Showing papers by "Erwin W. Gelfand published in 2004"
TL;DR: Variation in one gene, corticotropin-releasing hormone receptor 1 (CRHR1) was consistently associated with enhanced response to therapy in each of the three populations utilizing inhaled corticosteroids as the primary therapy in at least one treatment arm, and suggests this gene pathway as a potential novel therapeutic target.
Abstract: Corticosteroids mediate a variety of immunological actions and are commonly utilized in the treatment of a wide range of diseases. Unfortunately, therapy with this class of medications is associated with a large proportion of non-responders and significant side effects. Inhaled corticosteroids are the most commonly used asthma controller therapy. However, asthmatic response to corticosteroids also varies widely between individuals. We investigated the genetic contribution to the variation in response to inhaled corticosteroid therapy in asthma. The association of longitudinal change in lung function and single nucleotide polymorphisms from candidate genes crucial to the biologic actions of corticosteroids were evaluated in three independent asthmatic clinical trial populations utilizing inhaled corticosteroids as the primary therapy in at least one treatment arm. Variation in one gene, corticotropin-releasing hormone receptor 1 (CRHR1) was consistently associated with enhanced response to therapy in each of our three populations. Individuals homozygous for the variants of interest manifested a doubling to quadrupling of the lung function response to corticosteroids compared with lack of the variants (P-values ranging from 0.006 to 0.025 for our three asthmatic populations). As the primary receptor mediating the release of adrenocorticotropic hormone, which regulates endogenous cortisol levels, CRHR1 plays a pivotal, pleiotropic role in steroid biology. These data indicate that genetic variants in CRHR1 have pharmacogenetic effects influencing asthmatic response to corticosteroids, provide a rationale for predicting therapeutic response in asthma and other corticosteroid-treated diseases, and suggests this gene pathway as a potential novel therapeutic target.
300 citations
TL;DR: Acknowledging both the chronobiology of AR and circadian rhythm-dependent attributes of antiallergy medications might enhance the beneficial effects of allergy therapies.
Abstract: Allergic rhinitis (AR) is part of a systemic disease complex. There is a close relationship between AR and asthma, which has led to the "one airway, one disease" concept. Both conditions share common immunopathology and pathophysiology. In patients with AR, allergen-triggered early and late responses are mediated by a series of inflammatory cells. Within minutes of contact with allergen, IgE-sensitized mast cells degranulate, releasing both preformed and newly synthesized mediators. Immunologic processes in both nasal and bronchial tissue involve T H 2 lymphocytes and eosinophils. Eosinophils are the predominant cell in the chronic inflammatory process characteristic of the late-phase allergic response. Eosinophils release an array of proinflammatory mediators, including cysteinyl leukotrienes, cationic proteins, eosinophil peroxidase, and major basic protein, and might serve as a major source of IL-3, IL-5, GM-CSF, and IL-13. Neuropeptides also appear to contribute to the pathophysiology of AR symptoms. Both AR and asthma exhibit marked day-night variation in symptom severity. Acknowledging both the chronobiology of AR and circadian rhythm-dependent attributes of antiallergy medications might enhance the beneficial effects of allergy therapies.
189 citations
TL;DR: Data suggest an important role for effector CD8+ T cells in the development of AHR and airway inflammation, which may be associated with their Tc2-type cytokine production and their capacity to migrate into the lung.
Abstract: Allergic asthma is a complex syndrome characterized by airway obstruction, airway inflammation and airway hyper-responsiveness (AHR). Using a mouse model of allergen-induced AHR, we previously demonstrated that CD8-deficient mice develop significantly lower AHR, eosinophilic inflammation and interleukin (IL)-13 levels in bronchoalveolar lavage fluid compared with wild-type mice. These responses were restored by adoptive transfer of antigen-primed CD8(+) T cells. Previously, two distinct populations of antigen-experienced CD8(+) T cells, termed effector (T(EFF)) and central memory (T(CM)) cells, have been described. After adoptive transfer into CD8-deficient mice, T(EFF), but not T(CM), cells restored AHR, eosinophilic inflammation and IL-13 levels. T(EFF), but not T(CM), cells accumulated in the lungs, and intracellular cytokine staining showed that the transferred T(EFF) cells were a source of IL-13. These data suggest an important role for effector CD8(+) T cells in the development of AHR and airway inflammation, which may be associated with their Tc2-type cytokine production and their capacity to migrate into the lung.
179 citations
TL;DR: Results show that FcεRI is important for the development of AHR after an aerosolized allergen sensitization protocol and that this effect is mediated through Fc�RI on mast cells and production of IL-13 in the lung.
Abstract: In certain models of allergic airway disease, mast cells facilitate the development of inflammation and airway hyper-responsiveness (AHR). To define the role of the high affinity IgE receptor (FceRI) in the development of AHR, mice with a disruption of the α subunit of the high affinity IgE receptor (FceRI −/− ) were exposed on 10 consecutive days to nebulized OVA. Forty-eight hours after the last nebulization, airway responsiveness was monitored by the contractile response of tracheal smooth muscle to electrical field stimulation (EFS). After the 10-day OVA challenge protocol, wild-type mice demonstrated increased responsiveness to EFS, whereas similarly challenged FceRI −/− mice showed a low response to EFS, similar to nonexposed animals. Further, allergen-challenged FceRI −/− mice showed less airway inflammation, goblet cell hyperplasia, and lower levels of IL-13 in lung homogenates compared with the controls. IL-13-deficient mice failed to develop an increased response to EFS or goblet cell hyperplasia after the 10-day OVA challenge. We transferred bone marrow-derived mast cells from wild-type mice to FceRI −/− mice 1 day before initiating the challenge protocol. After the 10-day OVA challenge, recipient FceRI −/− mice demonstrated EFS-induced responses similar to those of challenged wild-type mice. Transferred mast cells could be detected in tracheal preparations. These results show that FceRI is important for the development of AHR after an aerosolized allergen sensitization protocol and that this effect is mediated through FceRI on mast cells and production of IL-13 in the lung.
123 citations
TL;DR: Findings show how γδ T cells can be both inhibitors and enhancers of AHR and airway inflammation, and they provide further support for the hypothesis that TCR expression and function cosegregate in γ Δ T cells.
Abstract: Allergic airway inflammation and hyperreactivity are modulated by gammadelta T cells, but different experimental parameters can influence the effects observed. For example, in sensitized C57BL/6 and BALB/c mice, transient depletion of all TCR-delta(+) cells just before airway challenge resulted in airway hyperresponsiveness (AHR), but caused hyporesponsiveness when initiated before i.p. sensitization. Vgamma4(+) gammadelta T cells strongly suppressed AHR; their depletion relieved suppression when initiated before challenge, but not before sensitization, and they suppressed AHR when transferred before challenge into sensitized TCR-Vgamma4(-/-)/6(-/-) mice. In contrast, Vgamma1(+) gammadelta T cells enhanced AHR and airway inflammation. In normal mice (C57BL/6 and BALB/c), enhancement of AHR was abrogated only when these cells were depleted before sensitization, but not before challenge, and with regard to airway inflammation, this effect was limited to C57BL/6 mice. However, Vgamma1(+) gammadelta T cells enhanced AHR when transferred before challenge into sensitized B6.TCR-delta(-/-) mice. In this study Vgamma1(+) cells also increased levels of Th2 cytokines in the airways and, to a lesser extent, lung eosinophil numbers. Thus, Vgamma4(+) cells suppress AHR, and Vgamma1(+) cells enhance AHR and airway inflammation under defined experimental conditions. These findings show how gammadelta T cells can be both inhibitors and enhancers of AHR and airway inflammation, and they provide further support for the hypothesis that TCR expression and function cosegregate in gammadelta T cells.
122 citations
TL;DR: To further understand this complex syndrome, the development of animal models which mimic elements of this chronic airway disease is essential.
Abstract: Asthma is a common syndrome in children and adults. Despite the increasing prevalence and socioeconomic burden, the underlying pathophysiology remains poorly defined in a large percentage of asthmatics. Animal models and, in particular, murine models of allergic airway disease have helped to reveal some of the potential underlying mechanisms and have played an important role in identifying the importance of T cells and TH2 cytokines in development of allergen-induced inflammation and airway hyperresponsiveness. In addition, other cell types including mast cells and eosinophils have been implicated in the development of some aspects of the disease. To further understand this complex syndrome, the development of animal models which mimic elements of this chronic airway disease is essential.
116 citations
TL;DR: This essay focuses on whether FEV1 is the best measure of asthma severity in childhood asthma, and whether this approach provides objective data to evaluate efficacy, because children with asthma are likely to haveFEV1 values within the normal range when clinically stable.
