CELLULAR-REQUIREMENTS FOR CYTOKINE PRODUCTION IN RESPONSE TO THE IMMUNOMODULATORS IMIQUIMOD AND S-27609

Imiquimod (R-837) and its analog, S-27609, belong to a class of imidaz oquinolinamines that have potent antitumor and antiviral effects in an imals, Much of their biologic activity is a result of the induction of cytokines, including interferon-alpha (IFN-alpha), tumor necrosis fac tor alpha (TNF), and others, In this study, the cells responsible for S-27609- and imiquimod-induced cytokine production were characterized. E rosette(+) T cells were not the major cell population responsible f or IFN-alpha and TNF in response to S-27609 or imiquimod, In contrast, E rosette(-) cells and unseparated PBMC produced similar concentratio ns of IFN-alpha and TNF in response to S-27609 and imiquimod, Eliminat ion of monocytes by treatment with the lysosomotropic agent L-leucine methyl ester (LME) or depletion using antibody to CD14 and immunomagne tic beads abrogated IFN-alpha and TNF production induced by S-27609, i miquimod, or LPS but not poly(I)/(C). LME treatment also abolished int erleukin (IL)-1 alpha, IL-beta, IL-6, and IL-8 production stimulated b y S-27609 and imiquimod, Removal of HLA-DR(+) or CD36(+) monocytes als o caused a significant reduction in S-27609- and imiquimod-induced IFN -alpha and TNF, Elimination of B cells, NK cells, and dendritic cells did not significantly reduce cytokine induction in response to S-27609 , Thus, the cell population responsible for the majority of cytokine r elease in human PBMC in response to S-27609 and imiquimod is a E roset te(-), CD14(+), CD36(+), HLA-DR(+) monocyte.