The vaccine adjuvant alum inhibits IL-12 by promoting PI3 kinase signaling while chitosan does not inhibit IL-12 and enhances Th1 and Th17 responses.
Alum is the principal vaccine adjuvant for clinical applications but it is a poor inducer of cellular immunity and is not an optimal adjuvant for vaccines where Th1 responses are required for protection. The mechanism underlying the inefficiency of alum in promoting Th1 responses is not fully understood. We show that aluminium hydroxide, aluminium phosphate, and calcium phosphate adjuvants inhibit the secretion of the Th1 polarizing cytokine, IL-12 by dendritic cells (DCs). Alum selectively inhibited DC expression of the IL-12p35 subunit and the inhibitory effect results from adjuvant-induced PI3 kinase signaling. To develop a more effective adjuvant for promoting cell-mediated immunity, we investigated alternative particulates and found that in contrast to alum, the cationic polysaccharide chitosan did not inhibit IL-12 secretion. A combination of chitosan and the TLR9 agonist CpG activated the NLRP3 inflammasome and enhanced secretion of IL-12 and the other key Th1 and Th17-cell polarizing cytokines. When used as an adjuvant, CpG-chitosan induced NLRP3-dependent antigen-specific Th1 and Th17 responses. A combination of alum and CpG also enhanced Th1 and Th17 responses but was less effective than CpG-chitosan. Therefore, chitosan is an attractive alternative to alum in adjuvants for vaccines where potent cell-mediated immunity is required.
Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
Andres
A
Mori
Ewa
E
Oleszycka
Fiona A
FA
Sharp
Michelle
M
Coleman
Yuki
Y
Ozasa
Manmohan
M
Singh
Derek T
DT
O'Hagan
Lidia
L
Tajber
Owen I
OI
Corrigan
Edel A
EA
McNeela
Ed C
EC
Lavelle
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000534:Alum Compounds / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D048271:Chitosan / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D007111:Immunity, Cellular; D053765:Interleukin-12 Subunit p35 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D053765:Interleukin-12 Subunit p35; C041524:aluminum sulfate; D048271:Chitosan; D019869:Phosphatidylinositol 3-Kinases