Early-life antibiotics attenuate regulatory T cell generation and increase the severity of murine house dust mite-induced asthma.

Introduction: Early-life exposure to antibiotics (ABX) has been linked to increases in asthma severity and prevalence in both children and laboratory animals. We explored the immunologic mechanisms behind this association using a mouse model of house dust mite (HDM)-induced asthma and early-life ABX exposure.

Methods: Mice were exposed to three short courses of ABX following weaning and experimental asthma was thereafter induced.

IL-15-deficient mice develop enhanced allergic responses to airway allergen exposure.

Background: Interleukin-15 is a pleiotropic cytokine that is critical for the development and survival of multiple haematopoietic lineages. Mice lacking IL-15 have selective defects in populations of several pro-allergic immune cells including natural killer (NK) cells, NKT cells, and memory CD8 T cells. We therefore hypothesized that IL-15 mice will have reduced inflammatory responses during the development of allergic airway disease (AAD).

Differential Expression and Function of PDE8 and PDE4 in Effector T cells: Implications for PDE8 as a Drug Target in Inflammation.

Abolishing the inhibitory signal of intracellular cAMP is a prerequisite for effector T (Teff) cell function. The regulation of cAMP within leukocytes critically depends on its degradation by cyclic nucleotide phosphodiesterases (PDEs). We have previously shown that PDE8A, a PDE isoform with 40-100-fold greater affinity for cAMP than PDE4, is selectively expressed in Teff vs.

Acetaminophen Attenuates House Dust Mite-Induced Allergic Airway Disease in Mice.

Epidemiologic evidence suggests that N-acetyl-para-aminophenol (APAP) may play a role in the pathogenesis of asthma, likely through pro-oxidant mechanisms. However, no studies have investigated the direct effects of APAP on the development of allergic inflammation. To determine the likelihood of a causal relationship between APAP and asthma pathogenesis, we explored the effects of APAP on inflammatory responses in a murine house dust mite (HDM) model of allergic airway disease.

Poor Long-Term Efficacy of Prevnar-13 in Sickle Cell Disease Mice Is Associated with an Inability to Sustain Pneumococcal-Specific Antibody Titers.

Background: One of the most common causes of morbidity and mortality in children with sickle cell disease (SCD) is infection with the pneumococcal bacterium (Streptococcus pneumoniae). Unfortunately, the polysaccharide-conjugate vaccine appears to be less effective in individuals with SCD when compared to the general population. We sought to better understand the relative efficacy of pneumococcal vaccination in a SCD mouse challenge model.

Cbl-b Deficiency in Mice Results in Exacerbation of Acute and Chronic Stages of Allergic Asthma.

Mice sensitized to ovalbumin (OVA) develop allergic airway disease (AAD) with short-term daily OVA aerosol challenge; inflammation resolves with long-term OVA aerosol exposure, resulting in local inhalational tolerance (LIT). Cbl-b is an E3 ubiquitin ligase involved with CD28 signaling; Cbl-b(-/-) effector T cells are resistant to regulatory T cell-mediated suppression in vitro and in vivo. The present study utilized Cbl-b(-/-) mice to investigate the role of Cbl-b in the development of AAD and LIT.

Label-free and depth resolved optical sectioning of iron-complex deposits in sickle cell disease splenic tissue by multiphoton microscopy.

Multiphoton microscopy (MPM) imaging of intrinsic two-photon excited fluorescence (TPEF) is performed on humanized sickle cell disease (SCD) mouse model splenic tissue. Distinct morphological and spectral features associated with SCD are identified and discussed in terms of diagnostic relevance. Specifically, spectrally unique splenic iron-complex deposits are identified by MPM; this finding is supported by TPEF spectroscopy and object size to standard histopathological methods.

Long-Term Exposure to House Dust Mite Leads to the Suppression of Allergic Airway Disease Despite Persistent Lung Inflammation.

Background: Allergic asthma is a major cause of worldwide morbidity and results from inadequate immune regulation in response to innocuous, environmental antigens. The need exists to understand the mechanisms that promote nonreactivity to human-relevant allergens such as house dust mite (HDM) in order to develop curative therapies for asthma. The aim of our study was to compare the effects of short-, intermediate- and long-term HDM administration in a murine asthma model and determine the ability of long-term HDM exposure to suppress allergic inflammation.

