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D E Bice

Publications and source records attributed to D E Bice.

At least 19 recordsLinked to original sources
PubMed2001

CCSP modulates airway dysfunction and host responses in an Ova-challenged mouse model.

Clara cell secretory protein (CCSP) is synthesized by nonciliated bronchiolar cells in the lung and modulates lung inflammation to infection. To determine the role of CCSP in the host response to allergic airway disease, CCSP-deficient [(-/-)] mice were immunized twice with ovalbumin (Ova) and challenged by Ova (2 or 5 mg/m(3)) aerosol. After 2, 3, and 5 days of Ova aerosol challenge (6 h/day), airway reactivity was increased in CCSP(-/-) mice compared with wild-type [CCSP(+/+)] mice. Neutrophils were markedly increased in the bronchoalveolar lavage fluid of CCSP(-/-) Ova mice, coinciding with increased myeloperoxidase activity and macrophage inflammatory protein-2 levels. Lung histopathology and inflammation were increased in CCSP(-/-) compared with wild-type mice after Ova challenge. Mucus production, as assessed by histological staining, was increased in the airway epithelium of CCSP(-/-) Ova mice compared with that in CCSP(+/+) Ova mice. These data suggest a role for CCSP in airway reactivity and the host response to allergic airway inflammation and provide further evidence for the role of the airway epithelium in regulating airway responses in allergic disease.

Animals↗
PubMed2001

Ovalbumin aerosols induce airway hyperreactivity in naïve DO11.10 T cell receptor transgenic mice without pulmonary eosinophilia or OVA-specific antibody.

The pathobiology of allergic asthma is being studied using murine models, most of which use systemic priming followed by pulmonary challenges with the immunizing antigen. In general, mice develop eosinophilic pulmonary inflammation, increased antigen-specific immunoglobulins, and airway hyperreactivity (AHR), all of which are dependent on antigen-specific T cell activation. To establish a model of allergic asthma, which did not require systemic priming, we exposed DO11.10 T cell receptor transgenic mice, which have an expanded repertoire of ovalbumin (OVA), peptide-specific T cells, to limited aerosols of OVA protein. DO11.10 +/- mice developed AHR in the absence of increases in total serum IgE, OVA-specific IgG, or eosinophilia. The AHR was accompanied by pulmonary recruitment of antigen-specific T cells with decreased expression of CD62L and CD45RB and increased expression of CD69, a phenotype indicative of T cell activation. Our results support recent hypotheses that T cells mediate AHR directly.

Administration, Intranasal↗
PubMed2000

Animal models of asthma: potential usefulness for studying health effects of inhaled particles.

Asthma is now recognized to be a chronic inflammatory disease that affects the whole lung. Incidence appears to be increasing despite improved treatment regimens. There is substantial epidemiological evidence suggesting a relationship between the incidence and severity of asthma (e.g., hospitalizations) and exposure to increased levels of air pollution, especially fine and ultrafine particulate material, in susceptible individuals. There have been a few studies in animal models that support this concept, but additional animal studies to test this hypothesis are needed. However, such studies must be performed with awareness of the strengths and weaknesses of the currently available animal models. For studies in mice, the most commonly used animal, a broad spectrum of molecular and immunological tools is available, particularly to study the balance between Th1 and Th2 responses, and inbred strains may be useful for genetic dissection of susceptibility to the disease. However, the mouse is a poor model for bronchoconstriction or localized immune responses that characterize the human disease. In contrast, allergic lung diseases in dogs and cats may more accurately model the human condition, but fewer tools are available for characterization of the mechanisms. Finally, economic issues as well as reagent availability limit the utility of horses, sheep, and primates.

Air Pollutants↗
PubMed1999

Dissociation of airway hyperresponsiveness from immunoglobulin E and airway eosinophilia in a murine model of allergic asthma.

