Abstract
The oxidizing capacity of phagocytic cells is suspected to play a major role in the generation of immunogenic drug metabolites, in particular those that cause extrahepatic immunopathological lesions. In the case of the antirheumatic drug gold(I) disodium thiomalate (Na2Au(I)TM), oxidation of the Au(I) ion to Au(III) appears to be responsible for the adverse immune reactions which may develop during gold therapy. Here, we show that the reactive metabolite Au(III) may be generated by mononuclear phagocytes (MΦ) exposed to Au(I). The generation of Au(III) was analyzed by means of the adoptive transfer popliteal lymph node assay (PLNA) in mice, using T lumphocytes previously sensitized to Au(III) as a detection probe. Donors of the Au(III)-primed T cells were either directly sensitized to Au(III) by injection of tetrachloroauric acid (HAu(III)Cl4), or indirectly via chronic treatment with Na2Au(I)TM. As donors of peritoneal cells (PC), we used mice which had received weekly i.m. injections of Na2Au(I)TM for 12 weeks and contained increased numbers of activated B cells. The PC of these mice were found to elicit a significant secondary response when used as antigenic material for the restimulation of Au(III)-primed T cells. The immunogenicity of PC obtained from Na2Au(I)TM-treated mice paralleled the total gold content of these cells. Noteworthily, MΦ exposed to Au(I) in vitro also proved capable of eliciting a specific secondary response of Au(III)-primed T cells. Hence, MΦ exposed to Au(I) generate the reactive intermediate Au(III) which, apparently via oxidation of self proteins, sensitizes T cells. As MΦ are constituents of many different organs and, moreover, communicate with T cells, their capacity to generate Au(III) may account for the various extrahepatic adverse immune reactions induced by Au(I) drugs.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Beelen RHJ, Fluitsma DM, Van der Meer JWM, Hoefsmit ECM (1980) Development of exudate-resident macrophages, on the basis of the pattern of peroxidatic activity in vivo and in vitro. In: Van Furth R (ed) Mononuclear phagocytes. Martinus Nijhoff The Hague, pp 87–112
Beverly B, Couri D (1987) Role of myeloperoxidase (MPO) in aurothiomalate metabolism. Fed Proc 46: 854
Bloksma N, Kubicka-Muranyi M, Schuppe H-C, Gleichmann E, Gleichmann H (1995) A predictive immunotoxicological test system: suitability of the popliteal lymph node assay in rats and mice. Crit Rev Toxicol (in press)
Ghadially FN (1979) The aurosome. J Rheumatol 6: 45–50
Ghadially FN, Lipsky PE, Yang Steppuhn SE, Lalonde JM (1982) The morphology and atomic composition of aurosomes produced by sodium aurothiomalate in human monocytes. Ann Pathol 2: 117–125
Gleichmann E, Kubicka-Muranyi M, Kind P et al. (1991) Insights into the mechanism of gold action provided by immunotoxicology: biooxidation of gold(I) to gold(III) detected by sensitized T-cells. Rheumatol Int 11: 219–220
Gleichmann H (1981) Studies on the mechanism of drug sensitization: T-cell-dependent popliteal lymph node reaction to diphenylhydantoin. Clin Immunol Immunopathol 18: 203–211
Graudal H, Möller Madsen B, Danscher G (1988) Autometallographic demonstration of gold in rheumatoid synovial tissue. Z Rheumatol 47: 347–350
Grootveld M, Blake DR, Sahinoglu T et al. (1990) Control of oxidative damage in rheumatoid arthritis by gold(I)-thiolate drugs. Free Radic Res Commun 10: 199–220
