PHAGOCYTES RENDER CHEMICALS IMMUNOGENIC - OXIDATION OF GOLD(I) TO THET-CELL SENSITIZING GOLD(III) METABOLITE GENERATED BY MONONUCLEAR PHAGOCYTES

The oxidizing capacity of phagocytic cells is suspected to play a majo r role in the generation of immunogenic drug metabolites, in particula r those that cause extrahepatic immunopathological lesions. In the cas e 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 th e adverse immune reactions which may develop during gold therapy. Here , we show that the reactive metabolite Au(III) may be generated by mon onuclear phagocytes (M Phi) 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 lymphocytes previously sensitized to Au( III) as a detection probe. Donors of the Au(III)-primed T cells were e ither directly sensitized to Au(III) by injection of tetrachloroauric acid (HAu(III)Cl-4), or indirectly via chronic treatment with Na2Au(I) TM. As donors of peritoneal cells (PC), we used mice which had receive d weekly i.m. injections of Na2Au(I)TM for 12 weeks and contained incr eased numbers of activated B cells. The PC of these mice were found to elicit a significant secondary response when used as antigenic materi al 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, M Phi exposed to Au(I) in vitro also proved capable of eliciting a specific secondary response of Au( III)-primed T cells. Hence, M Phi, exposed to Au(I) generate the react ive intermediate Au(III) which. apparently via oxidation of self prote ins, sensitizes T cells. As M Phi are constituents of many different o rgans and, moreover, communicate with T cells, their capacity to gener ate Au(III) may account for the various extrahepatic adverse immune re actions induced by Au(I) drugs.