In vivo activation of natural killer cells and priming of IL-2 responsive cytolytic cells by loxoribine (7-allyl-8-oxoguanosine).
Guanine ribonucleosides which have been substituted at the N7 and/or C8 positions have been shown previously to activate natural killer (NK) cells and to act as sparing agents for interleukin-2 (IL-2) in the in vitro generation of lymphokine activated killer (LAK) cells. In this paper we examined a disubstituted guanosine, 7-allyl-8-oxoguanosine (loxoribine), for the ability to activate NK cells and to interact with IL-2 in the generation of LAK cells in vivo. Following iv administration, loxoribine enhanced murine splenic NK activity in a dose-related fashion, with optimal responses occurring at 3 mg/mouse. Enhanced lysis of YAC-1 cells was seen within 6 hr of injection and NK activity remained elevated for over 96 hr. Mature B and T cells were not required for NK activation since SCID mice responded to loxoribine within the same dose range as did the normal, immunocompetent mice. Both effector and precursor cells were eliminated by the administration of anti-asialo GM1 antibodies and NK activation was totally blocked in mice injected with anti-NK 1.1 antibodies. To test whether loxoribine would act as a sparing agent for IL-2 stimulated LAK activation, mice were injected with 2 mg loxoribine followed by twice daily administration of 10,000 units IL-2. In assays performed 48, 72, and 96 hr after injection of loxoribine, the cytolytic activity with the combination therapy exceeded the activity expected from the algebraic sum of the responses to the individual agents. Single injections of 2 mg loxoribine and 25,000 units IL-2 also stimulated NK/LAK activity, but the greatest enhancement was seen when loxoribine was administered 24 hr before the IL-2. Analysis of mRNA transcripts for the alpha chain of the IL-2 receptor indicated that gene transcription was enhanced within hours of loxoribine administration.
Pope
B L
BL
R. W. Johnson Pharmaceutical Research Institute, Ontario, Canada.
Chourmouzis
E
E
Sigindere
J
J
MacIntyre
J P
JP
Capetola
R J
RJ
Lau
C Y
CY
D000818:Animals; D000941:Antigens / Q000276:immunology; D000950:Antigens, Ly; D000954:Antigens, Surface; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004334:Drug Administration Schedule; D005677:G(M1) Ganglioside / Q000276:immunology; D015870:Gene Expression; D006151:Guanosine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D007376:Interleukin-2 / Q000008:administration & dosage; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects*; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013997:Time Factors
D000941:Antigens; D000950:Antigens, Ly; D000954:Antigens, Surface; D007376:Interleukin-2; C527211:Klrb1c protein, mouse; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011506:Proteins; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D006151:Guanosine; D005677:G(M1) Ganglioside; C018835:asialo GM1 ganglioside; C068562:loxoribine