Abstract: This essay focuses on whether FEV1 is the best measure of asthma severity in childhood asthma. For better or worse, FEV1 has become the gold standard lung function measurement in asthma, as it can be easily and quickly measured with relatively simple equipment. The current asthma guidelines use FEV1 in addition to daytime and nighttime symptoms in judging asthma severity (1, 2). Patients with mild persistent asthma are said to have FEV1 values of more than 80% of predicted, patients with moderate persistent asthma have values of 60 to 80% of predicted, whereas those with severe persistent asthma have values of less than 60% of predicted (1, 2). Despite widespread acceptance, neither are these criteria evidence-based nor is the basis of criteria described. FEV1 is also the outcome variable favored by the U.S. Food and Drug Administration to judge efficacy of asthma-controller medications. Thus, nearly all studies evaluating response to medications in asthma require subjects to have FEV1 values of 60 to 80% of predicted as essential entry criteria. Although this approach provides objective data to evaluate efficacy, it may not be the best measure for children with asthma. This is in large part because children with asthma are likely to have FEV1 values within the normal range when clinically stable.
115 citations
TL;DR: It is suggested that Ag-primed CD8+ T cells are required for the full development of AHR and airway inflammation, which appears to be associated with IL-13 production from these primed T cells.
Abstract: The role of Th2/CD4 T cells, which secrete IL-4, IL-5, and IL-13, in allergic disease is well established; however, the role of CD8+ T cells (allergen-induced airway hyperresponsiveness (AHR) and inflammation) is less clear. This study was conducted to define the role of Ag-primed CD8+ T cells in the development of these allergen-induced responses. CD8-deficient (CD8−/−) mice and wild-type mice were sensitized to OVA by i.p. injection and then challenged with OVA via the airways. Compared with wild-type mice, CD8−/− mice developed significantly lower airway responsiveness to inhaled methacholine and lung eosinophilia, and exhibited decreased IL-13 production both in vivo, in the bronchoalveolar lavage (BAL) fluid, and in vitro, following Ag stimulation of peribronchial lymph node (PBLN) cells in culture. Reconstitution of sensitized and challenged CD8−/− mice with allergen-sensitized CD8+ T cells fully restored the development of AHR, BAL eosinophilia, and IL-13 levels in BAL and in culture supernatants from PBLN cells. In contrast, transfer of naive CD8+ T cells or allergen-sensitized CD8+ T cells from IL-13-deficient donor mice failed to do so. Intracellular cytokine staining of lung as well as PBLN T cells revealed that CD8+ T cells were a source of IL-13. These data suggest that Ag-primed CD8+ T cells are required for the full development of AHR and airway inflammation, which appears to be associated with IL-13 production from these primed T cells.
107 citations
TL;DR: In summary, acute exposure to O(3) induces AHR, neutrophilic inflammation, epithelial damage, and IL-1, and anIL-1Ra effectively prevents the development of altered airway function, inflammation, and structural damage.
Abstract: The role of an interleukin (IL)-1 receptor antagonist (IL-1Ra) on the development of airway hyperresponsiveness (AHR) and airway inflammation following acute O(3) exposure in mice was investigated. Exposure of C57/BL6 mice to O(3) at a concentration of 2.0 ppm or filtered air for 3 h resulted in increases in airway responsiveness to inhaled methacholine (MCh) 8 and 16 h after the exposure, and an increase in neutrophils in the bronchoalveolar lavage (BAL) fluid. IL-1beta expression, assessed by gene microarray, was increased 2-fold 4 h after O(3) exposure, and returned to baseline levels by 24 h. Levels of IL-1beta in lung homogenates were also increased 8 h after O(3) exposure. Administration of (human) IL-1Ra before and after O(3) exposure prevented development of AHR and decreased BAL fluid neutrophilia. Increases in chemokine levels in lung homogenates, tumor necrosis factor-alpha, MIP-2, and keratinocyte chemoattractant following O(3) exposure were prevented by IL-1Ra. Inhalation of dexamethasone, an inhibitor of IL-1 production, blocked the development of AHR, BAL fluid neutrophilia, and decreased levels of IL-1 following O(3) exposure. In summary, acute exposure to O(3) induces AHR, neutrophilic inflammation, epithelial damage, and IL-1. An IL-1Ra effectively prevents the development of altered airway function, inflammation, and structural damage.
83 citations
TL;DR: The presence of eosinophils with a different phenotype in the TLN at early time points after allergen challenge of sensitized mice supports their capacity to serve as antigen-presenting cells, sustaining allergic/inflammatory responses in the airways.
