T lymphocytes ignore procainamide, but respond to its reactive metabolites in peritoneal cells: demonstration by the adoptive transfer popliteal lymph node assay.
The drug procainamide (PA) is notorious for causing drug-induced systemic lupus erythematosus (SLE) in humans. Indirect evidence suggests that metabolism of PA to a reactive intermediate metabolite is involved in the pathogenesis of drug-induced SLE in that N-hydroxylation of the arylamine group of PA favors this condition, whereas N-acetylation prevents it. If this is correct, one would expect hydroxylamine-PA (HAPA) to be immunogenic, whereas N-acetyl-PA (N-ac-PA) should be nonimmunogenic. This hypothesis was confirmed by means of the popliteal lymph node assay (PLNA) in mice: injection of PA and N-ac-PA failed to induce a reaction in the direct PLNA, whereas HAPA induced a vigorous reaction. Using the adoptive transfer PLNA, splenic T cells of mice that had received three injections of HAPA were shown to be specifically sensitized to this metabolite, but not to PA or N-ac-PA. In this system, an anamnestic T cell response could also be elicited when homogenized peritoneal cells of mice that had been treated with PA for 4 months were used as the challenging antigen, indicating that the peritoneal cells of PA-treated animals contained or had been exposed to the reactive intermediate metabolite HAPA. Whereas in slow acetylator mice this 4-month PA treatment sufficed to generate HAPA in peritoneal cells, fast acetylators required additional stimulation of their oxidative metabolism in order to produce enough HAPA detectable by sensitized T cells. These findings clearly support the concept that reactive intermediate metabolites, such as HAPA, are generated by the oxidative metabolism of phagocytic cells and are immunogenic for T cells.
Kubicka-Muranyi
M
M
Division of Immunology, Heinrich Heine University of Duesseldorf, Federal Republic of Germany.
Goebels
R
R
Goebel
C
C
Uetrecht
J
J
Gleichmann
E
E
D000120:Acecainide / Q000276:immunology / Q000633:toxicity*; D000107:Acetylation; D000818:Animals; D005260:Female; D006801:Humans; D006900:Hydroxylation; D007156:Immunologic Memory; D008198:Lymph Nodes / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D010529:Peritoneal Cavity / Q000166:cytology; D010586:Phagocytes / Q000378:metabolism; D011342:Procainamide / Q000031:analogs & derivatives* / Q000276:immunology / Q000378:metabolism / Q000633:toxicity*; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D000120:Acecainide; C051948:procainamide 4-hydroxylamine; D011342:Procainamide