Nonspecific airway hyperresponsiveness (AHR) is a hallmark of human asthma. Both airway eosinophilia and high serum levels of total and antigen-specific immunoglobulin E (IgE) are associated with AHR. It is unclear, however, whether either eosinophilia or increased IgE levels contribute directly to, or predict, the development of AHR. Investigations conducted with various murine models of asthma and different mouse strains have resulted in conflicting evidence about the roles that IgE and airway eosinophilia play in the manifestation of AHR. We show that systemic priming with ovalbumin (OVA) in alum, followed by a single day of OVA aerosol challenge, is sufficient to induce AHR, as measured by increased pulmonary resistance in response to intravenously delivered methacholine in BALB/c, but not C57BL/6 or B6D2F1, mice. This was observed despite the fact that OVA-challenged BALB/c mice had less airway eosinophilia and smaller increases in total IgE than either C57BL/6 or B6D2F1 mice, and had less pulmonary inflammation and OVA-specific IgE than B6D2F1 mice. We conclude that airway eosinophilia, pulmonary inflammation, and high serum levels of total or OVA-specific IgE are all insufficient to induce AHR in C57BL/6 and B6D2F1 mice, whereas BALB/c mice demonstrate AHR in the absence of airway eosinophilia. These data confirm that the development of AHR is genetically determined, not only in naive mice, but also in actively immunized ones, and cannot be predicted by levels of airway eosinophilia, pulmonary inflammation, total IgE, or antigen-specific IgE.

Animals↗
PubMed1999

Allergen-induced IL-9 directly stimulates mucin transcription in respiratory epithelial cells.

A hallmark of asthma is mucin overproduction, a condition that contributes to airway obstruction. The events responsible for mucin overproduction are not known but are thought to be associated with mediators of chronic inflammation. Others have shown that T-helper 2 (Th2) lymphocytes are required for mucous cell metaplasia, which then leads to mucin overproduction in animal models of allergy. We hypothesized that Th2 cell mediators are present in asthmatic airway fluid and directly stimulate mucin synthesis in airway epithelial cells. Results in cultured airway epithelial cells showed that samples of asthmatic fluid stimulated mucin (MUC5AC) synthesis severalfold more potently than non-asthmatic fluid. Consistent with this, lavage fluid from the airways of allergen-challenged dogs stimulated mucin synthesis severalfold more potently than that from non-allergen-challenged dogs. Fractionation of dog samples revealed 2 active fractions at <10 kDa and 30-100 kDa. Th2 cytokines in these molecular weight ranges are IL-9 (36 kDa), IL-5 (56 kDa), and IL-13 (10 kDa). Antibody blockade of ligand-receptor interaction for IL-9 (but not IL-5 or IL-13) inhibited mucin stimulation by dog airway fluid. Furthermore, recombinant IL-9, but not IL-5 or IL-13, stimulated mucin synthesis. These results indicate that IL-9 may account for as much as 50-60% of the mucin-stimulating activity of lung fluids in allergic airway disease.

Adult↗
PubMed1997

Evaluation of association of blood and bronchoalveolar eosinophil numbers and serum total immunoglobulin E concentration with the expression of nonspecific airway reactivity in dogs.

OBJECTIVE: To characterize the relation between bronchoalveolar and blood eosinophil numbers, serum total IgE concentration, and nonspecific airway reactivity in healthy dogs. ANIMALS: 26 healthy Beagles. PROCEDURE: Prior to measurement of nonspecific airway responsiveness, dogs were anesthetized and bronchoscopy was performed to recover bronchoalveolar lavage (BAL) fluid. Repeated measurements were made in 6 dogs. RESULTS: The percentage of blood eosinophils varied between 0 and 13 (mean +/- SD, 5.6 +/- 3.6) %, the percentage of eosinophils in BAL fluid ranged between 0 and 63.5 (8.8 +/- 12.9) %, and total serum IgE concentration was 0.1 to 107.5 (23.4 +/- 29.1) U/ml. A strong association was evident between numbers of blood eosinophils and total serum IgE concentration (R2 = 0.413, P < 0.001), and a trend toward an association between numbers of blood eosinophils and numbers of eosinophils in BAL fluid was apparent (R2 = 0.110, P < 0.053). Significant associations were not found between any other aspects of the blood and BAL fluid cell profiles and total serum IgE concentration or airway reactivity. Serum total IgE concentration was not associated with airway reactivity. Further, in dogs examined on repeated occasions, variation in BAL fluid eosinophil numbers was not associated with any change in serum total IgE concentration or airway reactivity. CONCLUSIONS: Neither numbers of bronchoalveolar or blood eosinophils nor serum total IgE concentration have a significant role in determining airway reactivity in health dogs.

