Inflammasome-activating nanoparticles as modular systems for optimizing vaccine efficacy.
Innate immune system activation is a critical step in the initiation of an effective adaptive immune response; therefore, activation of a class of innate pathogen receptors called pattern recognition receptors (PRR) is a central feature of many adjuvant systems. It has recently been shown that one member of an intracellular PRR, the NLRP3 inflammasome, is activated by a number of classical adjuvants including aluminum hydroxide and saponins [Eisenbarth SC, Colegio OR, O'Connor W, Sutterwala FS, Flavell RA. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 2008;453(June (7198)):1122-6; Li H, Willingham SB, Ting JP, Re F. Cutting edge: inflammasome activation by alum and alum's adjuvant effect are mediated by NLRP3. J Immunol 2008;181(July (1)):17-21]. Inflammasome activation in vitro requires signaling of both the Toll-like receptor (TLR) and NLRP3 in antigen-presenting cells. Here we present a class of nanomaterials endowed with these two signals for rapid optimization of vaccine design. We constructed this system using a simple approach that incorporates lipopolysaccharides (LPS) onto the surface of nanoparticles constructed from a biocompatible polyester, poly(lactic-co-glycolic acid) (PLGA), loaded with antigen. We demonstrate that LPS-modified particles are preferentially internalized by dendritic cells compared to uncoated nanoparticles and the system, when administered to mice, elicits potent humoral and cellular immunity against a model antigen, ovalbumin. Wild-type macrophages pulsed with LPS-modified nanoparticles resulted in production of the proinflammatory cytokine IL-1beta consistent with inflammasome activation. In comparison, NLRP3-deficient and caspase-1-deficient macrophages showed negligible production of IL-1beta. Furthermore, when endocytosis and lysosomal destabilization were inhibited, inflammasome activity was diminished, supporting the notion that nanoparticles rupture lysosomal compartments and behave as 'danger signals' [Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 2008;9(August (8)):847-56]. The generality of this vaccination approach is tested by encapsulation of a recombinant West Nile envelope protein and demonstrated by protection against a murine model of West Nile encephalitis. The design of such an antigen delivery mechanism with the ability to stimulate two potent innate immune pathways represents a potent new approach to simultaneous antigen and adjuvant delivery.
Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA.
Stacey L
SL
Demento
Stephanie C
SC
Eisenbarth
Harald G
HG
Foellmer
Craig
C
Platt
Michael J
MJ
Caplan
W
W
Mark Saltzman
Ira
I
Mellman
Michel
M
Ledizet
Erol
E
Fikrig
Richard A
RA
Flavell
Tarek M
TM
Fahmy
D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D000917:Antibody Formation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D019344:Lactic Acid / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D053758:Nanoparticles / Q000627:therapeutic use*; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D014611:Vaccination / Q000379:methods*; D014759:Viral Envelope Proteins / Q000276:immunology; D014901:West Nile Fever / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D053060:West Nile Virus Vaccines / Q000276:immunology / Q000627:therapeutic use
D000276:Adjuvants, Immunologic; D002352:Carrier Proteins; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D014759:Viral Envelope Proteins; D053060:West Nile Virus Vaccines; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid