The goal of this study is to DEMONSTRATE THE ROLE FOR THE IMMUNE SYSTEM IN MEDIATING ANESTHETIC-INDUCED HEPATOTOXICITY. Halothane exposure(s) produce antibodies (and immune complexes) in animals and halothane-hepatitis patients that recognize a halothane intermediate (trifluoroacetyl-) conjugated to carrier protein. The identity of specific halothane-modified liver proteins that initiate this immune response and reason(s) that only patients with halothane-hepatitis generate these antibodies needs to be determined.
The Specific Aims are: 1.) ISOLATE AND CHARACTERIZE THE MAJOR LIVER ANTIGENS RESULTING FROM THE CONJUGATION OF HALOTHANE REACTIVE INTERMEDIATES TO LIVER PROTEIN. Antigens will be isolated from the livers (and immune complexes) of halothane exposed guinea pigs and rabbits and localized in liver sections of these animals. Synthetic model antigens will be prepared to represent these native antigens. 2.) CHARACTERIZE THE SPECIFICITY OF ANTIBODIES PRODUCED FOLLOWING HALOTHANE EXPOSURES. The isolated halothane-modified liver antigens and the synthetic antigens will be used to profile the specificity of antibodies. 3.) INVESTIGATE THE ROLE FOR A CELL MEDIATED IMMUNE RESPONSE. The presence of halothane sensitized T cells and their correlation with antibody production and hepatotoxicity will be investigated. 4.) CORRELATED THE OBSERVED IMMUNE RESPONSE(S) WITH THE HEPATOTOXICITY OF HALOTHANE. The effect of pre-existing antibodies against specific halothane-modified liver protein antigens on halothane hepatotoxicity will be examined. The effect of immunopotentiators or suppressors on the hepatoxicity will be examined. The effect of immunopotentiators or suppressors on the hepatoxicity will be investigated and in vitro immunotoxicity systems will demonstrate the potential cytotoxicity of these immune components. 5.) EXAMINE HALOTHANE- ANESTHETIZED PATIENTS FOR THE PRESENCE OF ANTIHALOTHANE ANTIBODIES AND CIRCULATING IMMUNE COMPLEXES. The antibodies will be characterized for their specificity; the identity of the antigen component of circulating immune complexes will be compared between exposed animals and patients. 6). EXAMINE ANIMALS AND PATIENTS EXPOSED TO THE OTHER VOLATILE HALOGENATED ANESTHETICS FOR THE PRODUCTION OF AN IMMUNE RESPONSE. Synthetic antigens of other halogenated anesthetics will be prepared to detect circulating antibodies in patients and animals. 7.) EXAMINE OTHER DRUGS KNOWN TO PRODUCE AN """"""""ALLERGIC HEPATITIS"""""""" FOR THEIR POSSIBLE MEDIATION BY AN IMMUNE RESPONSE. These studies will determine if a hypersensitivity immune response is instrumental in the pathogenic mechanisms of drug/anesthetic induced liver damage.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM034788-04A1
Application #
3286363
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1985-06-01
Project End
1992-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Arizona
Department
Type
Schools of Medicine
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85722
Hsieh, Ying-Hsin; Huang, Ying-Ju; Jin, Jin-Shan et al. (2014) Mechanisms of Rose Bengal inhibition on SecA ATPase and ion channel activities. Biochem Biophys Res Commun 454:308-12
Clarke, J B; Thomas, C; Chen, M et al. (1995) Halogenated anesthetics form liver adducts and antigens that cross-react with halothane-induced antibodies. Int Arch Allergy Immunol 108:24-32
Hastings, K L; Thomas, C; Brown, A P et al. (1995) Trifluoroacetylation potentiates the humoral immune response to halothane in the guinea pig. Immunopharmacol Immunotoxicol 17:201-13
Brown, A P; Gandolfi, A J (1994) Glutathione-S-transferase is a target for covalent modification by a halothane reactive intermediate in the guinea pig liver. Toxicology 89:35-47
Hubbard, A K; Lohr, C L; Hastings, K et al. (1993) Immunogenicity studies of a synthetic antigen of alpha methyl dopa. Immunopharmacol Immunotoxicol 15:621-37
Brown, A P; Hastings, K L; Gandolfi, A J et al. (1992) Formation and identification of protein adducts to cytosolic proteins in guinea pig liver slices exposed to halothane. Toxicology 73:281-95
Hastings, K L; Thomas, C; Hubbard, A K et al. (1991) Screening for antibodies associated with halothane hepatitis. Br J Anaesth 67:722-8
Hastings, K L; Schuman, S; Brown, A P et al. (1991) S-ethylthiotrifluoroacetate enhancement of the immune response to halothane in the guinea pig. Adv Exp Med Biol 283:739-44
Hubbard, A K; Levy, J P; Roth, T P et al. (1990) Use of structural alterations in the synthesis of halothane metabolite antigens to mimic halothane-induced immunogen. Drug Chem Toxicol 13:93-112
Hubbard, A K; Roth, T P; Schuman, S et al. (1989) Localization of halothane-induced antigen in situ by specific anti-halothane metabolite antibodies. Clin Exp Immunol 76:422-7

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