Animals↗
PubMed1996

Pulmonary immune memory: localized production of antibody in the lung after antigen challenge.

In comparison to primary immune responses after lung immunization, the level of antigen-specific antibody and the number of cells producing specific antibody are significantly increased after challenging the lungs with antigen. The response of immune memory cells in the lung to an antigen challenge could be responsible for this elevated immune response. However, increased numbers of antibody-producing cells, possibly produced in the lung-associated lymph nodes, are also found in the blood after an antigen challenge. Therefore, it is possible that both the response of immune memory cells in the lung, and the recruitment of antibody-producing cells from the blood, contribute to the elevated levels of antibody in the lung after an antigen challenge. This study compared the level of antibody produced in the lung by the response of pulmonary immune memory cells with the level of antibody produced by antibody-forming cells that enter the lung from blood after an antigen challenge. This comparison was made possible by immunizing and challenging two lung lobes of dogs with two antigens. The immune responses to both antigens were then evaluated in both lung lobes after primary immunization and challenge. Data from these evaluations showed that most antibody in the lung after an antigen challenge is produced by a localized anamnestic response of pulmonary immune memory cells. A significantly lower level of antibody entered the lung from the vasculature and/or was produced by antibody-forming cells that entered the lung from blood after an antigen challenge.

Animals↗
PubMed1996

Long-term antibody production in canine lung allografts: implications in pulmonary immunity and asthma.

Lung transplant recipients can become asthmatic if they receive donor lungs from asthmatics. The maintenance of sensitivity in the lung allograft for inhaled allergens supports the concept that the mechanisms responsible for asthma are localized in the lungs, with a minimal systemic component. Pulmonary immunity to inhaled allergens is one mechanism which could be localized to the lung that would play a pivotal role in asthma. For example, the continued production of antibody to inhaled allergens in a human lung allograft could cause asthmatic responsiveness in the recipient. In this study, we tested the hypothesis that pulmonary immune cells continue to produce antibody in a canine allograft lung for relatively long times after transplantation. This was accomplished by immunizing four dogs by instillation of keyhole limpet hemocyanin (KLH) into a single lung lobe. After two challenges, the immunized lung from each dog was transplanted into a nonimmune recipient. Immune evaluations of recipients showed that anti-KLH antibody continued to be produced only in the donor lung for as long as 320 days after transplantation. Data from this study suggest that (1) immune cells in the lung can function independently from systemic immunity, (2) antibody production in the lung makes a significant contribution to blood antibody levels, and (3) immune cells in donor lungs can continue to produce antibody for relatively long times after transplantation. Therefore, immune cells in donor lungs from asthmatics could continue to produce antibody to allergens after transplantation, and this locally produced antibody may be responsible for the asthmatic responses observed in the recipients.

Allergens↗
PubMed1995

The regulation of pulmonary immunity.

No evidence has emerged which suggests that the principles of immunity derived from studies on cells from other body sites are contradicted in the lung and its associated lymphoid tissue. What is clear, however, is that the environment dictates the types of cells, their relationship to one another, and what perturbing events will set in motion either the development of an "active" immune response or tolerance. Investigating mechanisms for the development of lung immunity has increased our understanding of how human diseases develop and is continuing to suggest new ways to manipulate pulmonary immune responses. Demonstration that lung cells regulate both nonspecific inflammation and immunity through the expression of adhesion molecules and the secretion of cytokines offers hope for ways to design more effective vaccines, enhance microbial clearance in immunosuppressed hosts, and to suppress manifestations of immunologically mediated lung disease. Important lung diseases targeted for intensive research efforts in the immediate future are tuberculosis, asthma, and fibrotic lung disease. Perhaps even the common cold might be conquered. Considering the pace of current research on lung immunity, it may not be too ambitious to predict that these diseases may be conquered in the next decade.

