T-CELLS IGNORE THE PARENT DRUG PROPYLTHIOURACIL BUT ARE SENSITIZED TOA REACTIVE METABOLITE GENERATED IN-VIVO

The antithyroid drug propylthiouracil (PTU) is known to cause adverse immunological side effects, such as a lupus-like syndrome and vasculit ic disorders. In vitro experiments have established that myeloperoxida se of activated neutrophils can oxidize PTU to the reactive intermedia te propyluracil 2-sulfonate (PTU-SO3-), and it has been proposed that PTU-SOS might be responsible for the PTU-associated side effects. Here , using the direct popliteal lymph node assay (PLNA) in mice we found that PTU-SO3-, indeed, induced a T-cell-dependent primary PLN response , whereas the parent compound PTU failed to do so. As shown by adoptiv e transfer PLNA, splenic T cells of mice that had received four inject ions of PTU-SO3- mounted a specific secondary response to the reactive metabolite, but not to PTU. When homogenized peritoneal phagocytes, w hich had been incubated with PTU in vitro, were used as the antigen, a primary response in the direct PLNA was elicited, suggesting that the phagocytes contained the reactive metabolite. Moreover, T cells sensi tized to the reactive metabolite PTU-SO3- were detected in mice that w ere undergoing long-term treatment with PTU plus an additional treatme nt with phorbol myristate acetate for stimulation of the oxidative met abolism of their phagocytic cells. Together, these findings support th e concept that phagocytes oxidize PTU to its immunogenic metabolite, P TU-SO3-, which then, presumably via covalently binding to self-protein s, induces T cell sensitization. (C) 1996 Academic Press, Inc.