Immunostimulatory activity of aminoalkyl glucosaminide 4-phosphates (AGPs): induction of protective innate immune responses by RC-524 and RC-529.
Earlier we showed that the structural requirements for adjuvanticity among the aminoalkyl glucosaminide 4-phosphate (AGP) class of synthetic immunostimulants may be less strict than those for other endotoxic activities, including the induction of nitric oxide synthase in murine macrophages and cytokine production in human whole blood. The known role of nitric oxide and pro-inflammatory cytokines in the activation of host defenses against infection prompted us to examine the ability of certain AGPs to enhance non-specific resistance in mice to Listeria monocytogenes and influenza infections as well as to stimulate the production of pro-inflammatory cytokines in mouse splenocytes, human PBMCs, and human U937 histiocytic lymphoma cells. Intranasal administration of RC-524 or RC-529 to mice 2 days prior to a lethal influenza challenge provided significant protection in each case. Similarly, the intravenous administration of these AGPs induced resistance to L. monocytogenes infection as measured by survival or reduction of bacteria in the spleen. Activation of the innate immune response by AGPs appears to involve activation of Toll-like receptor 4 (TLR4) because RC-524 failed to elicit a protective effect in C3H/HeJ mice which have a defect in TLR4 signaling or induce significant cytokine levels in C3H/HeJ splenocytes. Both AGPs also stimulated pro-inflammatory cytokine release in human cell cultures in a dose-dependent manner.
Baldridge
Jory R
JR
Corixa Corporation, Hamilton, Montana 59840, USA.
Cluff
Christopher W
CW
Evans
Jay T
JT
Lacy
Michael J
MJ
Stephens
Jeffrey R
JR
Brookshire
Valerie G
VG
Wang
Rong
R
Ward
Jon R
JR
Yorgensen
Yvonne M
YM
Persing
David H
DH
Johnson
David A
DA
D000281:Administration, Intranasal; D000818:Animals; D006017:Glycolipids / Q000494:pharmacology*; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation; D007251:Influenza, Human / Q000276:immunology* / Q000517:prevention & control; D007963:Leukocytes, Mononuclear; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008089:Listeria monocytogenes / Q000472:pathogenicity; D008088:Listeriosis / Q000276:immunology* / Q000517:prevention & control; D016403:Lymphoma, Large B-Cell, Diffuse; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D009569:Nitric Oxide; D011956:Receptors, Cell Surface; D013154:Spleen / Q000166:cytology; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014407:Tumor Cells, Cultured
D006017:Glycolipids; D008050:Lipid A; D008562:Membrane Glycoproteins; C475763:RC524; C475764:RC529; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D009569:Nitric Oxide