Adjuvant activity of 6-O-acyl-muramyldipeptides to enhance primary cellular and humoral immune responses in guinea pigs: adaptability to various vehicles and pyrogenicity.
Thirteen 6-O-acyl-N-acetylmuramyl-L-alanyl-D-isoglutamines (6-O-acyl-MDPs), including four inactive D-isoasparagine and L-isoglutamine analogs, were tested for their pyrogenicity and immunopotentiating activity to stimulate primary humoral and cellular immune responses in guinea pigs to a model protein antigen, ovalbumin, when administered in various vehicles. Among them, derivatives whose muramic acid residue was substituted by alpha-branched (and beta-hydroxylated) higher fatty acids at the carbon-6 position, especially 6-O-(2-tetradecylhexadecanoyl)-MDP (B3O-MDP) and, to a lesser extent, 6-O-(3-hydroxy-2-docosylhexacosanoyl)-MDP (BH48-MDP) and its L-serine analog [BH48-MDP(L-Ser)], were found to exert strong adjuvant activity in both the induction of delayed-type hypersensitivity and the stimulation of circulating precipitating antibody levels when combined with nonirritating vehicles (liposomes, squalene-in-water emulsion, and phosphate-buffered saline). These vehicles did not efficiently support the adjuvant activity of MDP, the parent molecule of the above lipophilic derivatives. Pyrogenicity tests showed that introduction of alpha-branched higher fatty acid groups but not of straight, long-chain fatty acids at the 6-position of the muramic acid residue resulted in marked decrease of the pyrogenicity inherent to MDP via intravenous administration.
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects*; D004655:Emulsions; D005260:Female; D005334:Fever / Q000139:chemically induced*; D006168:Guinea Pigs; D007111:Immunity, Cellular / Q000187:drug effects*; D008081:Liposomes / Q000008:administration & dosage; D014677:Pharmaceutical Vehicles; D011817:Rabbits; D013329:Structure-Activity Relationship
D000276:Adjuvants, Immunologic; D004655:Emulsions; D008081:Liposomes; D014677:Pharmaceutical Vehicles; D000119:Acetylmuramyl-Alanyl-Isoglutamine