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Engineering an effective immune adjuvant by designed control of shape and crystallinity of aluminum oxyhydroxide nanoparticles

Significance Statement

Aluminum-based adjuvants generally induce strong Th2 immune responses, with little or no Th1 immune responses. However, for the clearance of viral infections or tumor cells, cytotoxic Th1 responses are needed. To achieve the goal of inducing Th1 responses, additional stimuli, e.g., Toll-like receptor (TLR) agonists are needed. Our preliminary results have showed that long aspect ratio aluminum oxyhydroxide nanorods together with Toll-like receptor (TLR) agonists could induce stronger IL-1{Beta} production in murine bone marrow-derived dendritic cells (BMDCs) ex vivo, and higher IFN-{Gamma} by CD4 and CD8 T cells in vivo. Therefore, using engineered nanoparticles including aluminum oxyhydroxide nanorods together with TLR agonists, it is possible to develop combinatorial vaccine adjuvants to direct the T-cell differentiation towards Th1 cytotoxic responses for more effective prevention of infectious diseases and treatment of cancer in clinics.

Engineering Effective Immune Adjuvant by Designed Control of Shape Crystallinity of Aluminum Oxyhydroxide Nanoparticles- global medical discovery

 

 

 

 

 

 

 

 

 

 

 

Sun B, Ji Z, Liao YP, Wang M, Wang X, Dong J, Chang CH, Li R, Zhang H, Nel AE, Xia T.

ACS Nano. 2013 Dec 23;7(12):10834-49.

Division of NanoMedicine, Department of Medicine, ‡California NanoSystems Institute, and §Department of Chemistry, University of California , Los Angeles, California 90095, United States.

Abstract

 Adjuvants based on aluminum salts (Alum) are commonly used in vaccines to boost the immune response against infectious agents. However, the detailed mechanism of how Alum enhances adaptive immunity and exerts its adjuvant immune effect remains unclear. Other than being comprised of micron-sized aggregates that include nanoscale particulates, Alum lacks specific physicochemical properties to explain activation of the innate immune system, including the mechanism by which aluminum-based adjuvants engage the NLRP3 inflammasome and IL-1{Beta} production. This is putatively one of the major mechanisms required for an adjuvant effect. Because we know that long aspect ratio nanomaterials trigger the NLRP3 inflammasome, we synthesized a library of aluminum oxyhydroxide (AlOOH) nanorods to determine whether control of the material shape and crystalline properties could be used to quantitatively assess NLRP3 inflammasome activation and linkage of the cellular response to the material’s adjuvant activities in vivo. Using comparison to commercial Alum, we demonstrate that the crystallinity and surface hydroxyl group display of aluminum oxyhydroxide nanoparticles quantitatively impact the activation of the NLRP3 inflammasome in human THP-1 myeloid cells or murine bone marrow-derived dendritic cells (BMDCs). Moreover, these in vitro effects were correlated with the immunopotentiation capabilities of the aluminum oxyhydroxide nanorods in a murine OVA immunization model. These results demonstrate that shape, crystallinity and hydroxyl content play an important role in NLRP3 inflammasome activation and are therefore useful for quantitative boosting of antigen-specific immune responses. These results show that the engineered design of aluminum-based adjuvants in combination with dendritic cell property-activity analysis can be used to design more potent aluminum-based adjuvants.

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