Showing papers by "Erwin W. Gelfand published in 2012"

Intravenous Immune Globulin in Autoimmune and Inflammatory Diseases

Abstract: The author reviews the many proposed mechanisms by which intravenous immune globulin may exert its antiinflammatory and autoimmunity-inhibiting clinical effects. No single mechanism can explain its activity in diseases with diverse pathophysiological pathways.

Responsiveness to respiratory syncytial virus in neonates is mediated through thymic stromal lymphopoietin and OX40 ligand

Abstract: Background Recent studies revealed a critical role for thymic stromal lymphopoietin (TSLP) released from epithelial cells and OX40 ligand (OX40L) expressed on dendritic cells (DCs) in T H 2 priming and polarization. Objectives We sought to determine the importance of the TSLP-OX40L axis in neonatal respiratory syncytial virus (RSV) infection. Methods Mice were initially infected with RSV as neonates or adults and reinfected 5 weeks later. Anti-OX40L or anti-TSLP were administered during primary or secondary infection. Outcomes included assessment of airway function and inflammation and expression of OX40L, TSLP, and IL-12. Results OX40L was expressed mainly on CD11c + MHC class II (MHCII) + CD11b + DCs but not CD103 + DCs. Treatment of neonates with OX40L antibody during primary RSV infection prevented the subsequent enhancement of airway hyperresponsiveness and the development of airway eosinophilia and mucus hyperproduction on reinfection. Administration of anti-TSLP before neonatal RSV infection reduced the accumulation of lung DCs, decreased OX40L expression on lung DCs, and attenuated the enhancement of airway responses after reinfection. Conclusions In mice initially infected as neonates, TSLP expression induced by RSV infection is an important upstream event that controls OX40L expression, lung DC migration, and T H 2 polarization, accounting for the enhanced response on reinfection.

ERK1 is important for Th2 differentiation and development of experimental asthma

Abstract: The ERK1/2 signaling pathway regulates a variety of T-cell functions. We observed dynamic changes in the expression of ERK1/2 during T-helper cell differentiation. Specifically, the expression of ERK1/2 was decreased and increased by IL-12 and IL-4, respectively. To address this subject further, we examined the specific role of ERK1 in Th2 differentiation and development of experimental asthma using ERK1(-/-) mice. ERK1(-/-) mice were unable to mount airway inflammation and hyperreactivity in two different models of asthma, acute and chronic. ERK1(-/-) mice had reduced expression of Th2 cytokines IL-4 and IL-5 but not IL-17A or IFN-γ. They had reduced levels of allergen-specific IgE and blood eosinophils. T cells from immunized ERK1(-/-) mice manifested reduced proliferation in response to the sensitizing allergen. ERK1(-/-) T cells had reduced and short-lived expression of JunB following TCR stimulation, which likely contributed to their impaired Th2 differentiation. Immunized ERK1(-/-) mice showed reduced numbers of CD44(high) CD4 T cells in the spleen. In vitro studies demonstrated that Th2 but not Th1 cells from ERK1(-/-) mice had reduced numbers of CD44(high) cells. Finally, CD4 T cells form ERK1(-/-) mice expressed higher levels of BIM under growth factor-deprived conditions and reduced Mcl-1 on stimulation. As a result, the survival of CD4 T cells, especially CD44(high) Th2 cells, was much reduced in ERK1(-/-) mice. We conclude that ERK1 plays a nonredundant role in Th2 differentiation and development of experimental asthma. ERK1 controls Th2 differentiation and survival through its effect on JunB and BIM, respectively.

Inhibition of Pim1 kinase prevents peanut allergy by enhancing Runx3 expression and suppressing TH2 and TH17 T-cell differentiation