The sickle cell mouse lung: proinflammatory and primed for allergic inflammation.

Comorbid asthma in sickle cell disease (SCD) confers higher rates of vaso-occlusive pain and mortality, yet the physiological link between these two distinct diseases remains puzzling. We used a mouse model of SCD to study pulmonary immunology and physiology before and after the induction of allergic airway disease (AAD). SCD mice were sensitized with ovalbumin (OVA) and aluminum hydroxide by the intraperitoneal route followed by daily, nose-only OVA-aerosol challenge to induce AAD.

Pro-inflammatory role of natural killer cells in the development of allergic airway disease.

Background: Natural Killer (NK) cells have been implicated in the development of allergic airway inflammation. However, the in vivo role of NK cells has not been firmly established due to the lack of animal models with selective deficiencies in NK cells.

Objective: To determine the specific contribution of NK cells in a murine model of allergic airway disease (AAD).

Bromelain Inhibits Allergic Sensitization and Murine Asthma via Modulation of Dendritic Cells.

The incidence of atopic conditions has increased in industrialized countries. Persisting symptoms and concern for drug side-effects lead patients toward adjunctive treatments such as phytotherapy. Previously, we have shown that Bromelain (sBr), a mixture of cysteine proteases from pineapple, Ananas comosus, inhibits ovalbumin (OVA)-induced murine model of allergic airway disease (AAD).

Identification of risk factors for an unsuccessful transition from pediatric to adult sickle cell disease care.

Background: A successful transition from pediatric to adult sickle cell disease (SCD) care is paramount to continued improvements in survival. In order to enhance transition success, our pediatric SCD transition process was modified to include combined adult and pediatric provider clinics that incorporated participation by our local SCD community-based organization. All children ages 16 and over participated in this newly-formed transition program.

Transgenic sickle cell disease mice have high mortality and dysregulated immune responses after vaccination.

Background: Children with sickle cell disease (SCD) are susceptible to recurrent infections, which are often life threatening and necessitate frequent vaccinations. Given the altered baseline immunity and proinflammatory state associated with SCD, we sought to determine the relative safety and efficacy of vaccination in transgenic SCD mice.

Methods: Eight-week-old SCD mice were vaccinated with ovalbumin and aluminum hydroxide weekly for 3 wk by the intraperitoneal or intramuscular route.

Beyond the medical home: Special Care Family Academy for children and youth.

Children and youth with special health care needs require more health care and related services and consequently incur more costs than other individuals. Implementation of the "medical home" concept has benefitted children with special needs, resulting in fewer unmet medical needs and more consistent health care delivery. As advances in health care have enabled an increasingly higher percentage of children with special needs to live far into adulthood, the transition from adolescence to adulthood poses new challenges in obtaining medical care, education, job training, and employment opportunities.

LC-MS/MS Identification of a Bromelain Peptide Biomarker from Ananas comosus Merr.

Bromelain (Br) is a cysteine peptidase (GenBank AEH26024.1) from pineapple, with over 40 years of clinical use. The constituents mediating its anti-inflammatory activity are not thoroughly characterized and no peptide biomarker exists.

Splenic morphological changes are accompanied by altered baseline immunity in a mouse model of sickle-cell disease.

Although functional asplenia from infarctions may be a major contributor to increased infectious mortality in sickle-cell disease (SCD), this relationship has not been fully defined. We used the transgenic Berkeley SCD mouse to define blood and splenic immunophenotypic differences in this model compared with C57BL/6 and hemizygous controls. In the serum of SCD mice, we found increased IgG2a and suppressed IgM, IgG2b, and IgA levels.

Bromelain limits airway inflammation in an ovalbumin-induced murine model of established asthma.

Context: Allergic asthma continues to increase despite new pharmacological advances for both acute treatment and chronic-disease management. Asthma is a multifactorial disease process with genetic, allergic, infectious, environmental, and dietary origins. Researchers are investigating the benefits of lifestyle changes and alternative asthma treatments, including the ability of bromelain to inhibit inflammation.

Regulatory B cells from hilar lymph nodes of tolerant mice in a murine model of allergic airway disease are CD5+, express TGF-β, and co-localize with CD4+Foxp3+ T cells.