Animals↗
PubMed1994

Heat-killed pneumococci and pneumococcal capsular polysaccharides stimulate tumor necrosis factor-alpha production by murine macrophages.

Tumor necrosis factor-alpha (TNF) is an important humoral mediator of sepsis and endotoxin-induced shock. However, Streptococcus pneumoniae, a gram-positive organism, is the most common causative agent of community-acquired pneumonia and sepsis. We hypothesized that the pathogenesis of pneumococcal pneumonia and sepsis involves pneumococcus-stimulated TNF synthesis, and we tested that hypothesis in vitro by comparing heat-killed type III and type V pneumococcus and 23-valent purified pneumococcal capsular polysaccharides with Escherichia coli and purified lipopolysaccharide (LPS) as stimuli for TNF production by the murine macrophage cell line RAW 264.7. We evaluated TNF production in response to various doses and times of exposure to these agents, as well as the effects of indomethacin on TNF production in response to these agents. Stimulation with both types of heat-killed pneumococcus resulted in TNF production in a dose-response fashion, as did stimulation with E. coli. Fewer type III pneumococci (10 bacteria/ml) were required to stimulate significant TNF secretion than either type V pneumococcus or E. coli, but the overall dose-response curves of the three bacteria were similar. The dose-response curves for pneumococcal capsular polysaccharides and LPS were very similar, although at the highest concentration pneumococcal capsular polysaccharides stimulated more TNF secretion than did LPS (469 versus 213 U/ml). The kinetics of pneumococcus-stimulated TNF secretion were identical to the kinetics of LPS-stimulated TNF secretion. In the presence of indomethacin, pneumococcus-stimulated TNF production decreased by 87.5%, as compared with pneumococcus alone. In contrast, LPS with indomethacin stimulated 19.5% more TNF than LPS alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Intrapulmonary antigen deposition in the human lung: local responses.

We hypothesized that, as in animal models, localized deposition of antigen into the human lung would induce local inflammatory and immune responses in antigen-exposed sites. To test this hypothesis, segmental instillation of a well-characterized, highly immunogenic, soluble antigen, keyhole limpet hemocyanin (KLH) was performed in 10 healthy, nonsmoking volunteers. Ten to fifteen days after instillation, bronchoalveolar lavage (BAL) was performed in immunized segments (IS) and contralateral control segments (CS) and local responses to antigen instillation were assessed by comparing IS and CS BAL. Greater albumin concentrations and cell recoveries were found in IS than in CS BAL, suggesting local inflammation. Although total numbers of each cell type were increased, relative proportions of alveolar macrophages, lymphocytes, and neutrophils were similar in IS and CS BAL. CD4/CD8 ratios in IS BAL samples were greater than those in CS samples, because of higher numbers of CD4+ lymphocytes in IS than in CS BAL but similar numbers of CD8+ lymphocytes. Anti-KLH IgG and IgA concentrations were greater in IS than in CS BAL. However, anti-KLH IgG/albumin ratios were similar in IS BAL and serum, suggesting that anti-KLH IgG had reached IS by passive transudation from the circulation. In contrast, anti-KLH IgA/albumin concentrations were greater in IS BAL than in serum, suggesting local production, and/or active transport of serum-derived anti-KLH IgA into the IS. Fractionation of serum and IS BAL on sucrose gradients demonstrated that anti-KLH IgA activity was largely associated with 11S polymeric IgA in both locations.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1993

The effects of age on immune responses in the antigen-instilled dog lung. Antibody responses in the lung and lymphoid tissues following primary and secondary antigen instillation.