Abstract: Background The provirus integration site for Moloney murine leukemia virus (Pim) 1 kinase is an oncogenic serine/threonine kinase implicated in cytokine-induced cell signaling, whereas Runt-related transcription factor (Runx) has been implicated in the regulation of T-cell differentiation. The interaction of Pim1 kinase and Runx3 in the pathogenesis of peanut allergy has not been defined. Objectives We sought to determine the effects of Pim1 kinase modulation on Runx3 expression and T H 2 and T H 17 cell function in an experimental model of peanut allergy. Methods A Pim1 kinase inhibitor was administered to peanut-sensitized and challenged wild-type and Runx3 +/− mice. Symptoms, intestinal inflammation, and Pim1 kinase and Runx3 mRNA expression and protein levels were assessed. The effects of Pim1 kinase inhibition on T H 1, T H 2, and T H 17 differentiation in vivo and in vitro were also determined. Results Peanut sensitization and challenge resulted in accumulation of inflammatory cells and goblet cell metaplasia and increased levels of Pim1 kinase and T H 2 and T H 17 cytokine production but decreased levels of Runx3 mRNA and protein in the small intestines of wild-type mice. All of these findings were normalized with Pim1 kinase inhibition. In sensitized and challenged Runx3 +/− mice, inhibition of Pim1 kinase had less effect on the development of the full spectrum of intestinal allergic responses. In vitro inhibition of Pim1 kinase attenuated T H 2 and T H 17 cell differentiation and expansion while maintaining Runx3 expression in T-cell cultures from wild-type mice; these effects were reduced in T-cell cultures from Runx3 +/− mice. Conclusion These data support a novel regulatory axis involving Pim1 kinase and Runx3 in the control of food-induced allergic reactions through the regulation of T H 2 and T H 17 differentiation.

Inhibition of Pim1 Kinase Activation Attenuates Allergen-Induced Airway Hyperresponsiveness and Inflammation

Abstract: Pim kinases are a family of serine/threonine kinases whose activity can be induced by cytokines involved in allergy and asthma. These kinases play a role in cell survival and proliferation, but have not been examined, to the best of our knowledge, in the development of allergic disease. This study sought to determine the role of Pim1 kinase in the development of allergic airway responses. Mice were sensitized and challenged with antigen (primary challenge), or were sensitized, challenged, and rechallenged with allergen in a secondary model. To assess the role of Pim1 kinase, a small molecule inhibitor was administered orally after sensitization and during the challenge phase. Airway responsiveness to inhaled methacholine, airway and lung inflammation, cell composition, and cytokine concentrations were assessed. Lung Pim1 kinase concentrations were increased after ovalbumin sensitization and challenge. In the primary allergen challenge model, treatment with the Pim1 kinase inhibitor after sensitization and during airway challenges prevented the development of airway hyperresponsiveness, eosinophilic airway inflammation, and goblet cell metaplasia, and increased Th2 cytokine concentrations in bronchoalveolar fluid in a dose-dependent manner. These effects were also demonstrated after a secondary allergen challenge, where lung allergic disease was established before treatment. After treatment with the inhibitor, a significant reduction was evident in the number of CD4+ and CD8+ T cells and concentrations of cytokines in the airways. The inhibition of Pim1 kinase was effective in preventing the development of airway hyperresponsiveness, airway inflammation, and cytokine production in allergen-sensitized and allergen-challenged mice. These data identify the important role of Pim1 kinase in the full development of allergen-induced airway responses.

The Critical Role of Complement Alternative Pathway Regulator Factor H in Allergen-Induced Airway Hyperresponsiveness and Inflammation

Abstract: Activation of the alternative pathway of complement plays a critical role in the development of allergen-induced airway hyperresponsiveness (AHR) and inflammation in mice. Endogenous factor H, a potent inhibitor of the alternative pathway, is increased in the airways of sensitized and challenged mice, but its role in regulating inflammation or AHR has been unknown. We found that blocking the tissue-binding function of factor H with a competitive antagonist increased complement activation and tissue inflammation after allergen challenge of sensitized mice. Conversely, administration of a fusion protein that contains the iC3b/C3d binding region of complement receptor 2 linked to the inhibitory region of factor H, a molecule directly targeting complement-activating surfaces, protected mice in both primary and secondary challenge models of AHR and lung inflammation. Thus, although endogenous factor H does play a role in limiting the development of AHR, strategies to deliver the complement-regulatory region of factor H specifically to the site of inflammation provide greater protection than that afforded by endogenous regulators. Such an agent may be an effective therapy for the treatment of asthma.

A Novel Prostacyclin Agonist Protects against Airway Hyperresponsiveness and Remodeling in Mice

Abstract: Airway remodeling in bronchial asthma results from chronic, persistent airway inflammation. The effects of the reversal of airway remodeling by drug interventions remain to be elucidated. We investigated the effects of ONO-1301, a novel prostacyclin agonist with thromboxane inhibitory activity, on the prevention and reversibility of airway remodeling in an experimental chronic asthma model. Mice sensitized and challenged to ovalbumin (OVA) three times a week for 5 consecutive weeks were administered ONO-1301 or vehicle twice a day from the fourth week of OVA challenges. Twenty-four hours after the final OVA challenge, airway hyperresponsiveness (AHR) was assessed, and bronchoalveolar lavage was performed. Lung specimens were excised for staining to detect goblet-cell metaplasia, airway smooth muscle, and submucosal fibrosis. Mice administered ONO-1301 showed limited increases in AHR compared with mice administered the vehicle. The histological findings of airway remodeling were improved in ONO-1301–treate...

