title: A metabolite of the lupus-inducing drug procainamide prevents anergy induction in T cell clones.
abstract: Therapeutic treatment with procainamide is occasionally associated with the development of drug-induced lupus. This syndrome has become the prototype for an aseptic systemic autoimmune disease caused by a known environmental agent, but the underlying mechanisms remain puzzling. We explored the possibility that lupus-inducing drugs affect processes involved in T cell tolerance to self-Ag. An in vitro model of anergy using established T cell clones was used to determine whether procainamide or one of its metabolites could prevent development of T cell nonresponsiveness to cognate Ag. Addition of procainamide-hydroxylamine, but not procainamide or its further oxidation products during anergy induction by CD3 engagement, caused a dose-dependent recovery of the capacity of T cells to proliferate and secrete IFN-gamma upon subsequent Ag challenge. Resistance to anergy induction required 2 h of exposure to procainamide-hydroxylamine, and this state remained for 8 h, suggesting that uptake of the drug caused a reversible interference in signaling pathways involved in establishing anergy. We suggest that prevention of anergy induction by procainamide-hydroxylamine may also take place in vivo during establishment of T cell tolerance to self-Ag, thereby allowing the production of autoreactive T cells.
authors.affiliation: W. M. Keck Autoimmune Disease Center, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kretz-Rommel
authors.forename: R L
authors.initials: RL
authors.lastname: Rubin
mesh_terms: D000818:Animals; D017635:Clonal Anergy / Q000187:drug effects*; D007108:Immune Tolerance / Q000187:drug effects*; D008180:Lupus Erythematosus, Systemic / Q000139:chemically induced; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008805:Mice, Inbred A; D011342:Procainamide / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D013997:Time Factors
chemical_list: D011342:Procainamide