Abstract: Background Eosinophils play a major role in allergic airway inflammation because of their ability to release toxic mediators. In addition, they are able to migrate toward draining thoracic lymph nodes (TLNs) after intratracheal administration, where they can function as antigen-presenting cells. Objective In this study, we evaluated in vivo eosinophil migration toward the TLN after allergen sensitization and analyzed expression of molecules involved in antigen presentation. Methods Mice were sensitized by intraperitoneal injection of ovalbumin on days 1 and 10 and challenged once intranasally with ovalbumin on day 20. The kinetics of eosinophilia was evaluated in blood, lung tissue homogenate, bronchoalveolar lavage fluid, and TLN. Cell surface staining was analyzed by flow cytometry. Results The kinetics of eosinophil recruitment was similar in TLN, lung tissue, and blood, beginning at 12 hours and peaking at 48 hours after allergen challenge. Approximately 70% of TLN eosinophils expressed MHC class II molecules, compared with less than 25% in blood and lungs. Moreover, TLN eosinophils expressed higher levels of MHC class II and CD86 compared with blood and lung eosinophils. Most eosinophils expressed CD80 and CD54, whereas only a few eosinophils expressed CD40. Eosinophils in lungs and TLN appeared to be activated with lower CD62-ligand expression compared with blood eosinophils. Conclusion The presence of eosinophils with a different phenotype in the TLN at early time points after allergen challenge of sensitized mice supports their capacity to serve as antigen-presenting cells, sustaining allergic/inflammatory responses in the airways.
81 citations
TL;DR: Significant data indicated that activation of the complement system follows acute O3 exposure and is important to the development of AHR and airway neutrophilia, but this neutrophil response does not appear necessary for the developmentof AHR.
Abstract: Ozone (O3) can induce airway hyperresponsiveness (AHR) and neutrophilic inflammation. We evaluated the role of complement in development of AHR and inflammation after acute O3 exposure in mice. Mice were exposed to O3 at 2 ppm for 3 hours, and airway responsiveness to methacholine was measured 8 hours after O3 exposure. Complement was depleted or inhibited by intraperitoneal injection of cobra venom factor (CVF) or complement receptor-related gene y (Crry)-Ig, a potent C3 convertase inhibitor; neutrophils were depleted using an antineutrophil monoclonal antibody. CVF attenuated the development of AHR by O3. Administration of Crry-Ig also prevented the development of AHR. Bronchoalveolar lavage (BAL) fluid neutrophilia after O3 exposure was significantly decreased by administration of either CVF or Crry-Ig. Increased BAL fluid total protein after O3 exposure was lowered by depletion or inhibition of complement. In contrast to the effects of complement inhibition or depletion, depletion of BAL neutrophil counts by more than 90% with the monoclonal antibody did not affect the development of AHR after O3 exposure. These data indicated that activation of the complement system follows acute O3 exposure and is important to the development of AHR and airway neutrophilia. However, this neutrophil response does not appear necessary for the development of AHR.
TL;DR: It is suggested that RSV-specific IgE may contribute to the pathophysiology of airway dysfunction in children who develop this class of specific antibody.
Abstract: Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis during infancy and is associated with subsequent wheezing and asthma, but the nature of this association is not fully understood. We investigated the role of RSV-specific IgE antibodies in the pathophysiology of virus-induced airway dysfunction in a mouse model. Lung infection with RSV resulted in significant increases in mRNA expression for IgE and both of its high- and low-affinity receptors. In serum, virus-specific IgE antibodies reached peak levels by Day 21 after infection. Data from in vitro experiments show that RSV can induce mast cell degranulation, but only if these cells are sensitized with specific IgE. When passively sensitized in vivo with virus-specific IgE, mice developed exaggerated airway responsiveness to methacholine on airway infection, an effect that required the high-affinity receptor of IgE. These data suggest that RSV-specific IgE may contribute to the pathophysiology of airway dysfunction in children who develop this class of specific antibody.
TL;DR: Targeting the effects of CGRP on vasoregulation, bronchoprotection, anti-inflammatory actions and tissue repair is a future avenue for modulation of certain aspects of airway diseases.
TL;DR: It is demonstrated that early neutrophil influx following allergen challenge is mediated by IL-1, IL-18, and p38MAPK, and the effects of inhibiting p38 MAPK in decreasing AHR indicate activities independent of its prevention of neutrophils accumulation.
