Effect of anti-IgE therapy on food allergen specific T cell responses in eosinophil associated gastrointestinal disorders

<p>Abstract</p> <p>Background</p> <p>Anti-IgE therapy inhibits mast cell and basophil activation, blocks IgE binding to both FcεRI and CD23 and down regulates FcεRI expression by antigen (Ag) presenting cells (APCs). In addition to its classical role in immediate hypersensitivity, IgE has been shown <it>in vitro </it>to facilitate Ag presentation of allergens, whereby APC bound IgE preferentially takes up allergens for subsequent processing and presentation. The purpose of this study was to determine whether anti-IgE therapy, by blocking facilitated Ag presentation <it>in vivo</it>, attenuates allergen specific Th2 cell responses.</p> <p>Methods</p> <p>To test this hypothesis, food allergen specific T cell responses were examined during a 16-week clinical trial of omalizumab in nine subjects with eosinophilic gastroenteritis and food sensitization. Allergen specific T cell responses were measured using carboxyfluorescein succinimidyl ester dye dilution coupled with intracellular cytokine staining and polychromatic flow cytometry. Four independent indices of allergen specific T cell response (proliferation, Ag dose response, precursor frequency, and the ratio of Th2:Th1 cytokine expression) were determined.</p> <p>Results</p> <p>Eight of the 9 subjects had measurable food allergen specific responses, with a median proliferation index of 112-fold. Allergen specific T cell proliferation was limited to CD4 T cells, whereas CD8 T cell did not proliferate. Food allergen specific responses were Th2 skewed relative to tetanus specific responses in the same subjects. In contradistinction to the original hypothesis, anti-IgE treatment did not diminish any of the four measured indices of allergen specific T cell response.</p> <p>Conclusions</p> <p>In sum, using multiple indices of T cell function, this study failed to demonstrate that anti-IgE therapy broadly or potently inhibits allergen specific T cell responses. As such, these data do not support a major role for IgE facilitated Ag presentation augmenting allergen specific T cell responses <it>in vivo</it>.</p> <p>Trial registration</p> <p>ClinicalTrials.gov identifier <a href="http://www.clinicaltrials.gov/ct2/show/NCT00084097">NCT00084097</a></p

Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis

Neoplastic accumulation of mast cells in systemic mastocytosis (SM) associates with activating mutations in the receptor tyrosine kinase KIT. Constitutive activation of tyrosine kinase oncogenes has been linked to imbalances in oxidant/antioxidant mechanisms in other myeloproliferative disorders. However, the impact of KIT mutations on the redox status in SM and the potential therapeutic implications are not well understood. Here, we examined the regulation of reactive oxygen species (ROS) and of the antioxidant protein DJ-1 (PARK-7), which increases with cancer progression and acts to lessen oxidative damage to malignant cells, in relationship with SM severity. ROS levels were increased in both indolent (ISM) and aggressive variants of the disease (ASM). However, while DJ-1 levels were reduced in ISM with lower mast cell burden, they rose in ISM with higher mast cell burden and were significantly elevated in patients with ASM. Studies on mast cell lines revealed that activating KIT mutations induced constant ROS production and consequent DJ-1 oxidation and degradation that could explain the reduced levels of DJ-1 in the ISM population, while IL-6, a cytokine that increases with disease severity, caused a counteracting transcriptional induction of DJ-1 which would protect malignant mast cells from oxidative damage. A mouse model of mastocytosis recapitulated the biphasic changes in DJ-1 and the escalating IL-6, ROS and DJ-1 levels as mast cells accumulate, findings which were reversed with anti-IL-6 receptor blocking antibody. Our findings provide evidence of increased ROS and a biphasic regulation of the antioxidant DJ-1 in variants of SM and implicate IL-6 in DJ-1 induction and expansion of mast cells with KIT mutations. We propose consideration of IL-6 blockade as a potential adjunctive therapy in the treatment of patients with advanced mastocytosis, as it would reduce DJ-1 levels making mutation-positive mast cells vulnerable to oxidative damage

Spectra Observed Following Cargo Interrogation

The authors present calculations of photon spectra observed following irradiation of bare HEU, HEU embedded in steel and wood cargos, and steel and wood alone. These spectra might be useful starting points for statistical detection efforts aimed at determining whether fissile material is present in a cargo. Detailed comparisons between calculations and experiments are presented and overall quite good (small {chi}{sup 2}) agreement is found. they do not present a complete solution to the problem of determining whether a given spectrum contains contributions from post-fission photons. However, it is shown that a brute-force fitting of observed spectra in terms of a few calculated ''basis'' spectra gives meaningful predictions about the presence of {sup 235}U in cargo. Though this may not be the most powerful method, it does give well defined confidence limits and seems to have strong predictive power

