Biomedical subjects

Erwin W Gelfand

Publications and source records attributed to Erwin W Gelfand.

At least 37 records · Page 2Linked to original sources

PubMed2006

A focus on the asthma HEDIS measure and its implications for clinical practice.

With more than $16.1 billion in annual costs, the asthma management system is inadequate and needs revision to improve health and financial outcomes. Solutions may be found in the National Committee for Quality Assurance's guidelines and in such programs as Pay for Performance that financially reward providers for adherence to standards of practice based on Health Plan Employer Data and Information Set measures.

Asthma↗

PubMed2005

Syk activation in dendritic cells is essential for airway hyperresponsiveness and inflammation.

We evaluated the role of Syk, using an inhibitor, on allergen-induced airway hyperresponsiveness (AHR) and airway inflammation in a system shown to be B cell- and mast cell-independent. Sensitization of BALB/c mice with ovalbumin (OVA) and alum after three consecutive OVA challenges resulted in AHR to inhaled methacholine and airway inflammation. The Syk inhibitor R406 (30 mg/kg, administered orally, twice daily) prevented the development of AHR, increases in eosinophils and lymphocytes and IL-13 levels in bronchoalveolar lavage (BAL) fluid, and goblet cell metaplasia when administered after sensitization and before challenge with OVA. Levels of IL-4, IL-5, and IFN-gamma in BAL fluid and allergen-specific antibody levels in serum were not affected by treatment. Because many of these responses may be influenced by dendritic cell function, we investigated the effect of R406 on bone marrow-derived dendritic cell (BMDC) function. Co-culture of BMDC with immune complexes of OVA and IgG anti-OVA together with OVA-sensitized spleen mononuclear cells resulted in increases in IL-13 production. IL-13 production was inhibited if the BMDCs were pretreated with the Syk inhibitor. Intratracheal transfer of immune complex-pulsed BMDCs (but not nonpulsed BMDCs) to naive mice before airway allergen challenge induced the development of AHR and increases in BAL eosinophils and lymphocytes. All of these responses were inhibited if the transferred BMDCs were pretreated with R406. These results demonstrate that Syk inhibition prevents allergen-induced AHR and airway inflammation after systemic sensitization and challenge, at least in part through alteration of DC function.

Allergens↗

PubMed2005

Differences between IGIV products: impact on clinical outcome.

The use of immune globulin intravenous (IGIV) as replacement therapy in immunodeficiency disease and as anti-inflammatory or immunomodulatory therapy in a variety of autoimmune and inflammatory diseases has expanded dramatically over the last decade. With this expansion, new challenges and concerns have emerged. As well, new products have been introduced while others have been discontinued. This evolution poses the important issue of product selection, choosing the "right" product for an individual patient. As the manufacturing process, virus reduction methods, and final formulation and composition differ widely among these products, it is intuitive that clinical outcomes, including both safety and efficacy, could also differ. This review examines such differences among currently available products in the United States and their potential to affect clinical outcomes.

Chemistry, Pharmaceutical↗

PubMed2005

Introduction.

Explore the source record for details and available documents.

History, 20th Century↗

PubMed2005

Importance of the personal endotoxin cloud in school-age children with asthma.

BACKGROUND: A number of studies have observed associations between the amount of endotoxin in urban dust and chronic asthma severity, but a direct relationship between personal exposure to household endotoxin and acute asthma worsening has not yet been defined. OBJECTIVE: We sought to investigate the relationship between day-to-day changes in personal endotoxin exposure and asthma severity. METHODS: In the winter and spring of 1999 through 2000, endotoxin exposures were monitored in asthmatic schoolchildren by using portable, as opposed to stationary, monitors designed to measure inhalable and respirable particulate matter less than or equal to 2.5 and 10 microm in diameter. Children were followed with daily measurements of FEV(1) and asthma symptoms. RESULTS: Over a 24-hour period, median daily personal endotoxin exposures ranged from 0.08 EU/m(3) (measured at a particulate matter size range </=2.5 microm in diameter) to 0.37 EU/m(3) (measured at a particulate matter size range </=10 microm in diameter). Personal exposures were significantly (P < .001) higher than endotoxin measurements from either indoor or outdoor stationary monitors. Moreover, individual exposures did not correlate with stationary measurements, suggesting that exposures derived from sources in close proximity to the children's personal activities might be better correlated with disease severity. Increases in personal endotoxin exposures were associated with decreased FEV(1) values and increased symptoms. CONCLUSIONS: These findings demonstrate the importance of using personal monitoring to both measure and correlate endotoxin exposure with asthma severity.

Air Pollutants↗

PubMed2005

Distribution and leukocyte contacts of gammadelta T cells in the lung.

Pulmonary gammadelta T cells protect the lung and its functions, but little is known about their distribution in this organ and their relationship to other pulmonary cells. We now show that gammadelta and alphabeta T cells are distributed differently in the normal mouse lung. The gammadelta T cells have a bias for nonalveolar locations, with the exception of the airway mucosa. Subsets of gammadelta T cells exhibit further variation in their tissue localization. gammadelta and alphabeta T cells frequently contact other leukocytes, but they favor different cell-types. The gammadelta T cells show an intrinsic preference for F4/80+ and major histocompatibility complex class II+ leukocytes. Leukocytes expressing these markers include macrophages and dendritic cells, known to function as sentinels of airways and lung tissues. The continuous interaction of gammadelta T cells with these sentinels likely is related to their protective role.

Animals↗

PubMed2005

Inhibition of spleen tyrosine kinase prevents mast cell activation and airway hyperresponsiveness.

RATIONALE: Spleen tyrosine kinase (Syk) is important for Fc and B-cell receptor-mediated signaling. OBJECTIVE: To determine the activity of a specific Syk inhibitor (R406) on mast cell activation in vitro and on the development of allergen-induced airway hyperresponsiveness (AHR) and inflammation in vivo. METHODS: AHR and inflammation were induced after 10 d of allergen (ovalbumin [OVA]) exposure exclusively via the airways and in the absence of adjuvant. This approach was previously established to be IgE, FcepsilonRI, and mast cell dependent. Alternatively, mice were passively sensitized with OVA-specific IgE, followed by limited airway challenge. In vitro, the inhibitor was added to cultures of IgE-sensitized bone marrow-derived mast cells (BMMCs) before cross-linking with allergen. RESULTS: The inhibitor prevented OVA-induced degranulation of passively IgE-sensitized murine BMMCs and inhibited the production of interleukin (IL)-13, tumor necrosis factor alpha, IL-2, and IL-6 in these sensitized BMMCs. When administered in vivo, R406 inhibited AHR, which developed in BALB/c mice exposed to aerosolized 1% OVA for 10 consecutive d (20 min/d), as well as pulmonary eosinophilia and goblet cell metaplasia. A similar inhibition of AHR was demonstrated in mice passively sensitized with OVA-specific IgE and exposed to limited airway challenge. CONCLUSION: This study delineates a functional role for Syk in the development of mast cell- and IgE-mediated AHR and airway inflammation, and these results indicate that inhibition of Syk may be a target in the treatment of allergic asthma.

Animals↗

PubMed2005

Importance of myeloid dendritic cells in persistent airway disease after repeated allergen exposure.

RATIONALE: There is conflicting information about the development and resolution of airway inflammation and airway hyperresponsiveness (AHR) after repeated airway exposure to allergen in sensitized mice. METHODS: Sensitized BALB/c and C57BL/6 mice were exposed to repeated allergen challenge on 3, 7, or 11 occasions. Airway function in response to inhaled methacholine was monitored; bronchoalveolar lavage fluid inflammatory cells were counted; and goblet cell metaplasia, peribronchial fibrosis, and smooth muscle hypertrophy were quantitated on tissue sections. Bone marrow-derived dendritic cells were generated after differentiation of bone marrow cells in the presence of growth factors. RESULTS: Sensitization to ovalbumin (OVA) in alum, followed by three airway exposures to OVA, induced lung eosinophilia, goblet cell metaplasia, mild peribronchial fibrosis, and peribronchial smooth muscle hypertrophy; increased levels of interleukin (IL)-4, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor, transforming growth factor-beta(1), eotaxin-1, RANTES (regulated on activation, normal T-cell expressed and secreted), and OVA-specific IgG1 and IgE; and resulted in AHR. After seven airway challenges, development of AHR was markedly decreased as was the production of IL-4, IL-5, and IL-13. Levels of IL-10 in both strains and the level of IL-12 in BALB/c mice increased. After 11 challenges, airway eosinophilia and peribronchial fibrosis further declined and the cytokine and chemokine profiles continued to change. At this time point, the number of myeloid dendritic cells and expression of CD80 and CD86 in lungs were decreased compared with three challenges. After 11 challenges, intratracheal instillation of bone marrow-derived dendritic cells restored AHR and airway eosinophilia. CONCLUSIONS: These data suggest that repeated allergen exposure leads to progressive decreases in AHR and allergic inflammation, through decreases in myeloid dendritic cell numbers.