Abstract: The effect of modifying early neutrophil-mediated inflammation on the development of airway hyperresponsiveness (AHR) was investigated using an interleukin (IL)-1 receptor antagonist (IL-1Ra), an anti–IL-18 antibody (anti–IL-18) or a p38 mitogen-activated protein kinase (MAPK) inhibitor (M39). Balb/c mice were sensitized to ovalbumin (OVA) and challenged with a single intranasal dose of OVA. Treatment with the IL-1Ra or anti–IL-18 was initiated 20 min before challenge, whereas M39 was administered 4 h before the challenge. Eight hours after challenge, sensitized mice showed significantly higher numbers of neutrophils in bronchoalveolar lavage (BAL) fluid; treatment with IL-1Ra, anti–IL-18, or M39 significantly decreased the influx of neutrophils. At 48 h, none of the treatments affected eosinophil inflammation in BAL fluid and lung tissue, goblet cell hyperplasia, or cytokine levels (IL-4, IL-5, IL-12, IL-13, interferon-γ) in BAL fluid. Anti–IL-18 or IL-1Ra had no effect on the development of AHR, whereas...
TL;DR: Age at the time of initial sensitization was shown to be the critical factor dictating the nature of the response to later allergen challenge, as older mice remained responsive to allergenic challenge if sensitized at a young age.
Abstract: Age is an important factor in determining the quantity and quality of immune responses when challenged with allergen. In a model of allergen-induced airway hyperresponsiveness and inflammation, where the sensitization phase and challenge phases can be dissociated in time, we examined the impact of age on these two phases. Sensitization of young mice (1-20 wk), but not older animals (30-40 wk), led to the development of airway hyperresponsiveness, airway eosinophilia, Th2 cytokine responses, and allergen-specific IgE, regardless of the age when the challenge phase was conducted. Thus, age at the time of initial sensitization was shown to be the critical factor dictating the nature of the response to later allergen challenge, as older mice remained responsive to allergen challenge if sensitized at a young age. These effects were shown to be mediated by lung T cells from sensitized young mice. Moreover, the failure of old sensitized mice to mediate these effects was shown not to be the result of active suppression of the responses. These data define the importance of age at initial allergen exposure in dictating subsequent responses in the lung when exposed to allergen and may help to define why asthma, even in adults, is most often initiated in early childhood.
Journal Article•
TL;DR: It is shown that normal human mammary epithelial cells have a high amount ofcdk6 protein and activity, but all breast tumor-derived cell lines analyzed had reduced levels, with several having little or no cdk6.
Abstract: Many defects in cancer cells are in molecules regulating G(1)-phase cyclin-dependent kinases (cdks), which are responsible for modulating the activities of Rb family growth-suppressing proteins. Models for understanding how such defects affect proliferation assume that cdks are responsible for sequentially phosphorylating, and hence inactivating, the growth-suppressing functions of Rb family proteins, thus promoting cell cycle progression. However, cdks also play a role in formation of growth-suppressing forms of pRb family molecules, including the "hypophosphorylated" species of pRb itself. Here, it is shown that normal human mammary epithelial cells have a high amount of cdk6 protein and activity, but all breast tumor-derived cell lines analyzed had reduced levels, with several having little or no cdk6. Immunohistochemical studies showed reduced levels of cdk6 in breast tumor cells as compared with normal breast tissue in vivo. Cdk6 levels in two breast tumor cell lines were restored to those characteristic of normal human mammary epithelial cells by DNA transfection. The cells had a reduced growth rate compared with parental tumor cells; cells that lost ectopic expression of cdk6 reverted to the faster growth rate of parental cells. Cell lines with restored cdk6 levels accumulated higher amounts of the Rb family protein p130 as well as E2F4, a suppressing member of the E2F family of transcription factors, in their nuclei. The results suggest that cdk6 restrains rather than stimulates breast epithelial cell proliferation and that its loss or down-regulation could play a role in breast tumor development.
TL;DR: The Kunsberg school program improved asthma control and reduced disease severity for at‐risk inner‐city asthmatic children, leading to cost reduction for asthma management.
Abstract: Objective: Because children attend school daily, school‐based interventions for children with persistent asthma could provide effective disease management for inner‐city asthmatic children. The Kunsberg School in Denver, Colorado, enrolls children with chronic diseases, including asthma, into a daily program of school‐based disease management. This study sought to determine the impact of the Kunsberg program on asthma utilization. Methods: Children attending Kunsberg (n = 18) who received primary care at Denver Health were compared with a group of matched control children who also received primary care at Denver Health, but did not attend Kunsberg (n = 36). Asthma‐related utilization for an average of 2.9 years before and after Kunsberg enrollment was assessed. Results: The 18 Kunsberg and 36 control subjects were mostly minority children in low‐income families, without significant demographic differences between groups. Compared with controls, the Kunsberg cohort experienced fewer hospitalizations (0.5 v...
