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  • 1.
    Faulkner, Lee
    et al.
    Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, U.K.
    Martinsson, Klara
    Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, U.K.
    Santoyo-Castelazo, Anahi
    Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, U.K.
    Cederbrant, Karin
    Molecular Toxicology, Global Safety Assessment, AstraZeneca R&D, S-151 85 Södertälje, Sweden.
    Schuppe-Koistinen, Ina
    Molecular Toxicology, Global Safety Assessment, AstraZeneca R&D, S-151 85 Södertälje, Sweden.
    Powell, Helen
    Molecular Toxicology, Global Safety Assessment, AstraZeneca R&D, Alderley Park, Macclesfield SK10 4TG, U.K.
    Tugwood, Jonathan
    Molecular Toxicology, Global Safety Assessment, AstraZeneca R&D, Alderley Park, Macclesfield SK10 4TG, U.K.
    Naisbitt, Dean J
    Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, U.K.
    Park, B Kevin
    Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, U.K.
    The development of in vitro culture methods to characterize primary T-cell responses to drugs.2012In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 127, no 1, p. 150-8Article in journal (Refereed)
    Abstract [en]

    Adverse drug reactions represent a major stumbling block to drug development and those with an immune etiology are the most difficult to predict. We have developed an in vitro T-cell priming culture method using peripheral blood from healthy volunteers to assess the allergenic potential of drugs. The drug metabolite nitroso sulfamethoxazole (SMX-NO) was used as a model drug allergen to establish optimum assay conditions. Naive T cells were cocultured with monocyte-derived dendritic cells at a ratio of 25:1 in the presence of the drug for a period of 8 days, to expand the number of drug-responsive T cells. The T cells were then incubated with fresh dendritic cells, and drug and their antigen responsiveness analyzed using readouts for proliferation, cytokine secretion, and cell phenotype. All five volunteers showed dose-dependent proliferation as measured by 5-(and 6)-carboxyfluorescein diacetate succinimidyl ester content and by (3)H-thymidine uptake. CD4 T cells that had divided in the presence of SMX-NO had changed from a naive phenotype (CD45RA+) to a memory phenotype (CD45RO+). These memory T cells expressed the chemokine receptors CCR2, CCR4, and CXCR3 suggesting a mixture of T(H)1 and T(H)2 cells in the responding population, with a propensity for homing to the skin. Drug stimulation was also associated with the secretion of a mixture of T(H)1 cytokines (interferon γ) and T(H)2 cytokines (interleukin [IL]-5 and IL-13) as detected by ELISpot. We are currently developing this approach to investigate the allergenic potential of other drugs, including those where an association between specific human leucocyte antigen alleles and susceptibility to an immunological reaction has been established.

  • 2.
    Sand, Salomon
    et al.
    Swedish Natl Food Agcy, Sweden.
    Lindqvist, Roland
    Swedish Natl Food Agcy, Sweden.
    von Rosen, Dietrich
    Linköping University, Department of Mathematics, Mathematical Statistics . Linköping University, Faculty of Science & Engineering. Swedish Univ Agr Sci, Sweden.
    Ilback, Nils-Gunnar
    Swedish Natl Food Agcy, Sweden.
    Dose-Related Severity Sequence, and Risk-Based Integration, of Chemically Induced Health Effects2018In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 165, no 1, p. 74-89Article in journal (Refereed)
    Abstract [en]

    Risk assessment of chemical hazards is typically based on single critical health effects. This work aims to expand the current approach by characterizing the dose-related sequence of the development of multiple (lower- to higher-order) toxicological health effects caused by a chemical. To this end a "reference point profile" is defined as the relation between benchmark doses for considered health effects, and a standardized severity score determined for these effects. For a given dose of a chemical or mixture the probability for exceeding the reference point profile, thereby provoking lower- to higher-order effects, can be assessed. The overall impact at the same dose can also be derived by integrating contributions across all health effects following severity-weighting. In its generalized form the new impact metric relates to the probability of response for the most severe health effects. Reference points (points of departure) corresponding to defined levels of response can also be estimated. The proposed concept, which is evaluated for dioxin-like chemicals, provides an alternative for characterizing the low-dose region below the reference point for a severe effect like cancer. The shape and variability of the reference point profile add new dimensions to risk assessment, which for example extends the characterization of chemical potency, and the concept of acceptable effect sizes for individual health effects. Based on the present data the method shows high stability at low doses/responses, and is also robust to differences in severity categorization of effects. In conclusion, the novel method proposed enables risk-based integration of multiple dose-related health effects. It provides a first step towards a more comprehensive characterization of chemical toxicity, and suggests a potential for improved low-dose risk assessment.

  • 3.
    Suuronen, Erik J.
    et al.
    University of Ottawa Eye Institute, Ottawa Health Research Institute—Vision Centre, and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
    McLaughlin, Christopher R.
    University of Ottawa Eye Institute, Ottawa Health Research Institute—Vision Centre, and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
    Stys, Peter K.
    Ottawa Health Research Institute — Division of Neuroscience, University of Ottawa, Ottawa, ON, Canada.
    Nakamura, Masatsugu
    Santen Pharmaceutical Company Ltd., Ikoma-shi, Nara,, Japan.
    Munger, Rejean
    University of Ottawa Eye Institute, Ottawa Health Research Institute—Vision Centre, and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
    Griffith, May
    University of Ottawa Eye Institute, Ottawa Health Research Institute—Vision Centre, and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
    Functional innervation in tissue engineered models for in vitro study and testing purposes2004In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 82, no 2, p. 525-533Article in journal (Refereed)
    Abstract [en]

    The biotechnology industry is rapidly expanding and the emerging field of tissue engineering is projected to have a high impact in the near future. Recently the field of cellular, drug, and prosthetic delivery has melded with the field of tissue engineering to make simulated tissues. In addition to their roles as tissue substitutes for transplantation, these simulated tissues may provide more accurate models and environments for toxicology testing and the study of peripheral nerves. The current study demonstrates the importance of innervation, in general, for the function of engineered tissues. We observe that the presence of nerves in a tissue engineered (TE) human cornea model enhances the growth of the epithelium and the formation of its protective mucin layer. Innervation also confers protection to the epithelium from chemical insult, as determined by the level of post-treatment epithelial cell death. We demonstrate differential responses of the nerves to chemical stimuli by changes in intracellular sodium as measured by 2-photon microscopy. The 2-photon imaging techniques also allow for the visualization and study of the fine sensory axon fibers within the 3-dimensional tissue. This work demonstrates a role for innervation in the protective quality and function of the engineered tissue, and the potential to use the nerves themselves as indicators of the severity of an insult. These results are important to consider for the development of any optimized TE models for in vitro study and testing purposes.

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