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J. Exp. Med. 205 (4): 869-882

Copyright © 2008 by the Rockefeller University Press.


ARTICLE

Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells

Mirjam Kool1, Thomas Soullié1, Menno van Nimwegen1, Monique A.M. Willart1,2, Femke Muskens1, Steffen Jung3, Henk C. Hoogsteden1, Hamida Hammad1,2, , and Bart N. Lambrecht1,2

1 Department of Pulmonary Medicine, Erasmus University Medical Centre, 3015 GD Rotterdam, Netherlands
2 Laboratory of Immunoregulation, University Hospital Ghent, 9000 Ghent, Belgium
3 Weizmann Institute, Rehovot 76100, Israel

CORRESPONDENCE Bart N. Lambrecht: bart.lambrecht{at}ugent.be

Abstract: 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.


Abbreviations used: Ag, antigen; Alum, aluminum hydroxide; CLN, cervical LN; DLN, draining LN; DT, diphteria toxin; DTR, DT receptor; ILN, inguinal LN; i.t., intratracheal; MLN, mediastinal LN; Tg, transgenic.

M. Kool, T. Soullié, H. Hammad, and B.N. Lambrecht contributed equally to this paper.


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F. A. Sharp, D. Ruane, B. Claass, E. Creagh, J. Harris, P. Malyala, M. Singh, D. T. O'Hagan, V. Petrilli, J. Tschopp, et al. (2009)
PNAS 106, 870-875
   Abstract »    Full Text »    PDF »
Modified Adenine (9-Benzyl-2-Butoxy-8-Hydroxyadenine) Redirects Th2-Mediated Murine Lung Inflammation by Triggering TLR7.
A. Vultaggio, F. Nencini, P. M. Fitch, L. Fili, L. Maggi, P. Fanti, A. deVries, E. Beccastrini, F. Palandri, C. Manuelli, et al. (2009)
J. Immunol. 182, 880-889
   Abstract »    Full Text »    PDF »
NKT-cell help to B lymphocytes can occur independently of cognate interaction.
E. Tonti, G. Galli, C. Malzone, S. Abrignani, G. Casorati, and P. Dellabona (2009)
Blood 113, 370-376
   Abstract »    Full Text »    PDF »
Immune Responses of Mice with Different Genetic Backgrounds to Improved Multiepitope, Multitarget Malaria Vaccine Candidate Antigen FALVAC-1A.
S. A. Kaba, A. Price, Z. Zhou, V. Sundaram, P. Schnake, I. F. Goldman, A. A. Lal, V. Udhayakumar, and C. W. Todd (2008)
Clin. Vaccine Immunol. 15, 1674-1683
   Abstract »    Full Text »    PDF »
Cyclooxygenase Inhibition during Allergic Sensitization Increases STAT6-Independent Primary and Memory Th2 Responses.
W. Zhou, D. C. Newcomb, M. L. Moore, K. Goleniewska, J. F. O'Neal, and R. S. Peebles Jr. (2008)
J. Immunol. 181, 5360-5367
   Abstract »    Full Text »    PDF »
Cutting Edge: Alum Adjuvant Stimulates Inflammatory Dendritic Cells through Activation of the NALP3 Inflammasome.
M. Kool, V. Petrilli, T. De Smedt, A. Rolaz, H. Hammad, M. van Nimwegen, I. M. Bergen, R. Castillo, B. N. Lambrecht, and J. Tschopp (2008)
J. Immunol. 181, 3755-3759
   Abstract »    Full Text »    PDF »
Molecular and cellular signatures of human vaccine adjuvants.
F. Mosca, E. Tritto, A. Muzzi, E. Monaci, F. Bagnoli, C. Iavarone, D. O'Hagan, R. Rappuoli, and E. De Gregorio (2008)
PNAS 105, 10501-10506
   Abstract »    Full Text »    PDF »
Cutting Edge: Inflammasome Activation by Alum and Alum's Adjuvant Effect Are Mediated by NLRP3.
H. Li, S. B. Willingham, J. P.-Y. Ting, and F. Re (2008)
J. Immunol. 181, 17-21
   Abstract »    Full Text »    PDF »

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