TL;DR: Serum SP-D concentration is increased in mice bearing lung tumors and generally reflects the tumor burden but is also elevated during lung inflammation.
TL;DR: It is shown that p57Kip2, which is a member of the Cip/Kip family of cyclin-dependent kinase inhibitors, is present in the nuclei of normal resting T cells from peripheral blood and in theuclei of the T cell-derived Jurkat cell line, and is involved in the regulation of several aspects of theT cell cycle.
Abstract: The specific functions of p57 Kip2 in lymphocytes have not yet been fully elucidated. In this study, it is shown that p57 Kip2 , which is a member of the Cip/Kip family of cyclin-dependent kinase inhibitors, is present in the nuclei of normal resting (G 0 ) T cells from peripheral blood and in the nuclei of the T cell-derived Jurkat cell line. Activation through the TCR results in rapid transport of cytoplasmic cyclin-dependent kinase 6 ( cdk 6) to nuclei, where it associates with cyclin D and p57 Kip2 in active enzyme complexes. Using purified recombinant proteins, it was shown in vitro that addition of p57 Kip2 protein to a mixture of cyclin D2 and cdk 6 enhanced the association of the latter two proteins and resulted in phosphorylation of p57 Kip2 . To probe further the function of p57 Kip2 , Jurkat cells stably transfected with a plasmid encoding p57 Kip2 under control of an inducible (tetracycline) promoter were made. Induction of p57 Kip2 resulted in increased association of cdk 6 with cyclin D3, without receptor-mediated T cell stimulation. The overall amounts of cdk 6 and cyclin D3, and also of cdk 4 and cyclin E, remained unchanged. Most notably, increased p57 Kip2 levels resulted in marked inhibition of both cyclin E- and cyclin A-associated cdk 2 kinase activities and a decrease in cyclin A amounts. Therefore, although facilitating activation of cdk 6, the ultimate outcome of p57 Kip2 induction was a decrease in DNA synthesis and cell proliferation. The results indicate that p57 Kip2 is involved in the regulation of several aspects of the T cell cycle.
TL;DR: The use of aerosolized anti-TCR mAbs may offer an effective approach for the treatment of airway inflammation and AHR.
Abstract: Aerosolized monoclonal antibodies (mAbs) specific for T-cell receptors (TCR) were used to manipulate T-cell function in airways of ovalbumin (OVA)-sensitized and -challenged mice with airway hyperresp
TL;DR: Experimental research suggests that second- and third-generation H1-receptor antagonists may achieve anti-inflammatory effects in a clinical context, and some instances, higher concentrations are required to achieve comparable effects.
Abstract: SUMMARYObjective: To compare the anti-inflammatory effects of fexofenadine with other H -receptor antagonists in vitro.Data sources: Published literature.Study selection: Recent experimental studies on anti-inflammatory effects of H1-receptor antagonists. Databases searched: Medline, Medscape. Period covered: 1990-2003. Search terms: second-, third-generation antihistamines; sedating, nonsedating antihistamines; in vitro anti-inflammatory activity; cetirizine; ebastine; loratadine; fexofenadine; desloratadine.Results: Second- and third-generation H1-⁁ receptor antagonists may demonstrate significant in vitro anti-inflammatory activity at concentrations considered to be clinically relevant. In some instances, higher (supraclinical) concentrations are required to achieve comparable effects.Conclusions: Experimental research suggests that second- and third-generation H1-receptor antagonists may achieve anti-inflammatory effects in a clinical context. Further studies are required to support this conclusion.
TL;DR: Ambient levels of Environmental Protection Agency criteria air pollutants in Denver do not lead to clinically significant asthma worsening in urban children with moderate to severe asthma during winter months when children are primarily indoors.
