52 DIVERGENT EFFECTS OF BREDININ ON HUMAN T CELL SUBSETS

Abstract

Bredinin (4-carbamoyl-1-β-D-ribofuranosylimidazolium-5-olate) is an adenosine analog with immunosuppressive activities. This compound is phosphorylated by adenosine kinase to bredinin-5′-monophosphate which inhibits IMP dehydrogenase and depletes the cellular guanine nucleotides. Similarly, structurally related nucleoside analogs tiazofurin, ribavirin, and selenazofurin inhibit IMP dehydrogenase and exhibit potent antiviral activity. Since bredinin effectively kills the proliferating mammalian cells, bredinin has been clinically used as an immunosuppressive agent to prevent rejection reactions after kidney transplantation and to treat rheumatoid arthritis (RA). We have analyzed the effects of bredinin toward the activated T cell subsets in vitro. Peripheral blood mononuclear lymphocytes (PBLs) were obtained from 10 healthy subjects and 11 RA patients. PBLs were cultured with PHA in the presence or absence of bredinin for 5 days, and T4/T8 ratio was measured by flowcytometry. Bredinin treated T lymphocytes showed increased T4/T8 ratio in a dose dependent manner, showing that suppressor/cytotoxic T cells are more susceptible to bredinin than helper/inducer T cells. On the other hand, no significant changes were observed when cells were cultured with azidothymidine or deoxyguanosine. These results suggest that bredinin has a unique divergent effects on T lymphocyte subsets, and could be an useful therapeutic reagent for diseases with abnormal immune regulation.