In a biphasic, ovalbumin (OVA)-induced murine asthma model where allergic airway disease is followed by resolution and the development of local inhalational tolerance (LIT), transforming growth factor (TGF)-β-expressing CD5(+) B cells were selectively expanded locally in hilar lymph nodes (HLN) of LIT mice. LIT HLN CD5(+) B cells, but not LIT HLN CD5(-) B cells, induced expression of Foxp3 in CD4(+)CD25(-) T cells in vitro. These CD5(+) regulatory B cells (Breg) and CD4(+)Foxp3(+) T cells demonstrated similar increases in expression of chemokine receptors (CXCR4 and CXCR5) and co-localized in HLN B cell zones of LIT mice.

Phenotypic changes to the endogenous antigen-specific CD8+ T cell response correlates with the development and resolution of allergic airway disease.

The role of CD8(+) T cells in the pathogenesis of asthma remains controversial, as both pro- and anti-inflammatory functions have been suggested. This study was designed to examine the endogenous CD8(+) T cell response in a biphasic ovalbumin (OVA)-induced model of allergic airway disease (AAD) and its subsequent resolution with the development of local inhalational tolerance (LIT). We observed increases in OVA-specific CD8(+) T cell numbers in the local lung compartments (bronchoalveolar lavage, lung tissue, hilar lymph node) at AAD and LIT; systemic compartments (spleen, inguinal lymph node) displayed no such increases in CD8(+) T cell numbers.

A rapid lung de-cellularization protocol supports embryonic stem cell differentiation in vitro and following implantation.

Pulmonary diseases represent a large portion of neonatal and adult morbidity and mortality. Many of these have no cure, and new therapeutic approaches are desperately needed. De-cellularization of whole organs, which removes cellular elements but leaves intact important extracellular matrix (ECM) proteins and three-dimensional architecture, has recently been investigated for ex vivo generation of lung tissues.

IgG transmitted from allergic mothers decreases allergic sensitization in breastfed offspring.

Background: The mechanism(s) responsible for the reduced risk of allergic disease in breastfed infants are not fully understood. Using an established murine model of asthma, we demonstrated previously that resistance to allergic airway disease transmitted from allergic mothers to breastfed offspring requires maternal B cell-derived factors.

Objective: The aim of this study was to investigate the role of offspring neonatal Fc receptor for IgG uptake by intestinal epithelial cells (FcRn) in this breast milk transferred protection from allergy.

Surfactant protein A stimulates release of neutrophil chemotactic factors by alveolar type II pneumocytes.

Mucosal immunity is an important mechanism in the response to injury. Our hypothesis is that surfactant protein A (SP-A) is an autocrine factor that stimulates alveolar type II epithelial cell release of neutrophil chemotactic factors by binding to the SP-A receptor expressed by these cells. We examined (1) the effect of SP-A (20 μg/ml) or IL-1β (10 ng/ml) on release of neutrophil chemotactic factors by primary cultures of type II cells or alveolar macrophages, and (2) the effect of intratracheal instillation of the blocking antibody to the SP-A receptor on the response to oleic acid-induced lung injury in vivo.

Breastmilk from allergic mothers can protect offspring from allergic airway inflammation.

Objective: Breastfeeding is associated with a reduced risk of developing asthma in children. Using a murine model we previously demonstrated that mothers with Th1-type immunity to ovalbumin (OVA) transfer antigen-specific protection from OVA-induced allergic airway disease (AAD) to their offspring. The aim of this study was to evaluate the contribution of breastmilk and maternal B cell immunity from allergic mothers in the vertical transmission of protection from AAD.

Bromelain treatment reduces CD25 expression on activated CD4+ T cells in vitro.

Bromelain (Br), an extract from pineapple stem with cysteine protease activity, exerts anti-inflammatory effects in a number of inflammatory models. We have previously shown that Br treatment decreased activated CD4(+) T cells and has a therapeutic role in an ovalbumin-induced murine model of allergic airway disease. The current study was designed to determine the effect of Br on CD4(+) T cell activation, specifically the expression of CD25 in vitro.

Inhaled sodium pyruvate improved FEV1 and decreased expired breath levels of nitric oxide in patients with chronic obstructive pulmonary disease.

Exogenously administered sodium pyruvate has a variety of biological effects including antioxidant/anti-inflammatory effects. Chronic obstructive pulmonary disease (COPD) is an inflammatory disease of the airways mediated in part by reactive oxygen species (ROS) and reactive nitrogen species (RNS). The current therapies for COPD have limited efficacy.