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Report from the National Institute of Allergy and Infectious Diseases workshop on drug allergy.
Wheatley LM, Plaut M, Schwaninger JM, Banerji A, Castells M, Finkelman FD, Gleich GJ, Guttman-Yassky E, Mallal SA, Naisbitt DJ, Ostrov DA, Phillips EJ, Pichler WJ, Platts-Mills TA, Roujeau JC, Schwartz LB, Trepanier LA
(2015) J Allergy Clin Immunol 136: 262-71.e2
MeSH Terms: Carbamazepine, Dideoxynucleosides, Drug Hypersensitivity, Gene Expression, HLA Antigens, Haptens, Humans, Immunoglobulin E, National Institute of Allergy and Infectious Diseases (U.S.), Practice Guidelines as Topic, Receptors, Antigen, T-Cell, Stevens-Johnson Syndrome, Terminology as Topic, Translational Medical Research, United States, Virus Diseases
Show Abstract · Added March 30, 2020
Allergic reactions to drugs are a serious public health concern. In 2013, the Division of Allergy, Immunology, and Transplantation of the National Institute of Allergy and Infectious Diseases sponsored a workshop on drug allergy. International experts in the field of drug allergy with backgrounds in allergy, immunology, infectious diseases, dermatology, clinical pharmacology, and pharmacogenomics discussed the current state of drug allergy research. These experts were joined by representatives from several National Institutes of Health institutes and the US Food and Drug Administration. The participants identified important advances that make new research directions feasible and made suggestions for research priorities and for development of infrastructure to advance our knowledge of the mechanisms, diagnosis, management, and prevention of drug allergy. The workshop summary and recommendations are presented herein.
Published by Elsevier Inc.
0 Communities
1 Members
0 Resources
MeSH Terms
STAT6 deficiency ameliorates severity of oxazolone colitis by decreasing expression of claudin-2 and Th2-inducing cytokines.
Rosen MJ, Chaturvedi R, Washington MK, Kuhnhein LA, Moore PD, Coggeshall SS, McDonough EM, Weitkamp JH, Singh AB, Coburn LA, Williams CS, Yan F, Van Kaer L, Peebles RS, Wilson KT
(2013) J Immunol 190: 1849-58
MeSH Terms: Adjuvants, Immunologic, Animals, Cell Line, Claudin-2, Colitis, Ulcerative, Cytokines, Disease Models, Animal, Down-Regulation, Gene Expression Regulation, Haptens, Humans, Intestinal Mucosa, Male, Mice, Mice, Knockout, Natural Killer T-Cells, Oxazolone, STAT6 Transcription Factor, Severity of Illness Index, Th2 Cells
Show Abstract · Added February 27, 2014
Patients suffering from ulcerative colitis (UC) exhibit chronic colonic inflammation caused by a dysregulated mucosal immune response and epithelial barrier disruption. Th2 cytokines, including IL-13, have been implicated in the pathogenesis of UC. IL-13 induces phosphorylation of STAT6, and we previously demonstrated increased epithelial p-STAT6 in children with UC. In this study, we investigated the role of STAT6 in oxazolone colitis, a murine model of UC, by inducing colitis in STAT6-deficient (STAT6(-/-)) and wild type (WT) mice. We observed increased epithelial cell, T cell, macrophage, and NKT cell STAT6 phosphorylation, as well as increased p-STAT6(+) IL-13-producing NKT cells, in colitic WT mice. Colitis was attenuated in STAT6(-/-) mice, with improvements in weight, colon length, and histopathology. There was decreased induction of the pore-forming tight junction protein claudin-2 in STAT6(-/-) mice. Similarly, short hairpin RNA STAT6 knockdown reduced claudin-2 induction and transepithelial resistance decrease in IL-13-treated human T84 cells. Tissue expression of IL-13, IFN-γ, IL-17, and IL-10 mRNA was similarly induced in WT and STAT6(-/-) colitic mice; however, we observed increased mRNA expression for the Th2-inducing cytokines IL-33 and thymic stromal lymphopoietin in WT mice with colitis, which was abrogated in STAT6(-/-) mice. Mesenteric lymph node cells from STAT6(-/-) mice with colitis exhibited reduced secretion of IL-4, IL-5, IL-13, and IFN-γ. IL-33 augmented mesenteric lymph node cell secretion of IL-5, IL-13, IL-6, and IFN-γ. These data implicate STAT6 in the pathogenesis of colitis in vivo with important roles in altering epithelial barrier function and regulating Th2-inducing cytokine production.