To evaluate the effects of age on immunity induced by lung immunization, 11 aged (12-17 years; median age = 14) and 12 young (2-5 years) male Beagle dogs were instilled with 10 mg of keyhole limpet hemocyanin (KLH) in the right cardiac lung lobe and 10(10) sheep red blood cells (SRBC) in the left cardiac lung lobe. Five aged and six young dogs were sacrificed at day 9 after primary antigen instillation. The remainder were given challenge antigen instillations of KLH and SRBC at day 21 and sacrificed 7 days later. Serum, bronchoalveolar lavage fluid and lung tissue from immunized and control lobes, tracheobronchial, mesenteric and popliteal lymph nodes, spleen, and blood were taken at sacrifice. Anti-KLH IgA, IgG and IgM antibody production by cells in lung tissue and lavage fluid from the KLH-exposed lobe was lower at primary immunization and challenge in aged than young dogs. Lavage fluid IgA and IgG levels from the KLH exposed lobe at primary immunization and challenge were lower in aged versus young dogs, while IgM levels were lower only after primary immunization. Localized lung immune memory responses were also markedly lower in aged dogs when compared with young dogs. Anti-SRBC responses were similar to the anti-KLH responses. Our data show that systemic immune responses are significantly lower in aged dogs following primary antigen instillation, but not after antigen challenge in the lung. This was not the case for localized lung immune responses, which were significantly lower in aged dogs even following antigen challenge. The data also show that antibody production by lavage cells is a good index of interstitial lung cell antibody production.

Aging↗
PubMed1993

Long-term antibody production after lung immunization and challenge: role of lung and lymphoid tissues.

After localized lung immunization and challenge, antigen-specific antibody continues to be produced in the immunized lung lobes of dogs for years after the last antigen exposure. Lavage fluid from immunized lung lobes contains significantly more antigen-specific antibody than lavage fluid from control lung lobes, and only cells from lung lobes exposed to antigen produce antibody. Although cells lavaged from the lung produce antibody, it is possible that cells in the lung interstitium or lymphoid tissues may be more important in long-term antibody production after lung immunization and challenge. The goal of this study was to compare the levels of antibody production by cells from dogs 2 yr after pulmonary immunization and challenge. Cells were evaluated from lung lavage, lung tissue, tracheobronchial lymph nodes, and distant lymphoid tissues. The results showed that cells lavaged from lung lobes immunized and challenged with sheep red blood cells (SRBC) were producing anti-SRBC IgG antibody 2 yr after the last antigen challenge. However, cells obtained by mincing tissues from immunized lung lobes were producing significantly higher levels of antibody than lavage cells. In contrast, lavage or tissue cells obtained from the control lobes did not produce detectable antibody. Only a low level of anti-SRBC IgG was produced by cells from the tracheobronchial lymph nodes, and minimal antibody was produced by cells from blood, spleen, or mesenteric and popliteal lymph nodes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Interspecies comparison of cellular localization of the cyanide metabolizing enzyme rhodanese within olfactory mucosa.

The observation of high levels of xenobiotic metabolizing enzyme activity in the olfactory mucosa has produced speculation on the functional significance of these enzymes in the nose. Hypothesized roles include protection of the nasal epithelium, lung, and other downstream tissues, and termination or modification of olfactory responses. The enzyme rhodanese metabolizes cyanide, which is a commonly inhaled toxicant and an odorant and therefore of interest to both toxicologists and olfactory neurobiologists. The cellular localization of this enzyme within the olfactory mucosa will have important consequences for its ability to protect specific cells, as well as its ability to alter the concentration of inhaled cyanide at receptors, and therefore could provide clues as to its function in this tissue. We have compared the distribution of this enzyme in two species, the rat and the cow, using immunohistochemical localization techniques employing species-specific polyclonal antisera raised in our laboratory. In the rat, rhodanese-like immunoreactivity was greatest within the apical portion of the sustentacular cells, the basal cells, and the duct cells of Bowman's glands. Very little to no reaction was observed in the acinar cells of Bowman's glands. In the cow, however, the acinar cells and duct cells of Bowman's glands showed intense immunoreactivity with little to no reaction observed in the sustentacular or basal cells. The differences in localization of rhodanese in these two species may have important implications for cell types at risk during inhalation of cyanide or organonitrile compounds metabolized to cyanide within the nasal mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Beryllium-induced lung disease in the dog following two exposures to BeO.

