The efficiency of vaccines relies heavily on the nature of the adjuvant that is used at the time of immunization. However, until now the choice for adjuvants is rather limited and still largely empirical. As we understand it currently, most adjuvants act by inducing a specific differentiation program for dendritic cells (DC), endowing them with the ability to present antigens more efficiently and to recruit discrete subsets of T cells that will carry out the adaptive immune response. Therefore, the integration of signaling by DC is what defines adjuvanticity. Next to a series of ligands that bind directly to Toll-like receptors and trigger single signaling pathways, DC programming can be induced in a more complex way by NKT cells, a subset of regulatory T cells. We have identified a natural, endogenous ligand of NKT cells with powerful adjuvant properties called sulglucosylceramide (SuGC). Because it is an endogenous substance that might be used physiologically by the immune system, we believe that its use as an adjuvant for vaccine has great potential. We have already shown that SuGC could be an efficient adjuvant for the immunization against nominal protein antigens and during the course of a viral disease. Its activity, mediated by NKT cells, impact CD4 and CDS responses as well as B cell antibody production. To further our knowledge about SuGC and to be able to bring it to pre-clinical trials, we propose three specific aims.
Aim 1 : Characterize the adjuvant properties of SuGC at the molecular level by dissecting its role in a normal immune response and studying its programation of DC.
Aim 2 : Optimization of SuGC and Characterization of its Pharmacological Properties. The natural compounds will be studied systematically through synthetic chemistry. Variants of SuGC will be characterized for their ability to stimulate NKT cells in vitro and in vivo, induce dendritic cell maturation in vivo, and act as adjuvants of immune responses. Pharmacological distribution and stability of SuGC and its variants will be studied in vivo.
Aim 3 : Using SuGC in the vaccination against lipids. The delivery of lipids by using lipid transfer proteins as delivery systems has proven efficacious in raising T cell-dependent anti-lipid antibody responses in animals. Because of its superior qualities as an adjuvant, SuGC will be studied in the context of lipid vaccination and evaluated for the protection of anti-lipid immune responses in an animal model.
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| Freigang, Stefan; Zadorozhny, Victoria; McKinney, Michele K et al. (2010) Fatty acid amide hydrolase shapes NKT cell responses by influencing the serum transport of lipid antigen in mice. J Clin Invest 120:1873-84 |
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