0 Communities
8 Members
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20 MeSH Terms
Mechanisms of drug toxicity and relevance to pharmaceutical development.
Guengerich FP
(2011) Drug Metab Pharmacokinet 26: 3-14
MeSH Terms: Animals, Biomarkers, Biotransformation, Chemical and Drug Induced Liver Injury, Cytochrome P-450 Enzyme System, Drug Discovery, Drug Evaluation, Preclinical, Drug Hypersensitivity, Drug-Related Side Effects and Adverse Reactions, Haptens, Humans, Liver, Models, Animal, Pharmaceutical Preparations, Protein Binding, Proteomics, Safety-Based Drug Withdrawals, Toxicogenetics
Show Abstract · Added March 26, 2014
Toxicity has been estimated to be responsible for the attrition of approximately one-third of drug candidates and is a major contributor to the high cost of drug development, particularly when not recognized until late in clinical trials or post-marketing. The causes of drug toxicity can be classified in several ways and include mechanism-based (on-target) toxicity, immune hypersensitivity, off-target toxicity, and bioactivation/covalent modification. In addition, idiosyncratic responses are rare but can be one of the most problematic issues; several hypotheses for these have been advanced. Although covalent binding of drugs to proteins was described almost 40 years ago, the significance to toxicity has been difficult to establish; recent literature in this field is considered. The development of more useful biomarkers and short-term assays for rapid screening of drug toxicity early in the drug discovery/development process is a major goal, and some progress has been made using "omics" approaches.
0 Communities
1 Members
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18 MeSH Terms
Structural and kinetic evidence for strain in biological catalysis.
Romesberg FE, Santarsiero BD, Spiller B, Yin J, Barnes D, Schultz PG, Stevens RC
(1998) Biochemistry 37: 14404-9
MeSH Terms: Amino Acid Sequence, Animals, Antibodies, Monoclonal, Antibody Affinity, Catalysis, Crystallography, X-Ray, Ferrochelatase, Haptens, Humans, Immunoglobulin Fab Fragments, Kinetics, Mesoporphyrins, Mice, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Protein Conformation, Recombinant Fusion Proteins
Show Abstract · Added March 15, 2018
A classic hypothesis for enzyme catalysis is the induction of strain in the substrate. This notion was first expressed by Haldane with the lock and key analogy-"the key does not fit the lock perfectly but exercises a certain strain on it" (1). This mechanism has often been invoked to explain the catalytic efficiency of enzymes but has been difficult to establish conclusively (2-7). Here we describe X-ray crystallographic and mutational studies of an antibody metal chelatase which strongly support the notion that this antibody catalyzes metal ion insertion into the porphyrin ring by inducing strain. Analysis of the germline precursor suggests that this strain mechanism arose during the process of affinity maturation in response to a conformationally distorted N-alkylmesoporphyrin.
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1 Members
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18 MeSH Terms
Immunological origins of binding and catalysis in a Diels-Alderase antibody.
Romesberg FE, Spiller B, Schultz PG, Stevens RC
(1998) Science 279: 1929-33
MeSH Terms: Amino Acid Sequence, Antibodies, Antibodies, Catalytic, Antibody Affinity, Antibody Specificity, Binding Sites, Binding Sites, Antibody, Catalysis, Chemistry, Organic, Cloning, Molecular, Crystallography, X-Ray, Evolution, Molecular, Germ-Line Mutation, Haptens, Hydrogen Bonding, Immunoglobulin Fab Fragments, Models, Molecular, Molecular Sequence Data, Mutation, Organic Chemistry Phenomena, Protein Conformation, Recombinant Proteins
Show Abstract · Added March 15, 2018
The three-dimensional structure of an antibody (39-A11) that catalyzes a Diels-Alder reaction has been determined. The structure suggests that the antibody catalyzes this pericyclic reaction through a combination of packing and hydrogen-bonding interactions that control the relative geometries of the bound substrates and electronic distribution in the dienophile. A single somatic mutation, serine-91 of the light chain to valine, is largely responsible for the increase in affinity and catalytic activity of the affinity-matured antibody. Structural and functional studies of the germ-line precursor suggest that 39-A11 and related antibodies derive from a family of germ-line genes that have been selected throughout evolution for the ability of the encoded proteins to form a polyspecific combining site. Germ line-encoded antibodies of this type, which can rapidly evolve into high-affinity receptors for a broad range of structures, may help to expand the binding potential associated with the structural diversity of the primary antibody repertoire.
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1 Members
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22 MeSH Terms