Drug-specific in vitro release of IL-2, IL-5, IL-13 and IFN-gamma in patients with delayed-type drug hypersensitivity

BACKGROUND: The most prevalent drug hypersensitivity reactions are T-cell mediated. The only established in vitro test for detecting T-cell sensitization to drugs is the lymphocyte transformation test, which is of limited practicability. To find an alternative in vitro method to detect drug-sensitized T cells, we screened the in vitro secretion of 17 cytokines/chemokines by peripheral blood mononuclear cells (PBMC) of patients with well-documented drug allergies, in order to identify the most promising cytokines/chemokines for detection of T-cell sensitization to drugs. METHODS: Peripheral blood mononuclear cell of 10 patients, five allergic to beta-lactams and five to sulfanilamides, and of five healthy controls were incubated for 3 days with the drug antigen. Cytokine concentrations were measured in the supernatants using commercially available 17-plex bead-based immunoassay kits. RESULTS: Among the 17 cytokines/chemokines analysed, interleukin-2 (IL-2), IL-5, IL-13 and interferon-gamma (IFN-gamma) secretion in response to the drugs were significantly increased in patients when compared with healthy controls. No difference in cytokine secretion patterns between sulfonamide- and beta-lactam-reactive PBMC could be observed. The secretion of other cytokines/chemokines showed a high variability among patients. CONCLUSION: The measurement of IL-2, IL-5, IL-13 or IFN-gamma or a combination thereof might be a useful in vitro tool for detection of T-cell sensitization to drugs. Secretion of these cytokines seems independent of the type of drug antigen and the phenotype of the drug reaction. A study including a higher number of patients and controls will be needed to determine the exact sensitivity and specificity of this test.

Search for squarks and gluinos with the ATLAS detector in final states with jets and missing transverse momentum using 4.7 fb⁻¹ of sqrts=7 TeV proton-pro collision data

A search for squarks and gluinos in final states containing jets, missing transverse momentum and no high-p(T) electrons or muons is presented. The data represent the complete sample recorded in 2011 by the ATLAS experiment in 7 TeV proton-proton collisions at the Large Hadron Collider, with a total integrated luminosity of 4.7 fb(-1). No excess above the Standard Model background expectation is observed. Gluino masses below 860 GeV and squark masses below 1320 GeV are excluded at the 95% confidence level in simplified models containing only squarks of the first two generations, a gluino octet and a massless neutralino, for squark or gluino masses below 2 TeV, respectively. Squarks and gluinos with equal masses below 1410 GeV are excluded. In minimal supergravity/constrained minimal supersymmetric Standard Model models with tan beta = 10, A(0) = 0 and mu > 0, squarks and gluinos of equal mass are excluded for masses below 1360 GeV. Constraints are also placed on the parameter space of supersymmetric models with compressed spectra. These limits considerably extend the region of supersymmetric parameter space excluded by previous measurements with the ATLAS detector.

Search for nonpointing and delayed photons in the diphoton and missing transverse momentum final state in 8 TeV pp collisions at the LHC using the ATLAS detector

A search has been performed, using the full 20.3  fb −1 data sample of 8 TeV proton-proton collisions collected in 2012 with the ATLAS detector at the LHC, for photons originating from a displaced vertex due to the decay of a neutral long-lived particle into a photon and an invisible particle. The analysis investigates the diphoton plus missing transverse momentum final state, and is therefore most sensitive to pair production of long-lived particles. The analysis technique exploits the capabilities of the ATLAS electromagnetic calorimeter to make precise measurements of the flight direction, as well as the time of flight, of photons. No excess is observed over the Standard Model predictions for background. Exclusion limits are set within the context of gauge mediated supersymmetry breaking models, with the lightest neutralino being the next-to-lightest supersymmetric particle and decaying into a photon and gravitino with a lifetime in the range from 250 ps to about 100 ns.

Insights into post-translational processing of beta-galactosidase in an animal model resembling late infantile human G-gangliosidosis

G(M1)-gangliosidosis is a lysosomal storage disorder caused by a deficiency of ss-galactosidase activity. Human GM1-gangliosidosis has been classified into three forms according to the age of clinical onset and specific biochemical parameters. In the present study, a canine model for type II late infantile human GM1-gangliosidosis was investigated 'in vitro' in detail. For a better understanding of the molecular pathogenesis underlying G(M1)-gangliosidosis the study focused on the analysis of the molecular events and subsequent intracellular protein trafficking of beta-galactosidase. In the canine model the genetic defect results in exclusion or inclusion of exon 15 in the mRNA transcripts and to translation of two mutant precursor proteins. Intracellular localization, processing and enzymatic activity of these mutant proteins were investigated. The obtained results suggested that the beta-galactosidase C-terminus encoded by exons 15 and 16 is necessary for correct C-terminal proteolytic processing and enzyme activity but does not affect the correct routing to the lysosomes. Both mutant protein precursors are enzymatically inactive, but are transported to the lysosomes clearly indicating that the amino acid sequences encoded by exons 15 and 16 are necessary for correct folding and association with protective protein/cathepsin A, whereas the routing to the lysosomes is not influenced. Thus, the investigated canine model is an appropriate animal model for the human late infantile form and represents a versatile system to test gene therapeutic approaches for human and canine G(M1)-gangliosidosis.