Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells.
Alum (aluminum hydroxide) is the most widely used adjuvant in human vaccines, but the mechanism of its adjuvanticity remains unknown. In vitro studies showed no stimulatory effects on dendritic cells (DCs). In the absence of adjuvant, Ag was taken up by lymph node (LN)-resident DCs that acquired soluble Ag via afferent lymphatics, whereas after injection of alum, Ag was taken up, processed, and presented by inflammatory monocytes that migrated from the peritoneum, thus becoming inflammatory DCs that induced a persistent Th2 response. The enhancing effects of alum on both cellular and humoral immunity were completely abolished when CD11c(+) monocytes and DCs were conditionally depleted during immunization. Mechanistically, DC-driven responses were abolished in MyD88-deficient mice and after uricase treatment, implying the induction of uric acid. These findings suggest that alum adjuvant is immunogenic by exploiting "nature's adjuvant," the inflammatory DC through induction of the endogenous danger signal uric acid.
Kool
Mirjam
M
Department of Pulmonary Medicine, Erasmus University Medical Centre, 3015 GD Rotterdam, Netherlands.
Soullié
Thomas
T
van Nimwegen
Menno
M
Willart
Monique A M
MA
Muskens
Femke
F
Jung
Steffen
S
Hoogsteden
Henk C
HC
Hammad
Hamida
H
Lambrecht
Bart N
BN
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000534:Alum Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D017951:Antigen Presentation / Q000187:drug effects; D000941:Antigens / Q000008:administration & dosage / Q000494:pharmacology; D039521:CD11c Antigen / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects; D045142:Cross-Priming / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D007109:Immunity / Q000187:drug effects*; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation / Q000276:immunology*; D007273:Injections, Intramuscular; D007274:Injections, Intraperitoneal; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D010047:Ovalbumin / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014527:Uric Acid / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D000941:Antigens; D039521:CD11c Antigen; D053594:Myeloid Differentiation Factor 88; D014527:Uric Acid; C041524:aluminum sulfate; D010047:Ovalbumin