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 antiviral and antitumour properties mediated by the induction of cytokines, in particular interferon alpha (IFN-alpha). This study evaluated these compounds for their ability to induce cytokines and cytokine specific messenger RNAs (mRNA) in cynomologus monkeys (Macaca fascicularis). Peripheral blood mononuclear cell (PBMC) cultures from monkeys produced IFN, interleukin 1beta (IL-1beta), IL-6 and IL-8 after treatment with imiquimod, S-27609 and S-28463. Tumour necrosis factor alpha (TNF-alpha) was also increased in cultures stimulated with S-27609 or S-28463. Monkey PBMCs stimulated with imiquimod, S-27609 and S-28463 showed increased mRNA levels of IFN-alpha, IL-1alpha, IL-6 and the IFN inducible protein, MxA above those seen in untreated cultures. S-27609 and S-28463 also had higher TNF-alpha mRNA expression than cultures not receiving drugs. When compared to lipopolysaccharide (LPS), S-27609 was less effective at inducing IL-1beta, IL-6, IL-8 and TNF-alpha but induced higher concentrations of IFN. Similar results were seen when evaluating cytokine mRNA levels. Upon oral administration to monkeys, S-28463 stimulated a dose-dependent increase in serum concentrations of IFN, TNF-alpha, IL-1 receptor antagonist (IL-1Ra) and IL-6, while imiquimod induced increases in IFN and IL-1Ra concentrations. Finally, skin biopsies from monkeys treated topically with S-28463 had increases over baseline in mRNA for IFN-alpha, IL-1alpha, IL-6 and MxA protein. The data show that imidazoquinolines induce cytokines and cytokine specific mRNA in cynomolgus monkeys. These results demonstrate the usefulness of human amplimers and human ELISAs in the detection of cytokine specific mRNAs and proteins in cynomolgus monkeys.
Wagner
T L
TL
3M Pharmaceuticals, Department of Pharmacology, 3M Center, 270-2S-06, St Paul, MN 55144, USA.
Horton
V L
VL
Carlson
G L
GL
Myhre
P E
PE
Gibson
S J
SJ
Imbertson
L M
LM
Tomai
M A
MA
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000284:Administration, Oral; D000287:Administration, Topical; D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D000077271:Imiquimod; D007369:Interferon Inducers / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D008956:Models, Chemical; D012333:RNA, Messenger / Q000378:metabolism; D012867:Skin / Q000378:metabolism
C095471:4-amino-alpha,alpha,2-trimethyl-1H-imidazo(4,5-c)quinoline-1-ethanol; D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D016207:Cytokines; D007369:Interferon Inducers; D012333:RNA, Messenger; C099445:S 28463; D000077271:Imiquimod