Debris collection from implosion of microballoons

Recovery of krypton from implosion of glass microballoons has been studied in the development of a radiochemical diagnostic for determination of /sub fuel/. Collection onto metal surfaces following implosions performed on the OMEGA laser with 1-3 TW (1-2 kJ) of 0.35 ..mu..m light is consistent with an ion implantation mechanism. The dependence of the intrinsic collection efficiency on the energy fluence to the collector surface and its variation in implosions carried out under the same nominal conditions indicate ion energies extending to at least 0.1 MeV and energy distribution functions that are sensitive to the details of the implosion dynamics. Intrinsic sticking efficiencies approaching 0.5 can be obtained in the limit of low total energy fluence to the collector surface (less than or equal to 0.1 J cm/sup -2/)

Seasonal dynamics of the airborne bacterial community and selected viruses in a children's daycare center

Children's daycare centers appear to be hubs of respiratory infectious disease transmission, yet there is only limited information about the airborne microbial communities that are present in daycare centers. We have investigated the microbial community of the air in a daycare center, including seasonal dynamics in the bacterial community and the presence of specific viral pathogens. We collected filters from the heating, ventilation, and air conditioning (HVAC) system of a daycare center every two weeks over the course of a year. Amplifying and sequencing the 16S rRNA gene revealed that the air was dominated by Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes that are commonly associated with the human skin flora. Clear seasonal differences in the microbial community were not evident; however, the community structure differed when the daycare center was closed and unoccupied for a 13-day period. These results suggest that human occupancy, rather than the environment, is the major driver in shaping the microbial community structure in the air of the daycare center. Using PCR for targeted viruses, we detected a seasonal pattern in the presence of respiratory syncytial virus that included the period of typical occurrence of the disease related to the virus; however, we did not detect the presence of adenovirus or rotavirus at any time

Safety and efficacy of dexpramipexole in eosinophilic asthma (EXHALE): a randomized controlled trial

BACKGROUND: There is a need for new and effective oral asthma therapies. Dexpramipexole, an oral eosinophil-lowering drug, has not previously been studied in asthma. OBJECTIVE: We sought to evaluate the safety and efficacy of dexpramipexole in lowering blood and airway eosinophilia in subjects with eosinophilic asthma. METHODS: We performed a randomized, double-blind, placebo-controlled proof-of-concept trial in adults with inadequately controlled moderate to severe asthma and blood absolute eosinophil count (AEC) greater than or equal to 300/μL. Subjects were randomly assigned (1:1:1:1) to dexpramipexole 37.5, 75, or 150 mg BID (twice-daily) or placebo. The primary end point was the relative change in AEC from baseline to week 12. Prebronchodilator FEV1 week-12 change from baseline was a key secondary end point. Nasal eosinophil peroxidase was an exploratory end point. RESULTS: A total of 103 subjects were randomly assigned to dexpramipexole 37.5 mg BID (N = 22), 75 mg BID (N = 26), 150 mg BID (N = 28), or placebo (N = 27). Dexpramipexole significantly reduced placebo-corrected AEC week-12 ratio to baseline, in both the 150-mg BID (ratio, 0.23; 95% CI, 0.12-0.43; P < .0001) and the 75-mg BID (ratio, 0.34; 95% CI, 0.18-0.65; P = .0014) dose groups, corresponding to 77% and 66% reductions, respectively. Dexpramipexole reduced the exploratory end point of nasal eosinophil peroxidase week-12 ratio to baseline in the 150-mg BID (median, 0.11; P = .020) and the 75-mg BID (median, 0.17; P = .021) groups. Placebo-corrected FEV1 increases were observed starting at week 4 (nonsignificant). Dexpramipexole displayed a favorable safety profile. CONCLUSIONS: Dexpramipexole demonstrated effective eosinophil lowering and was well tolerated. Additional larger clinical trials are needed to understand the clinical efficacy of dexpramipexole in asthma

Detector design for high-resolution MeV photon imaging of cargo containers using spectral information

Monte Carlo simulations of a pixelated detector array of inorganic scintillators for high spatial resolution imaging of 1-9 MeV photons are presented. The results suggest that a detector array of 0.5 cm x 0.5 cm x 5 cm pixels of bismuth germanate may provide sufficient efficiency and spatial resolution to permit imaging of an object with uncertainties in dimension of several mm. The cross talk between pixels is found to be in the range of a few percent when pixels are shielded by {approx} 1mm of lead or tungsten. The contrast at the edge of an object is greatly improved by rejection of events depositing less than {approx} 1 MeV. Given the relatively short decay time of BGO, the simulations suggest that such a detector may prove adequate for the purpose of rapid scanning of highly-shielded cargos for possible presence of high atomic number (including clandestine fissionable) materials when used with low current high duty factor x-ray sources