also induced, with a prominent IgG1, as well as IgG2a and IgG2b, titer. To assess the derivation of these antibodies, a K99 isotype-specific B-cell ELISPOT analysis was conducted by using mononuclear cells from the lamina propria of the small intestines (LP), Peyer's patches (PP), and spleens of vaccinated and control BALB/c mice. This analysis revealed elevated numbers of K99 fimbria-specific IgA-producing cells in the LP, PP, and spleen, whereas elevated K99 fimbria-specific IgG-producing cells were detected only in the PP and spleen. These antibodies were important for protective immunity. One-day-old neonates from dams orally immunized with AP112 were provided passive protection against oral challenge with wild-type ETEC, in contrast to challenged neonates from unvaccinated dams or from dams vaccinated with a control Salmonella vector. These results confirm that oral Salmonella vaccine vectors effectively deliver K99 fimbriae to mucosal inductive sites for sustained elevation of IgA and IgG antibodies and for eliciting protective immunity.

Animals↗
PubMed1993

Cardiovascular activity during mental stress following vigorous exercise in sportsmen and inactive men.

Thirty-six competitive sportsmen and 36 inactive men participated in a two-session experiment. Session 1 involved exercise to exhaustion so as to assess maximal oxygen consumption (VO2 max). In Session 2, both groups were randomized into three experimental conditions: 20 min of exercise at high intensity (70% VO2max) or moderate intensity (50% VO2max) or a light exercise control. Following 30 min of recovery, all subjects performed mental arithmetic and public speech tasks in a counterbalanced order. Cardiovascular, electrodermal, respiratory, and subjective variables were recorded. Sportsmen had higher VO2max, lower body fat, and lower resting heart rate (HR) than inactive men. A postexercise hypotensive response was observed among subjects in the 70% and 50% VO2max conditions, accompanied by baroreceptor reflex inhibition in the 70% condition. Systolic pressure was lower during mental arithmetic and during recovery from the speech task in the high-intensity than in the control group. Diastolic pressure was lower following mental arithmetic in the high-intensity group. No differences in HR reactivity, electrodermal, or respiratory parameters were observed, but baroreceptor reflex sensitivity was inhibited during mental arithmetic. The results are discussed in relation to previous reports of suppressed cardiovascular reactivity to mental stress tests following vigorous exercise and the role of stress-related processes in the antihypertensive response to physical training.

Adult↗
PubMed1993

The relationship between secretory immunity, mood and life-events.

Twelve subjects volunteered to take part in a short trial involving daily life-event and mood recording over a period of up to two weeks. On each day subjects also provided timed saliva samples. Aggregated data across the trial period revealed that unstimulated secretion rate of secretory immunoglobulin A from whole saliva correlated strongly and significantly with net desirable event reporting, defined as a subject's tendency to report relatively frequent desirable events and relatively infrequent undesirable events. Correlations with positive and negative mood were insignificant, although the pattern of results was in line with hypotheses. Within-subject analyses revealed a totally contrary pattern of results. In particular, negative mood was significantly associated with higher sIgA secretion rate. Analyses involving total sIgA concentration paralleled those using secretion rate. Results are discussed in relation to psychoneuroimmunological models of illness vulnerability, particularly upper respiratory infection, and previous findings in regard to secretory immunity.

Adult↗
PubMed1992

Inferior vena cava "birds nest" filters--2 year follow-up.

This study examines long term efficacy and saftey of "birds nest" filters (Cook), and the use of doppler ultrasound to assess patency. Of the seventeen "birds nest" filters inserted twelve were available for study. All patients were reviewed for evidence of recurrent pulmonary emboli or filter complication. Mean length of follow up was 10 months, (7 had follow up of > 12 months). Three have had further episodes of deep venous thrombosis, with probable recurrent pulmonary embolism in one. No patient had evidence of thrombosis of the inferior vena cava. No fracture or migration of the "birds nest" filters was found. Ten of the twelve filters studied with ultrasound could be visualized within the cava. In all, turbulent flow was detected with colour and duplex doppler study. We conclude that insertion and use of the "birds nest" filters is safe, with a high long term patency rate and few initial or long term complications. Doppler ultrasound is a simple and rapid method of assessing venous patency.

Follow-Up Studies↗
PubMed1991

Outpatient transurethral balloon urethroplasty.

Transurethral balloon dilatation was performed on 6 patients, who were assessed pre- and post-procedure on symptomatic and urodynamic criteria. Follow-up was on average 11.7 months. Only 1 patient had a successful result, despite early initial improvement in five. In view of our results and reports from other centres we cannot recommend transurethral balloon dilatation of the prostate as treatment in patients with bladder outlet obstruction due to benign prostatic hypertrophy, except in exceptional circumstances.

Aged↗