The mechanism of action of a synthetic immunomodulator, 3,6-bis(2-piperidinoethoxy)acridine trihydrochloride (CL 246,738), in natural killer cell activation in animals.
CL 246,738 is a low molecular weight, synthetic immunomodulator. The present study was done to determine the interaction among interferon (IFN), macrophages, and natural killer (NK) cells in mice following oral administration of CL 246,738. Splenic NK activity as evidenced by lysis of YAC-1 lymphoma cells in vitro was found to be augmented by the compound not only in normal mice, but also in immunodeficient beige and nude mice. Lytic activity remained elevated from one to seven days after a single treatment and the peak activation varied depending on the source of NK cells. NK cell activity associated with the peritoneal exudate cell population peaked at day 1 and returned to normal by day 2, whereas NK cell activity of peripheral blood lymphocytes peaked at day 3 and remained significantly elevated until day 7. Liver associated NK activity peaked at day 4 and remained significantly elevated at day 7 after treatment with CL 246,738. Lung associated NK activity was elevated by day 1 after treatment, peaked at day 4 and returned to normal by day 7 after drug administration. The drug was also effective in inducing IFN in all mouse strains tested. When these drug-treated mice were given antibody to IFN-(alpha + beta) but not to IFN-(beta), both IFN levels and NK cell activity decreased, suggesting the importance of IFN-(alpha) in this system. Furthermore, mice that had received carrageenan prior to, but not after CL 246,738 administration showed reduced serum IFN titers as well as decreased NK cell activity, indicating that macrophages played an intermediate role in immune enhancement by the drug.(ABSTRACT TRUNCATED AT 250 WORDS)
Ruszala-Mallon
V
V
Chemotherapy Research Department, American Cyanamid Company, Lederle Laboratories, Pearl River, NY 10965.
Silva
J
J
Lumanglas
A L
AL
Durr
F E
FE
Wang
B S
BS
D000166:Acridines / Q000494:pharmacology*; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000375:Aging / Q000276:immunology; D000818:Animals; D007372:Interferons / Q000037:antagonists & inhibitors / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology
D000166:Acridines; D000276:Adjuvants, Immunologic; C045570:3,6-bis(2-piperidinoethoxy)acridine trihydrochloride; D007372:Interferons