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Effect of premedications in a murine model of asparaginase hypersensitivity.
J Pharmacol Exp Ther 2015; 352(3):541-51JP

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+Show Affiliations

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.).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.).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.).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.).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.).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.).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.).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.).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.).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.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25573198

Citation

Fernandez, Christian A., et al. "Effect of Premedications in a Murine Model of Asparaginase Hypersensitivity." The Journal of Pharmacology and Experimental Therapeutics, vol. 352, no. 3, 2015, pp. 541-51.
Fernandez CA, Smith C, Karol SE, et al. Effect of premedications in a murine model of asparaginase hypersensitivity. J Pharmacol Exp Ther. 2015;352(3):541-51.
Fernandez, C. A., Smith, C., Karol, S. E., Ramsey, L. B., Liu, C., Pui, C. H., ... Relling, M. V. (2015). Effect of premedications in a murine model of asparaginase hypersensitivity. The Journal of Pharmacology and Experimental Therapeutics, 352(3), pp. 541-51. doi:10.1124/jpet.114.220780.
Fernandez CA, et al. Effect of Premedications in a Murine Model of Asparaginase Hypersensitivity. J Pharmacol Exp Ther. 2015;352(3):541-51. PubMed PMID: 25573198.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of premedications in a murine model of asparaginase hypersensitivity. AU - Fernandez,Christian A, AU - Smith,Colton, AU - Karol,Seth E, AU - Ramsey,Laura B, AU - Liu,Chengcheng, AU - Pui,Ching-Hon, AU - Jeha,Sima, AU - Evans,William E, AU - Finkelman,Fred D, AU - Relling,Mary V, Y1 - 2015/01/08/ PY - 2015/1/10/entrez PY - 2015/1/13/pubmed PY - 2015/4/1/medline SP - 541 EP - 51 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 352 IS - 3 N2 - 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/25573198/Effect_of_premedications_in_a_murine_model_of_asparaginase_hypersensitivity L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=25573198 DB - PRIME DP - Unbound Medicine ER -