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.
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