Low-Dose Lipopolysaccharide Affects Lung Allergic Responses by Regulating Jagged1 Expression on Antigen-Pulsed Dendritic Cells

Abstract: Background: Notch signaling pathways govern immune function and the regulation of Th1 and Th2 differentiation. We previously demonstrated essential interactions between Notch on CD4

Susceptibility to Vaccinia Virus Infection and Spread in Mice Is Determined by Age at Infection, Allergen Sensitization and Mast Cell Status

Abstract: Background: Patients, especially young children, with atopic dermatitis are at an increased risk of developing eczema vaccinatum, a severe reaction to the smallpox vaccine, either t

Microbial Heat Shock Protein 65 Attenuates Airway Hyperresponsiveness and Inflammation by Modulating the Function of Dendritic Cells

Abstract: Heat shock proteins (HSPs), produced in response to stress, are suppressive in disease models. We previously showed that Mycobacterium leprae HSP65 prevented development of airway hyperresponsiveness and inflammation in mice. Our goal in this study was to define the mechanism responsible for the suppressive effects of HSP. In one in vivo approach, BALB/c mice were sensitized to OVA, followed by primary OVA challenges. Several weeks later, HSP65 was administered prior to a single, provocative secondary challenge. In a second in vivo approach, the secondary challenge was replaced by intratracheal instillation of allergen-pulsed bone marrow-derived dendritic cells (BMDCs). The in vitro effects of HSP65 on BMDCs were examined in coculture experiments with CD4(+) T cells. In vivo, HSP65 prevented the development of airway hyperresponsiveness and inflammation. Additionally, Th1 cytokine levels in bronchoalveolar lavage fluid were increased. In vitro, HSP65 induced Notch receptor ligand Delta1 expression on BMDCs, and HSP65-treated BMDCs skewed CD4(+) T cells to Th1 cytokine production. Thus, HSP65-induced effects on allergen-induced airway hyperresponsiveness and inflammation were associated with increased Delta1 expression on dendritic cells, modulation of dendritic cell function, and CD4(+) Th1 cytokine production.

Asthma Control And Disordered Microbial Communities In The Lower Airways Of Patients With Poorly Controlled Asthma

Abstract: S U N D A Y 486 Asthma Control And Disordered Microbial Communities In The Lower Airways Of Patients With Poorly Controlled Asthma E. Goleva, J. K. Harris, R. J. Martin, A. Dakhama, R. Alam, E. W. Gelfand, D. Y. M. Leung; National Jewish Health, Denver, CO, University of Colorado Denver, Denver, CO. RATIONALE: the role of lower airway bacterial communities in asthma is poorly understood. METHODS: BAL samples were obtained from 23 adults with chronic asthma (FEV1 73.6613.1%, PC20 1.462.3 mg/ml) and 20 normal control subjects. Bacterial DNA was extracted using Qiagen EZ1 system and sequenced using 454 FLX chemistry. Taxonomic identification was performed with RDP classifier and BLAST. Asthma control was measured by asthma control questionnaires (ACQ). RESULTS: Based on microbiome data, asthmatics were subdivided into three groups: group A with commensal flora only (n56); group B with expansions (>10% of 16s RNA sequences) in organisms also seen in normal controls (n59); group C with expansions (>10%) of unique organisms not seen in the normal microbiome (n58) (Comamonas testosteroni (n51), Simonsiella muelleri (n51), Asticcacaulis (n54), Streptococcus pseudopneumoniae (n52)). A progressive reduction in the number of sequences for Genera Prevotella (Rsq50.65, p<0.0001) and Veillonella (Rsq50.53, p50.0006), considered to be major airway commensal flora, was observed in groups B and C. The lowest number of commensal sequences was observed in group C. There was progressively lower asthma control from groups A to C (ACQ test score 0.8660.28, 1.6360.23, 2.0260.24, for groups A-C, respectively, p50.0175, ANOVA). Alpha diversity metrics significantly increased for bacterial diversity/richness from groups A to C (Sequences(observed) p50.0011, ANOVA; richness(Ho) p50.0017, ANOVA). CONCLUSIONS: Expansion of selected groups of bacteria in the lower airways of asthmatics was associated with reduced numbers of commensal flora organisms and increased richness/bacterial diversity. The loss of asthma control was the greatest with expansion of unique organisms.