Oral adjuvant activity for nasal influenza vaccines caused by combination of two trihydroxy fatty acid stereoisomers from the tuber of Pinellia ternata.
Pinellic acid from the tuber of Pinellia ternata was isolated as an effective oral adjuvant for nasal influenza vaccine, and identified 9S,12S,13S-trihydroxy-10E-octadecenoic acid (9S,12S,13S) by the enantioselective total synthesis [Nagai et al., Int. Immunopharmacol., 2, 1183-93 (2002); Shirahata et al., Tetrahedron, 62, 9483-96 (2006)]. However, present study showed that synthetic 9S,12S,13S that was nearly 100% pure was not effective as an oral adjuvant. HPLC analysis also showed that the adjuvant active pinellic acid fraction from tuber of P. ternata contained the 9S,12S,13S as the main component and at least two minor components. Therefore seven other chemically synthesized stereoisomers were tested in combination with the 9S,12S,13S for oral adjuvant activity. Only the 9S,12S,13S in combination with the 9S,12R,13R isomer in a weight% ratio of 90.4:9.6 (pinellic acid mixture, PAM) was a potent oral adjuvant and elicited both antiviral IgA antibody (Ab) in bronchoalveolar lavage fluids and nasal washes and antiviral IgG(1) Ab in mice sera. Oral administration of the PAM followed by nasal influenza vaccination and infection with A/PR/8/34 virus showed increases in survival rate (22%, control versus 78% test) in mice orally administered PAM as adjuvant. Histopathological examination of lung tissue of mice given oral PAM with vaccine followed by influenza virus infection showed attenuated infiltration of inflammatory cells with decreases in the alveolar spaces and increases in the alveolar septa. The result of this study refutes the our previous study and suggests that the combination of 9S,12S,13S and 9S,12R,13R isomers is necessary for effective oral adjuvant activity when used in conjunction with nasal influenza vaccine.
Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Takayuki
T
Nagai
Yuliko
Y
Shimizu
Tatsuya
T
Shirahata
Toshiaki
T
Sunazuka
Hiroaki
H
Kiyohara
Satoshi
S
Omura
Haruki
H
Yamada
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000737:chemistry; D000281:Administration, Intranasal; D000284:Administration, Oral; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004365:Drugs, Chinese Herbal / Q000627:therapeutic use; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage* / Q000737:chemistry; D005260:Female; D006801:Humans; D006880:Hydroxy Acids / Q000008:administration & dosage* / Q000737:chemistry; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype; D007252:Influenza Vaccines / Q000008:administration & dosage* / Q000276:immunology; D007251:Influenza, Human / Q000517:prevention & control*; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009829:Oleic Acids / Q000008:administration & dosage* / Q000737:chemistry; D030021:Pinellia / Q000737:chemistry; D013237:Stereoisomerism
D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D004365:Drugs, Chinese Herbal; D005231:Fatty Acids, Unsaturated; D006880:Hydroxy Acids; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007252:Influenza Vaccines; D009829:Oleic Acids; C478149:pinellic acid; C059227:9,12,13-trihydroxy-10-octadecenoic acid