title: Evidence for arsenic as the immunosuppressive component of gallium arsenide.
abstract: Gallium arsenide (GaAs) has been shown previously to suppress the in vivo antibody-forming cell (AFC) response to sheep erythrocytes (SRBC) when administered intratracheally at concentrations between 50 and 200 mg/kg. In the present studies, direct addition of GaAs to in vitro-generated antibody cultures resulted in dose-dependent suppression of the primary antibody response, and was only seen when GaAs was added within 36 hr following immunization. Using atomic absorption spectrophotometry on tissue samples from mice exposed to 200 mg/kg GaAs, arsenic concentrations were found to peak in the spleen at 24 hr and decline, whereas gallium concentrations continue to rise through 14 days. Concentrations of each metal in the spleen at 24 hr are comparable to the concentrations achieved for each metal when GaAs is added at 25 microM to the in vitro model system. The 24 hr time point was chosen for comparison because all in vivo-in vitro studies were conducted using spleens from mice 24 hr after GaAs exposure. NaAsO2 and Ga(NO3)3 suppressed the AFC response dose-dependently, and in a time-dependent manner similar to GaAs when added to the in vitro system. However, based on IC50 values for each salt, the role of the gallium component in the immunosuppression appears weak. Oxalic acid (OA) and meso-2,3-dimercaptosuccinic acid (DMSA), chelators of gallium and arsenic respectively, were added to cultures with GaAs to confirm that arsenic was the primary immunosuppressive component. DMSA dose-dependently blocked GaAs-induced immunosuppression in vitro, while OA had no effect. The metal-binding compounds were determined to be specific for the metals used in these studies and did not cross-react with one another. DMSA was evaluated for its ability to prevent suppression of the AFC response in splenocytes from GaAs-exposed mice and was able to block GaAs-induced suppression of the AFC response when given sc every 4 hr beginning 1 hr prior to GaAs exposure. These data indicate that the arsenic component of GaAs is the major contributor to the GaAs-induced immunosuppression and that this effect occurs within the first 36 hr of the 5-day culture period in a concentration-dependent manner.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298.
authors.forename: L A
authors.initials: LA
authors.lastname: Burns
authors.forename: E E
authors.initials: EE
authors.lastname: Sikorski
authors.forename: J J
authors.initials: JJ
authors.lastname: Saady
authors.forename: A E
authors.initials: AE
authors.lastname: Munson
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001151:Arsenic / Q000008:administration & dosage / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D001152:Arsenicals; D018053:Arsenites; D002478:Cells, Cultured / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005708:Gallium / Q000008:administration & dosage / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D007108:Immune Tolerance / Q000187:drug effects*; D007075:Immunoglobulin M / Q000096:biosynthesis; D051379:Mice; D008954:Models, Biological; D010070:Oxalates / Q000494:pharmacology; D019815:Oxalic Acid; D017670:Sodium Compounds; D013054:Spectrophotometry, Atomic; D013154:Spleen / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D004113:Succimer / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D001152:Arsenicals; D018053:Arsenites; D007075:Immunoglobulin M; D010070:Oxalates; D017670:Sodium Compounds; C043055:gallium arsenide; C017947:sodium arsenite; D019815:Oxalic Acid; D005708:Gallium; D004113:Succimer; D001151:Arsenic; C027235:gallium nitrate