Allergens↗

PubMed2005

The enhancement or prevention of airway hyperresponsiveness during reinfection with respiratory syncytial virus is critically dependent on the age at first infection and IL-13 production.

Respiratory syncytial virus (RSV) infection in early life is suspected to play a role in the development of post-bronchiolitis wheezing and asthma. Reinfection is common at all ages, but factors that determine the development of altered airway function after reinfection are not well understood. This study was conducted in a mouse model to define the role of age in determining the consequences on airway function after reinfection. Mice were infected shortly after birth or at weaning and were reinfected 5 wk later, followed by assessment of airway function, airway inflammation, and lung histopathology. Infection of mice at weaning elicited a protective airway response upon reinfection. In this age group, reinfection resulted in increased airway inflammation, but without development of airway hyperresponsiveness (AHR) or eosinophilia and decreased IL-13 levels. By contrast, neonatal infection failed to protect the airways and resulted in enhanced AHR after reinfection. This secondary response was associated with the development of airway eosinophilia, increased IL-13 levels, and mucus hyperproduction. Both CD4- and CD8-positive T cells were a source of IL-13 in the lung, and inhibition of IL-13 abolished AHR and mucus production in these mice. Inoculation of UV-inactivated virus failed to elicit these divergent responses to reinfection, emphasizing the requirement for active lung infection during initial exposure. Thus, neonatal RSV infection predisposes to the development of airway eosinophilia and enhanced AHR via an IL-13-dependent mechanism during reinfection, whereas infection at a later age protects against the development of these altered airway responses after reinfection.

Aging↗

PubMed2005

Modulation of p53 activity by IkappaBalpha: evidence suggesting a common phylogeny between NF-kappaB and p53 transcription factors.

BACKGROUND: In this work we present evidence that the p53 tumor suppressor protein and NF-kappaB transcription factors could be related through common descent from a family of ancestral transcription factors regulating cellular proliferation and apoptosis. P53 is a homotetrameric transcription factor known to interact with the ankyrin protein 53BP2 (a fragment of the ASPP2 protein). NF-kappaB is also regulated by ankyrin proteins, the prototype of which is the IkappaB family. The DNA binding sequences of the two transcription factors are similar, sharing 8 out of 10 nucleotides. Interactions between the two proteins, both direct and indirect, have been noted previously and the two proteins play central roles in the control of proliferation and apoptosis. RESULTS: Using previously published structure data, we noted a significant degree of structural alignment between p53 and NF-kappaB p65. We also determined that IkappaBalpha and p53 bind in vitro through a specific interaction in part involving the DNA binding region of p53, or a region proximal to it, and the amino terminus of IkappaBalpha independently or cooperatively with the ankyrin 3 domain of IkappaBalpha In cotransfection experiments, kappaBalpha could significantly inhibit the transcriptional activity of p53. Inhibition of p53-mediated transcription was increased by deletion of the ankyrin 2, 4, or 5 domains of IkappaBalpha Co-precipitation experiments using the stably transfected ankyrin 5 deletion mutant of kappaBalpha and endogenous wild-type p53 further support the hypothesis that p53 and IkappaBalpha can physically interact in vivo. CONCLUSION: The aggregate results obtained using bacterially produced IkappaBalpha and p53 as well as reticulocyte lysate produced proteins suggest a correlation between in vitro co-precipitation in at least one of the systems and in vivo p53 inhibitory activity. These observations argue for a mechanism involving direct binding of IkappaBalpha to p53 in the inhibition of p53 transcriptional activity, analogous to the inhibition of NF-kappaB by kappaBalpha and p53 by 53BP2/ASPP2. These data furthermore suggest a role for ankyrin proteins in the regulation of p53 activity. Taken together, the NFkappaB and p53 proteins share similarities in structure, DNA binding sites and binding and regulation by ankyrin proteins in support of our hypothesis that the two proteins share common descent from an ancestral transcriptional factor.