Hurtenbach U, Gleichmann H, Nagata N, Gleichmann E (1987) Immunity to d-penicillamine: genetic, cellular, and chemical requirements for induction of popliteal lymph node enlargement in the mouse. J Immunol 139: 411–416
Isab AA, Sadler PJ (1977) Reactions of gold(III)ions with ribonuclease A and methionine derivatives in aqueous solution. Biochim Biophys Acta 492: 322–330
Johnston RB, Godzik CA, Cohn ZA (1978) Increased superoxide anion production by immunologically activated and chemically elicited macrophages. J Exp Med 148: 115–127
Kavanaugh AF, Lipsky PE (1992) Gold, penicillamine, antimalarials, and sulfasalazine. In: Gallin JI, Goldstein IM, Snyderman R (eds) Inflammation. Raven Press, New York, pp 1083–1101
Klinkhammer C, Popowa P, Gleichmann H (1988) Specific immunity to the diabetogen streptozotocin: cellular requirements for induction of lymphoproliferation. Diabetes 37: 74–80
Kubicka-Muranyi M, Behmer O, Uhrberg M, Klonowski H, Bister J, Gleichmann E (1993a) Murine systemic autoimmune disease induced by mercuric chloride (HgCl2): Hg-specific helper T-cells react to antigen stored in macrophages. Int J Immunopharmacol 15: 151–161
Kubicka-Muranyi M, Goebel C, Griem P, Schuppe HC, Uetrecht JP, Gleichmann E (1993b) Adverse immune reactions to drugs (gold, procainamide) and environmental chemicals (mercury, platinum): the role of phagocytic cells in generating immunogenic metabolites. In: Eibl MM, Huber C, Decker HH, Wahn U (eds) Symposium in immunology I+II, Springer Berlin, Heidelberg, pp 189–210
Kubicka-Muranyi M, Goebels R, Goebel C, Uetrecht JP, Gleichmann E (1993c) T lymphocytes ignore procainamide, but respond to its reactive metabolites in peritoneal cells: demonstration by the adoptive transfer popliteal lymph node assay. Toxicol Appl Pharmacol 122: 88–94
Lipsky PE, Ziff M (1977) Inhibition of antigen-and mitogen-induced human lymphocyte proliferation by gold compounds. J Clin Invest 59: 455–466
Littman BH, Hall RE (1985) Effects of gold sodium thiomalate on functional correlates of human monocyte maturation. Arthr Rheum 28: 1384–1392
Lockie LM, Smith DM (1985) Forty-seven years experience with gold therapy in 1019 rheumatoid arthritis patients. Semin Arthritis Rheum 14: 238–246
Miltenyi S, Müller W, Weichel W, Radbruch A (1990) High gradient magnetic cell separation with MACS. Cytometry 11: 231
Möller Madsen B, Mogensen SC, Danscher G (1984) Ultrastructural localization of gold in macrophages and mast cells exposed to aurothioglucose. Exp Mol Pathol 40: 148–154
Möller Madsen B, Mogensen SC, Danscher G, Rungby J, Thorlacius Ussing O, Graudal H (1985) Mouse peritoneal cells exposed to sodium aurothiomalate in vivo. Int J Tissue React 7: 439–442
Nathan CP, Root RK (1977) Hydrogen peroxidase release from mouse peritoneal macrophages. J Exp Med 146: 1648–1662
Panayi GS (1990) New ideas on the pathogenesis of rheumatoid arthritis. Ann Ital Med Int 5: 1–4
Pietsch P, Vohr HW, Degitz K, Gleichmann E (1989) Immunological alterations inducible by mercury compounds. II. HgCl2 and gold sodium thiomalate enhance serum IgE and IgG concentrations in susceptible mouse strains. Int Arch Allergy Appl Immunol 90: 47–53
Robinson CJG, Balazs T, Egorov IK (1986) Mercuric chloride-, gold sodium thiomalate-and d-penicillamine-induced antinuclear antibodies in mice. Toxicol Appl Pharmacol 86: 159–169
Rothbard JB, Gefter ML (1991) Interactions between immunogenic peptides and MHC proteins. Annu Rev Immunol 9: 527–565
Rötzschke O, Falk K (1994) Origin, structure and motifs of naturally processed MHC class II ligands. Curr Opin Immunol 6: 45–51