Abstract: Background Urban minority children with asthma are at higher risk for severe exacerbations leading to hospitalizations and deaths. Because multiple studies have reported associations between air pollution and asthma worsening, elevated levels of air pollution are cited as a possible trigger for increased asthma morbidity in urban areas. Few studies have prospectively followed panels of urban children with asthma to determine whether air pollution levels are associated with clinically relevant outcomes such as asthma exacerbations. Objective To determine the association between levels of ambient air pollutants and asthma exacerbations in urban poor children with moderate to severe asthma. Methods A school-based panel of children with difficult-to-control disease was followed over a period of 3 consecutive winters in Denver, Colo. The panel consisted of predominantly urban African American children with moderate to severe asthma. Levels of Environmental Protection Agency criteria air pollutants were measured on a daily basis with concurrent monitoring of lung function, bronchodilator use, symptoms, and asthma exacerbations. Results After controlling for time-varying factors such as upper respiratory infections and meteorologic factors, a weak association was found between ambient carbon monoxide levels and bronchodilator use. Ozone levels were associated with daytime symptoms only. No association was observed between daily air pollution concentrations and daily levels of FEV 1 , peak flow, nighttime symptom scores, or asthma exacerbations over the 3-year period. Conclusion Ambient levels of Environmental Protection Agency criteria air pollutants in Denver do not lead to clinically significant asthma worsening in urban children with moderate to severe asthma during winter months when children are primarily indoors.
TL;DR: The response of human B cells to binding of immune complexes depends on the relative expression of activating (FcγIIA) versus inhibitory (fcγIIB) receptors.
Abstract: Background: The CD32 (FcγII) receptor is involved in the regulation of the B cell response to antigen. The sole Fc receptor demonstrated in mice is the inhibitory FcγIIB receptor. Crosslinking this receptor does not lead to downstream signaling or cell activation. Instead, when immune complexes bind to Fcy on murine B cells, cell activation through the B cell antigen receptor is attenuated. The objective of this study was to evaluate the expression of the FcγII receptor and the response to immune complex stimulation in human B cells. Methods: Human lymphoblastoid, peripheral and tonsillar B cells were stained with anti-CD32 antibodies IV.3 and 8.26 to determine the relative expression of the activating (FcγIIA) and inhibitory (FcγIIB) isoforms of CD32. Tetanus immune complexes were added to B cells and the activation of c-Jun amino-terminal kinase was assayed. Results: Unlike murine cells, human B cells express high levels of the activating form of the Fcγ receptor IIA. Addition of immune complexes to peripheral B cells resulted in signaling of Jun kinase, an important downstream kinase involved in the regulation of B cell function. The level of expression of FcγIIA on human B cells was not uniform, but depended on activation status. Peripheral blood B cells expressed high levels of FcγIIA, while tonsillar B cells predominantly expressed FcγIIB. Furthermore, when peripheral B cells were activated, the expression of FcγIIA relative to FcγIIB decreased. Conclusion: The response of human B cells to binding of immune complexes depends on the relative expression of activating (FcγIIA) versus inhibitory (FcγIIB) receptors.
Patent•
24 Mar 2004TL;DR: In this paper, a method for regulation of airway hyperresponsiveness by modulating the action of γδ T cells in a patient was proposed, and methods for identifying compounds that regulate airway hypersresponsiveness with respect to T cell action were identified.
Abstract: Disclosed is a method for regulation of airway hyperresponsiveness by modulating the action of γδ T cells in a patient Also disclosed are methods for identifying compounds that regulate airway hyperresponsiveness by modulating γδ T cell action
01 Jan 2004
TL;DR: IGIV has shown benefit in reducing symptoms and the need for cortecosteroids or cytotaxic drugs in a number of dermatologic conditions and in many of these diseases the initial benefits seen in open-labeled trials must be confirmed in controlled clinical trials.
Abstract: Immunoglobulin (Ultravenous, IGIV) is now used in a variety of immune-mediated diseases. Its presumed mechanism of action involves both anti-inflammatory and immunomodulatory activities. A number of dermatologic conditions are believed to be immune mediated and in these disorders, IGIV has shown benefit in reducing symptoms and the need for cortecosteroids or cytotaxic drugs. In many of these diseases, the initial benefits seen in open-labeled trials must be confirmed in controlled clinical trials.
TL;DR: The message of Rupert Timpl’s untimely and unexpected death on October 20, 2003, struck me completely unprepared during a hiking tour through the Dolomites in Northern Italy, just across the Austrian border, a few miles from my hometown Innsbruck in Tyrol, Austria.