Amino Acid Sequence↗

PubMed2005

Requirement for leukotriene B4 receptor 1 in allergen-induced airway hyperresponsiveness.

RATIONALE: Leukotriene B4 (LTB4) is a rapidly synthesized, early leukocyte chemoattractant that signals via its cell surface receptor, leukotriene B4 receptor 1 (BLT1), to attract and activate leukocytes during inflammation. A role for the LTB4-BLT1 pathway in allergen-induced airway hyperresponsiveness and inflammation is not well defined. OBJECTIVES: To define the role of the LTB4 receptor (BLT1) in the development of airway inflammation and altered airway function. METHODS: BLT1-deficient (BLT1 -/-) mice and wild-type mice were sensitized to ovalbumin by intraperitoneal injection and then challenged with ovalbumin via the airways. Airway responsiveness to inhaled methacholine, bronchoalveolar lavage fluid cell composition and cytokine levels, and lung inflammation and goblet cell hyperplasia were assessed. RESULTS: Compared with wild-type mice, BLT1 -/- mice developed significantly lower airway responsiveness to inhaled methacholine, lower goblet cell hyperplasia in the airways, and decreased interleukin (IL)-13 production both in vivo, in the bronchoalveolar lavage fluid, and in vitro, after antigen stimulation of lung cells in culture. Intracellular cytokine staining of lung cells revealed that bronchoalveolar lavage IL-13 levels and numbers of IL-13(+)/CD4+ and IL-13(+)/CD8+ T cells were also reduced in BLT1 -/- mice. Reconstitution of sensitized and challenged BLT1 -/- mice with allergen-sensitized BLT1 +/+ T cells fully restored the development of airway hyperresponsiveness. In contrast, transfer of naive T cells failed to do so. CONCLUSION: These data suggest that BLT1 expression on primed T cells is required for the full development of airway hyperresponsiveness, which appears to be associated with IL-13 production in these cells.

Allergens↗

PubMed2005

Airway hyperresponsiveness in the absence of CD4+ T cells after primary but not secondary challenge.

CD4+ T cells have been shown to play a role in the development of airway hyperresponsivness (AHR) and airway eosinophilia in mice using ablation as well as adoptive transfer experiments. However, as other T cell subsets (CD8, NKT) may play a role in these models, we examined the responses of sensitized CD4-deficient mice after either primary or secondary airway allergen challenge. After sensitization, CD4-deficiency in mice was not associated with airway eosinophilia, allergen-specific IgE, or elevated levels of interleukin (IL)-4 or IL-13. Increases in lung CD8 T cells and IL-5 were observed and shown to be essential for AHR as demonstrated after CD8 T cell depletion or anti-IL-5 treatment. In contrast to the response of sensitized CD4-deficient mice to primary allergen challenge, they failed to develop AHR after secondary allergen challenge. Although the importance of this CD4+ T cell-independent pathway in normal mice is unclear at this time, these studies identify the diversity of the cellular pathway, which may contribute to the development of AHR after primary allergen exposure of sensitized mice.

Adoptive Transfer↗

PubMed2005

Leukotriene B4 receptor-1 is essential for allergen-mediated recruitment of CD8+ T cells and airway hyperresponsiveness.

Recent studies in both human and rodents have indicated that in addition to CD4+ T cells, CD8+ T cells play an important role in allergic inflammation. We previously demonstrated that allergen-sensitized and -challenged CD8-deficient (CD8-/-) mice develop significantly lower airway hyperresponsiveness (AHR), eosinophilic inflammation, and IL-13 levels in bronchoalveolar lavage fluid compared with wild-type mice, and that all these responses were restored by adoptive transfer of in vivo-primed CD8+ T cells or in vitro-generated effector CD8+ T cells (T(EFF)). Recently, leukotriene B4 and its high affinity receptor, BLT1, have been shown to mediate in vitro-generated T(EFF) recruitment into inflamed tissues. In this study we investigated whether BLT1 is essential for the development of CD8+ T cell-mediated allergic AHR and inflammation. Adoptive transfer of in vivo-primed BLT1+/+, but not BLT1-/-, CD8+ T cells into sensitized and challenged CD8-/- mice restored AHR, eosinophilic inflammation, and IL-13 levels. Moreover, when adoptively transferred into sensitized CD8-/- mice, in vitro-generated BLT1+/+, but not BLT1-/-, T(EFF) accumulated in the lung and mediated these altered airway responses to allergen challenge. These data are the first to show both a functional and an essential role for BLT1 in allergen-mediated CD8+ T(EFF) recruitment into the lung and development of AHR and airway inflammation.