Rubin RL, Curnutte JT (1989) Metabolism of procainamide to the cytotoxic hydroxylamine by neutrophils activated in vitro. J Clin Invest 83: 1336–1343
Schuhmann D, Kubicka-Muranyi M, Mirtschewa J, Günther J, Kind P, Gleichmann E (1990) Adverse immune reactions to gold I. Chronic treatment with an Au(I) drug sensitizes mouse T cells not to Au(I), but to Au(III) and induces autoantibody formation. J Immunol 145: 2132–2139
Shaw CF (1979) The mammalian biochemistry of gold: an inorganic perspective of chrysotherapy. Inorg Perspect in Biol and Med 2: 287–355
Shaw CF, Schraa S, Gleichmann E, Grover YP, Dunemann L, Jagarlamudi A (1994) Redox chemistry and [Au(CN)2]− in the formation of gold metabolites. Metal-Based Drugs 1: 351–362
Sinigaglia F (1994) The molecular basis of metal recognition by T cells. J Invest Dermatol 102: 398–401
Takahashi K, Griem P, Goebel C, Gonzalez J, Gleichmann E (1994) The antirheumatic drug gold, a coin with two faces: Au(I) and Au(III). Desired and undesired effects on the immune system. Metal-Based Drugs 1: 483–496
Tonn T, Goebel C, Wilhelm M, Gleichmann E (1994) Gold kinetics under long-term treatment with gold(I) disodium thiomalate: a comparison in three different mouse strains. Br J Rheumatol 33: 724–730
Uetrecht JP (1992) The role of leukocyte-generated reactive metabolites in the pathogenesis of idiosyncratic drug reactions. Drug Metab Rev 24: 299–366
Uetrecht JP, Sokoluk B (1992) comparative metabolism and covalent binding of procainamide by human leukocytes. Drug Metab Dispos Biol Fate Chem 20: 120–123
Uetrecht JP, Zahid N, Rubin R (1988) Metabolism of procainamide to a hydroxylamine by human neutrophils and mononuclear leukocytes. Chem Res Toxicol 1: 74–78
Van Furth R (1980) Cells of the mononuclear phagocyte system. Nomenclature in terms of sites and condition. In: Van Furth R (ed) Mononuclear phagocytes. Functional aspects, part I. Martinus Nijhoff, The Hague, Boston, Amsterdam, pp 1–30
Verwilghen J, Kingsley GH, Gambling L, Panayi GS (1992) Activation of gold-reactive T lymphocytes in rheumatoid arthritis patients treated with gold. Arthr Rheum 35: 1413–1418
Vidard L, Rock KL, Benacerraf B (1992) Diversity in MHC class II ovalbumin T cell epitopes generated by distinct proteases. J Immunol 149: 498–504
Wijffels JFAM, de Rover Z, Van Rooijen N (1991) Chronic inflammation induces the expression of dendritic cell markers not related to functional antigen presentation on peritoneal exudate macrophages. Immunobiology 184: 83
Witkiewicz P, Shaw CF (1981) Oxidative cleavage of peptide and protein disulphide bonds by gold(III): a mechanism for gold toxicity. J C S Chem Comm 1111–1114
Author information
Authors and Affiliations
Additional information
This work was supported by the Postgraduate Training Program “Toxicology and Environmental Hygiene” which was granted to Heinrich Heine University Düsseldorf by Deutsche Forschungsgemeinschaft, Bonn, Germany, parts were also supported by grant no. CT 92-0316 “In vitro immunotoxicology” from the BIOTECH program of the EU, Brussels, Belgium.
Rights and permissions
About this article
Cite this article
Goebel, C., Kubicka-Muranyi, M., Tonn, T. et al. Phagocytes render chemicals immunogenic: oxidation of gold(I) to the T cell-sensitizing gold(III) metabolite generated by mononuclear phagocytes. Arch Toxicol 69, 450–459 (1995). https://doi.org/10.1007/s002040050198
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s002040050198