We have shown previously that dogs exposed once to aerosols of beryllium oxide (BeO) calcined at 500 or 1000 degrees C developed granulomatous lung lesions as well as Be-specific immune responses in the blood and lung. In this report, we investigate the immunopathologic consequences of exposing dogs twice to aerosols of BeO. Dogs previously exposed to aerosols of 500 or 1000 degrees C calcined BeO to achieve an initial lung burden (ILB) of either 50 or 17 micrograms/kg body wt were exposed a second time to BeO calcined at 500 degrees C, 2.5 years after the first exposure, to achieve an ILB of about 50 micrograms/kg body wt. Immune responses of peripheral blood and lung lymphocytes were measured at 0, 14, 30, 60, 90, 120, 150, 165, 180, and 210 days postexposure (dpe), and dogs were euthanized at 210 dpe. Be-specific immune responses occurred in blood at 30 dpe and again at 150 to 210 dpe. Only sporadic positive responses were seen among lung lymphocytes when cells were cultured in 10% fetal bovine serum. In contrast, samples collected at 165, 180, and 210 dpe and incubated with 10% dog serum showed a large number of positive responses in both blood and lung. Histologic lesions were characterized by perivascular and interstitial infiltrates of lymphocytes and macrophages with progression to patchy granulomatous pneumonia accompanied by focal septal fibrosis. We conclude that Be-induced granulomatous and fibrotic lung lesions are accompanied by Be-specific immune responses within the lung but these changes do not appear to be cumulative if enough time has elapsed between exposures.

Aerosols↗
PubMed1992

Long-term consequences of 239PuO2 exposure in dogs: persistent T lymphocyte dysfunction.

Young Beagle dogs were exposed by inhalation to aerosols of 239PuO2 and observed for their lifespans as part of a large, ongoing study of the biological effects of inhaled radionuclides. The purpose of our study was to compare certain immune responses of the 239PuO2-exposed dogs at middle age (7-10 years old) and old age (12-14 years old), with those of unexposed, age-matched or young (3-4 years old) animals. Some of the aged, exposed dogs had developed lung tumours. Lymphocyte proliferative responses to phytohaemagglutinin (PHA) were lower in aged control dogs than in either young or middle-aged control dogs. Both aged and middle-aged, radiation-exposed dogs had decreased responses to PHA when compared to age-matched controls. Responses to concanavalin A (Con A) were not affected by age in control dogs, but tended to decrease in the oldest group of radiation-exposed dogs. Responses to both PHA and Con A were severely depressed in tumour-bearing dogs. The cytolytic activity of natural killer cells was not affected by age, radiation exposure, or tumour presence. We concluded that inhalation of 239PuO2 by young Beagle dogs resulted in an earlier-than-normal decrease in the ability of T cells to respond to mitogenic stimulation. In other words the depressed responses to PHA that were observed might represent radiation-induced, accelerated ageing of the T cell response.

Administration, Inhalation↗
PubMed1992

Primary immunization in the canine lung. Soluble antigen induces a localized response.

Primary immunization of the dog by intralobar instillation of particulate antigen induces an intense, localized pulmonary antibody response. In contrast, although soluble antigen can also induce local antibody responses after repeated deposition in the canine respiratory tract, its ability to induce local responses after primary immunization has not been well characterized. To document such responses, we immunized five beagle dogs using a bronchoscope to instill 10 mg keyhole limpet hemocyanin (KLH) into a single lung lobe (immunized) and saline into a contralateral lung lobe (control). Over the next 3 wk, we monitored specific immune responses in blood and bronchoalveolar lavage (BAL) fluids obtained from the immunized and control lung lobes. Primary intrapulmonary immunization of dogs with KLH resulted in anti-KLH antibody responses both in blood and in immunized and control BAL fluids. However, immunoglobulin class-specific expression of response differed between the immunized and control lung lobes. Specific IgM and IgA responses were significantly greater in the immunized lobes. In contrast, specific IgG, and cells producing specific IgG, were quantitatively similar in lavage fluids derived from immunized and control lung lobes. These studies demonstrate that primary immunization of the dog by intralobar instillation of soluble antigen stimulates a local IgM and IgA response and an IgG response that distributes to both immunized and unimmunized lung. This pattern of immunoglobulin class-specific pulmonary antibody response has the potential to importantly influence regional responses to intrapulmonary antigen.

Animals↗