title: Effect of premedications in a murine model of asparaginase hypersensitivity.
abstract: A murine model was developed that recapitulates key features of clinical hypersensitivity to Escherichia coli asparaginase. Sensitized mice developed high levels of anti-asparaginase IgG antibodies and had immediate hypersensitivity reactions to asparaginase upon challenge. Sensitized mice had complete inhibition of plasma asparaginase activity (P = 4.2 × 10(-13)) and elevated levels of mouse mast cell protease 1 (P = 6.1 × 10(-3)) compared with nonsensitized mice. We investigated the influence of pretreatment with triprolidine, cimetidine, the platelet activating factor (PAF) receptor antagonist CV-6209 [2-(2-acetyl-6-methoxy-3,9-dioxo-4,8-dioxa-2,10-diazaoctacos-1-yl)-1-ethyl-pyridinium chloride], or dexamethasone on the severity of asparaginase-induced allergies. Combining triprolidine and CV-6209 was best for mitigating asparaginase-induced hypersensitivity compared with nonpretreated, sensitized mice (P = 1.2 × 10(-5)). However, pretreatment with oral dexamethasone was the only agent capable of mitigating the severity of the hypersensitivity (P = 0.03) and partially restoring asparaginase activity (P = 8.3 × 10(-4)). To rescue asparaginase activity in sensitized mice without requiring dexamethasone, a 5-fold greater dose of asparaginase was needed to restore enzyme activity to a similar concentration as in nonsensitized mice. Our results suggest a role of histamine and PAF in asparaginase-induced allergies and indicate that mast cell-derived proteases released during asparaginase allergy may be a useful marker of clinical hypersensitivity.
authors.affiliation: Department of Pharmaceutical Sciences (C.A.F., C.S., S.E.K., L.B.R., C.L., W.E.E., M.V.R.) and Department of Oncology (S.E.K., C.-H.P., S.J.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Medicine, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio (F.D.F.); Department of Internal Medicine, Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, Ohio (F.D.F.); and Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (F.D.F.).
authors.forename: Christian A
authors.initials: CA
authors.lastname: Fernandez
authors.affiliation: Department of Pharmaceutical Sciences (C.A.F., C.S., S.E.K., L.B.R., C.L., W.E.E., M.V.R.) and Department of Oncology (S.E.K., C.-H.P., S.J.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Medicine, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio (F.D.F.); Department of Internal Medicine, Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, Ohio (F.D.F.); and Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (F.D.F.).
authors.forename: Colton
authors.initials: C
authors.lastname: Smith
authors.affiliation: Department of Pharmaceutical Sciences (C.A.F., C.S., S.E.K., L.B.R., C.L., W.E.E., M.V.R.) and Department of Oncology (S.E.K., C.-H.P., S.J.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Medicine, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio (F.D.F.); Department of Internal Medicine, Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, Ohio (F.D.F.); and Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (F.D.F.).
authors.forename: Seth E
authors.initials: SE
authors.lastname: Karol
authors.affiliation: Department of Pharmaceutical Sciences (C.A.F., C.S., S.E.K., L.B.R., C.L., W.E.E., M.V.R.) and Department of Oncology (S.E.K., C.-H.P., S.J.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Medicine, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio (F.D.F.); Department of Internal Medicine, Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, Ohio (F.D.F.); and Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (F.D.F.).
authors.forename: Laura B
authors.initials: LB
authors.lastname: Ramsey
authors.affiliation: Department of Pharmaceutical Sciences (C.A.F., C.S., S.E.K., L.B.R., C.L., W.E.E., M.V.R.) and Department of Oncology (S.E.K., C.-H.P., S.J.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Medicine, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio (F.D.F.); Department of Internal Medicine, Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, Ohio (F.D.F.); and Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (F.D.F.).
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences (C.A.F., C.S., S.E.K., L.B.R., C.L., W.E.E., M.V.R.) and Department of Oncology (S.E.K., C.-H.P., S.J.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Medicine, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio (F.D.F.); Department of Internal Medicine, Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, Ohio (F.D.F.); and Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (F.D.F.).
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.affiliation: Department of Pharmaceutical Sciences (C.A.F., C.S., S.E.K., L.B.R., C.L., W.E.E., M.V.R.) and Department of Oncology (S.E.K., C.-H.P., S.J.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Medicine, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio (F.D.F.); Department of Internal Medicine, Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, Ohio (F.D.F.); and Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (F.D.F.).
authors.forename: Sima
authors.initials: S
authors.lastname: Jeha
authors.affiliation: Department of Pharmaceutical Sciences (C.A.F., C.S., S.E.K., L.B.R., C.L., W.E.E., M.V.R.) and Department of Oncology (S.E.K., C.-H.P., S.J.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Medicine, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio (F.D.F.); Department of Internal Medicine, Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, Ohio (F.D.F.); and Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (F.D.F.).
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.affiliation: Department of Pharmaceutical Sciences (C.A.F., C.S., S.E.K., L.B.R., C.L., W.E.E., M.V.R.) and Department of Oncology (S.E.K., C.-H.P., S.J.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Medicine, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio (F.D.F.); Department of Internal Medicine, Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, Ohio (F.D.F.); and Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (F.D.F.).
authors.forename: Fred D
authors.initials: FD
authors.lastname: Finkelman
authors.affiliation: Department of Pharmaceutical Sciences (C.A.F., C.S., S.E.K., L.B.R., C.L., W.E.E., M.V.R.) and Department of Oncology (S.E.K., C.-H.P., S.J.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Medicine, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio (F.D.F.); Department of Internal Medicine, Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, Ohio (F.D.F.); and Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (F.D.F.) mary.relling@stjude.org.
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D000818:Animals; D001215:Asparaginase / Q000633:toxicity*; D003907:Dexamethasone / Q000008:administration & dosage*; D004342:Drug Hypersensitivity / Q000201:enzymology / Q000517:prevention & control*; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D011292:Premedication / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D003907:Dexamethasone; D001215:Asparaginase