Acceleration of age-associated immune decline and mortality by early repeated administration of bestatin to C57BL/6 mice.
The effect of chronic treatment with an immunostimulating agent, bestatin, on age-associated immune decline was assessed in C57BL/6 mice. Animals were given weekly doses of bestatin (100 micrograms/mouse, i.p.) from 7 months of age until death, and immune responses (natural killer cell activity, T cell cytotoxicity in vitro and in vivo, delayed-type hypersensitivity reaction, lymphoproliferative responses to mitogens, production of interleukin-2, macrophage functions) were tested at 11, 15, and 20 months. Most of the functions were reduced in 15-17-month-old mice, but evidence of reduced macrophage activities appeared only in limiting conditions (low lipopolysaccharide stimulation for interleukin-1 production and low concentration of macrophages in the cytostatic test). Bestatin administration produced a transient increase in natural killer (NK) cell activity and in vivo T cell cytotoxicity, followed (15-20 months of age) by a depression of NK and T cell-mediated responses. Only macrophage functions were stimulated in 20-month-old bestatin-treated mice. This unresponsiveness coincides with an accelerated mortality of bestatin-treated mice and a significant increase in the number of spontaneous tumor-bearing animals. The stimulation of T cells by bestatin seems to be mediated by a primary activation of macrophages to release immune mediators. Several reasons for the bestatin-induced immunodepression can be postulated including a high dose of bestatin, leading to toxicity or unresponsiveness; induction of suppressor cells; and overproliferation of T cells due to the mitogenic activity of bestatin, which may act as a promoting factor for tumor development.
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000633:toxicity*; D000375:Aging; D000818:Animals; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007153:Immunologic Deficiency Syndromes / Q000139:chemically induced* / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D007375:Interleukin-1 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D007930:Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D008017:Life Expectancy; D008223:Lymphoma / Q000401:mortality / Q000662:veterinary; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D012376:Rodent Diseases / Q000401:mortality; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D007375:Interleukin-1; D007376:Interleukin-2; D007930:Leucine; C012211:ubenimex