Abstract: Accessible online at: www.karger.com/iaa The message of Rupert Timpl’s (fig. 1) untimely and unexpected death on October 20, 2003, struck me completely unprepared during a hiking tour through the Dolomites in Northern Italy, just across the Austrian border, a few miles from my hometown Innsbruck in Tyrol, Austria. It was brought to me by one of my students who hiked with our group and who had just spent a few days in Martinsried at the Max-Planck Institute for Biochemistry (MPI) near Munich, Germany, where Rupert has worked for nearly three decades – the last years as Head of the Department of Connective Tissue Research and as Acting Director of the whole MPI before his retirement in 2000. During that beautiful clear October day in the Dolomites (fig. 2) with several hours of walking time before me, the sudden confrontation with the fact that I would not see Rupert again, afforded the opportunity to immediately and intensively reflect on the role that he played both in my professional as well as in my private life. It first came to my mind that of all the associates of Rupert my own connection was the longest lasting, since it already started in 1965 when we first met in a small laboratory of a peripheral hospital, the Hanuschkrankenhaus, in Vienna. At that time, I was on my first postdoctoral position at the Institute for General and Experimental Pathology, University of Vienna, Medical School, where one of our associate professors, Carl Steffen, had a joint appointment as the head of the Central Diagnostic Laboratory of that hospital. There, Steffen had started a group of connective tissue immunologists, led by the young eager beaver Rupert, at that time still a graduate student who already had an impressive list of highly cited publications and – typically for him – also supervised three postdocs, Fig. 1. Dr. Rupert Timpl, Max-Planck-Institut für Biochemie, Martinsried.
TL;DR: Despite normal FEV 1, peripheral airway dysfunction was evident based upon HRCT findings, and this study demonstrates significant associations between air trapping measured by quantitative HRCT and multiple measures of lung function.
Abstract: Rationale Currently there are no simple, non-invasive measures of peripheral airway obstruction in children with asthma. This study sought to compare air trapping as measured by quantitative high resolution CT (HRCT) with various measures of lung function and airway inflammation in children with mild to moderate asthma. Methods Eighteen children, 10 to 18 years of age, were studied. Body box plethysmography, forced oscillation pre- and post-bronchodilator, exhaled nitric oxide (eNO), total eosinophil count (TEC) and serum eosinophil cationic protein (ECP) levels were monitored. A single-cut HRCT at end-expiration above the diaphragm was obtained. Degree of air trapping was determined using the pixel index (PI) at −856 and −910 Hounsfeld units (HU). P Results Baseline FEV 1 (mean ± SD) was 86.2 ± 11% predicted. The PI at −856 HU correlated with FEV 1 /FVC (R=0.70), TLC (R=0.74), TGV (R=0.57), FEF25-75% (R=0.62), and ECP level (R=0.74). The PI at −910 HU correlated with these variables and with bronchodilator reversibility using resistance at 5 (R=0.51) and 10 Hz (R=0.51) and reactance at 10 Hz (R=0.50). Findings on HRCT did not correlate with changes in FEV 1 , RV, or eNO. Conclusions Despite normal FEV 1 , peripheral airway dysfunction was evident based upon HRCT findings. Further, this study demonstrates significant associations between air trapping measured by quantitative HRCT and multiple measures of lung function.
TL;DR: There is loss of elastic recoil in asthmatic children and some patients are capable of producing elevated FEV1 values due to larger airways and much lower airway resistance, which is responsible for the higherFEV1's seen in pediatric asthma.
Abstract: Rationale We recently reported a group of children with asthma and elevated FEV1. This study was performed in order to understand the physiologic mechanisms that allow this to occur. Methods Children with asthma and an FEV1 >115% (high group) were compared to patients with an FEV1 Results Baseline TLC, TGV, and FEV1 values were highest in the high group and FEV1 values were lowest in the low group. All groups had higher than predicted RV values. Airway and upstream resistances were reduced in the high group and upstream resistance was elevated in the low group. There was a significant loss of elastic recoil in the low group. Post-bronchodilator there was further loss of elastic recoil in the low group and a loss in the high group. The change in FVC, TLC, RV, and TGV was not different between the groups but the low group had an improvement in FEV1. Airway and upstream resistances and conductance improved in the low group while the high group demonstrated a modest increase in upstream resistance post-bronchodilator. Conclusions There is loss of elastic recoil in asthmatic children. Despite this some patients are capable of producing elevated FEV1 values due to larger airways and much lower airway resistance. Unlike adults, children with asthma can have reduced elastic recoil and still maintain the patency of their airways allowing them to produce greater airflow. We believe this is responsible for the higher FEV1's seen in pediatric asthma.