INDUCTION OF CYTOKINES IN CYNOMOLGUS MONKEYS BY THE IMMUNE-RESPONSE MODIFIERS, IMIQUIMOD, S-27609 AND S-28463

Imiquimod, S-27609 and S-28463 are imidazoquinolines known to have ant iviral and antitumour properties mediated by the induction of cytokine s, in particular interferon alpha (IFN-alpha), This study evaluated th ese compounds for their ability to induce cytokines and cytokine speci fic messenger RNAs (mRNA) in cynomolgus monkeys (Macaca fascicularis). Peripheral blood mononuclear cell (PBMC) cultures from monkeys produc ed IFN, interleukin 1 beta (IL-1 beta), 1L-1 beta and 1L-8 after treat ment with imiquimod, S-27609 and S-28463, Tumour necrosis factor alpha (TNF-alpha.) was also increased in cultures stimulated,vith S-27609 o r S-28463, Monkey PBMCs stimulated with imiquimod, S-27609 and S-28463 showed increased mRNA levels of IFN-alpha, IL-1 alpha, IL-6 and the I FN inducible protein, MxA above those seen in untreated cultures, S-27 609 and S-28463 also had higher TNF-alpha mRNA expression than culture s not receiving drugs, When compared to lipopolysaccharide (LPS), S-27 609 was less effective at inducing IL-1 beta, IL-6, IL-8 and TNF-alpha but induced higher concentrations of IFN. Similar results were seen w hen evaluating cytokine mRNA levels, Upon oral administration to monke ys, S-28463 stimulated a dose-dependent increase in serum concentratio ns of IFN, TNF-alpha, IL-1 receptor antagonist (IL-1Ra) and IL-6, whil e imiquimod induced increases in IFN and IL-1Ra concentrations, Finall y, skin biopsies from monkeys treated topically with S-28463 had incre ases over baseline in mRNA for IFN-alpha, IL-1 alpha, IL-6 and MxA pro tein, The data show: that imidazoquinolines induce cytokines and cytok ine specific mRNA in cynomolgus monkeys, These results demonstrate the usefulness of human amplimers and human ELISAs in the detection of cy tokine specific mRNAs and proteins in cynomolgus monkeys. (C) 1997 Aca demic Press Limited.