Adoptive Transfer↗

PubMed2005

Mismatched antigen prepares gamma delta T cells for suppression of airway hyperresponsiveness.

Gammadelta T cells suppress airway hyperresponsiveness (AHR) induced in allergen-challenged mice but it is not clear whether the suppression is allergen specific. The AHR-suppressive cells express TCR-Vgamma4. To test whether the suppressive function must be induced, we adoptively transferred purified Vgamma4(+) cells into gammadelta T cell-deficient and OVA-sensitized and -challenged recipients (B6.TCR-Vgamma4(-/-)/6(-/-)) and measured the effect on AHR. Vgamma4(+) gammadelta T cells isolated from naive donors were not AHR-suppressive, but Vgamma4(+) cells from OVA-stimulated donors suppressed AHR. Suppressive Vgamma4(+) cells could be isolated from lung and spleen. Their induction in the spleen required sensitization and challenge. In the lung, their function was induced by airway challenge alone. Induction of the suppressors was associated with their activation but it did not alter their ability to accumulate in the lung. Vgamma4(+) gammadelta T cells preferentially express Vdelta4 and -5 but their AHR-suppressive function was not dependent on these Vdeltas. Donor sensitization and challenge not only with OVA but also with two unrelated allergens (ragweed and BSA) induced Vgamma4(+) cells capable of suppressing AHR in the OVA-hyperresponsive recipients, but the process of sensitization and challenge alone (adjuvant and saline only) was not sufficient to induce suppressor function, and LPS as a component of the allergen was not essential. We conclude that AHR-suppressive Vgamma4(+) gammadelta T cells require induction. They are induced by allergen stimulation, but AHR suppression by these cells does not require their restimulation with the same allergen.

Adoptive Transfer↗

PubMed2005

Immunoglobulin replacement therapy in primary antibody deficiency diseases--maximizing success.

Antibody or humoral immunodeficiencies comprise the largest group of primary immunodeficiency diseases. Since the first description of patients with low gammaglobulin levels more than four decades ago, a great wealth of information has been accumulated. Especially in the last several years, the application of molecular and genetic techniques has unraveled many of these disorders, identifying disorders of B cell development, failure of class switch recombination and abnormalities of specific antibody production. Regardless of the underlying defect, the mainstay of therapy has been and remains immunoglobulin (Ig) replacement therapy, currently by intravenous infusion or subcutaneous injection. With advances in manufacturing, a number of products are not only safe for intravenous administration but doses can be increased to provide even more effective infection prophylaxis. However, manufacturing processes, methods of viral inactivation and removal and final composition differ widely among the available preparations. How these variables impact clinical outcome is not clear, but they have the potential to do so. As a result, careful selection of an intravenous immunoglobulin (IVIG), matching patient needs and risks to those risks associated with a specific IVIG, is necessary to optimize outcomes and maximize the success of Ig replacement therapy.

Antibody Formation↗

PubMed2005

Do NHLBI lung function criteria apply to children? A cross-sectional evaluation of childhood asthma at National Jewish Medical and Research Center, 1999-2002.

