Lymphokine-activated killer (LAK) cells. V. 8-Mercaptoguanosine as an IL-2-sparing agent in LAK generation.
Guanine ribonucleosides, substituted at the C8 position with either a bromine or a thiol group, have recently been shown to regulate several immunologic responses. We have previously shown that 8-mercaptoguanosine (8MG) can replace the requirement for cytokines in the generation of MHC-restricted CTL. In this paper, we examined the ability of 8MG to induce MHC-nonrestricted killer cells. We found that 8MG did not induce significant lytic activity from normal resting lymphocytes. However, 8MG was able to synergize with minimal amounts of IL-2 in inducing lytic activity similar to lymphokine-activated killers (LAK) in that both NK-sensitive and NK-resistant tumor cells were killed. Both the precursors and effectors of 8MG-LAK activity were similar to NK cells and were CD4- CD8- asialo-GM1+ NK1.1+. Similar to IL-2-induced LAK, 8MG-LAK were B220+. 8MG appeared to "stage" these precursor lymphocytes to become more responsive to IL-2 because optimal induction of 8MG-LAK required preincubation with 8MG before the addition of IL-2. This "staging" appeared to be due to the release of a "second signal" since it was readily inhibited by cyclosporine A. Anti-IFN-alpha beta was as efficient as cyclosporine A in inhibiting 8MG-LAK generation, whereas anti-IFN-gamma and anti-IL-1 did not exhibit significant inhibition. These findings suggest that 8MG can be of possible utility as an IL-2-sparing agent in LAK generation from NK cells.
Iowa City Veterans Administration, IA.
R A
RA
Thompson
Z K
ZK
Ballas
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D006151:Guanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016219:Immunotherapy, Adoptive; D007372:Interferons / Q000502:physiology; D007376:Interleukin-2 / Q000494:pharmacology*; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects* / Q000276:immunology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009369:Neoplasms / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects; D013872:Thionucleosides / Q000494:pharmacology*
D000276:Adjuvants, Immunologic; D007376:Interleukin-2; D013872:Thionucleosides; D006151:Guanosine; D007372:Interferons; C037031:8-thioguanosine