Although National Heart Lung Institute (NHLBI) guidelines categorize asthma severity based on spirometry, few studies have evaluated the utility of these spirometric values in grading asthma severity in children. Asthma is thought to be progressive, but little is known about the loss of lung function in childhood. This study sought to determine the spirometric indices in children from 4-18 years of age. Retrospective cross-sectional analysis was performed on all spirometries done in children at the National Jewish Medical and Research Center from 1999-2002. In total, 2,728 children performed 24,388 measures. The mean +/- SD values for forced vital capacity (FVC), forced expired volume in 1 sec (FEV(1)), FEV(1)/FVC ratio, and forced expiratory flow (FEF)(25-75) were 92.7 +/- 16.2, 92.2 +/- 18.0, 85.3 +/- 9.3, and 78.0 +/- 36.5 percent predicted, respectively. Seventy-seven percent of FEV(1) values were >/= 80%, 18.6% were between 60-80%, and 3.1% were <60% of predicted. FEV(1) was highest in 5-year-old children; it declined thereafter, reaching a nadir at 11 years, followed by a partial recovery from 12-18 years. Expressed in liters, FEV(1) values were lower than expected at every age, with the greatest difference at 18 years. FEV(1)/FVC ratios declined through childhood, suggesting impaired airway but not lung growth in children with asthma. In conclusion, the majority of asthmatic children attending a tertiary care facility had FEV(1) values within normal range. With increasing age, the increase in FEV(1) lags behind that of nonasthmatics, so that by 18 years, maximum FEV(1) is impaired. The NHLBI FEV(1) cutoff values do not appear to accurately stratify pediatric asthma, and no useful FEV(1) cutoff could be generated.

Adolescent↗

PubMed2005

Quantitative computed tomography detects peripheral airway disease in asthmatic children.

The aim of this study was to compare air-trapping as quantified by high-resolution computed tomography (HRCT) of the chest with measures of lung function and airway inflammation in children with mild to moderate asthma. Plethysmography indices, respiratory resistance, and reactance before and after bronchodilator with impulse oscillation (IOS), exhaled nitric oxide (eNO), total eosinophil count (TEC), and serum eosinophil cationic protein (ECP) levels were measured in 21 subjects. A single-cut HRCT image at end-expiration was obtained. Air-trapping was quantified and expressed in terms of the pixel index (PI) by determining the percentage of pixels in lung fields below -856 and -910 Hounsfeld units (HU). Pairwise linear correlations between PI and other parameters were evaluated. Subjects had only mild airflow limitation based on prebronchodilator forced expiratory volume in 1 sec (FEV(1)), but were hyperinflated and had air-trapping based on elevated total lung capacity (TLC) and residual volume (RV)/TLC ratio, respectively. The PI at -856 HU was positively correlated with % predicted TLC, total gas volume (TGV), and ECP level, and was inversely correlated with FEV(1)/forced vital capacity (FVC) and % predicted forced expiratory flow between 25-75% FVC (FEF(25-75)). The PI at -910 HU correlated similarly with these variables, and also correlated positively with IOS bronchodilator reversibility. This data suggest that quantitative HRCT may be a useful tool in the evaluation of peripheral airflow obstruction in children with asthma.

Adolescent↗

PubMed2005

Physiologic assessment of allergic rhinitis in mice: role of the high-affinity IgE receptor (FcepsilonRI).

BACKGROUND: There have been few reports using animal models to study the development of allergic rhinitis. Characterization of such a model in mice would be advantageous given the availability of reagents and gene-manipulated strains. OBJECTIVE: We sought to develop a murine model of allergic rhinitis in the absence of lower airway changes. METHODS: After sensitization and challenge, both wild-type and FcepsilonRI-deficient mice were studied for their ability to develop early- and late-phase nasal responses. In the invasive approach, direct measurements of nasal airway resistance (R(NA)) were obtained; in the noninvasive approach using whole-body plethysmography, respiratory frequency and expiratory and inspiratory times were monitored. In both approaches, nasal responses were determined either acutely after challenge (early phase) or 24 hours after challenge (late phase). RESULTS: After challenge of sensitized mice, R(NA) significantly increased. In parallel, respiratory frequency significantly decreased and was highly correlated with the increases in R(NA). Sensitized wild-type mice had an early-phase nasal response and persistent nasal blockage (late-phase response) after allergen challenge. In contrast, sensitized and challenged FcepsilonRI alpha-chain-deficient mice did not have an early-phase nasal reaction and exhibited reduced nasal blockage and lower IL-13 levels in nasal tissue homogenates. CONCLUSIONS: These data indicate that FcepsilonRI is essential to development of an early-phase nasal response and contributes to the development of the late-phase nasal response. These invasive and noninvasive approaches provide new opportunities to evaluate the mechanisms underlying the development of nasal responses to allergen and to assess various therapeutic interventions.

Administration, Intranasal↗