Voie d'immunisation et séquence d'administration de l ... - TEL

tel-00827710, version 1 - 29 May 2013
1) Adjuvants used in therapies
(a) Adjuvants developed empirically
Despite extensive investigation, it is still not understood how adjuvants currently used in
experimental models and/or in clinical applications function to modulate the immune
response. In particular, the most common adjuvants used are Complete Freund’s adjuvant, oil-
in-water emulsions, saponin-based adjuvants or aluminum salts. It was initially thought that
these molecules only act as passive depot or delivery vehicles when formulated in
combination with antigen. However, recent data suggest that they have also an impact on
innate immune response by inducing cellular damage at the site of injection, leading to
necrotic cell death and release of DAMPs, promoting increased antigen uptake, or stimulating
the inflammasome pathway (Maraskovsky et al., 2009; Marrack et al., 2009).
(b) New adjuvants
While the functional mechanisms of empirically discovered adjuvants are still not completely
understood, new adjuvants have been developed more recently based on our knowledge about
what is needed to stimulate the innate immune response. Specifically, most PRRs are
potential targets for adjuvant stimulation, and the choice of receptors to engage depends on
how the immune response should be modulated to obtain the desired extent of activation.
Natural and synthetic agonists of various PRRs, especially TLRs, have been developed as
adjuvants.
2) Adjuvants inducing type I IFN production
(a) Type I IFN
Type I IFN refers to a family of highly related cytokines that have and promote antimicrobial
activity. Isaacs and Lindenmann discovered type I IFN 50 years ago, based on their ability to
“interfere” with virus replication and spread (Isaacs and Lindenmann, 1957). Three families
of IFN molecules with antiviral properties have since been identified (Pestka et al., 2004).
Type I IFN consist of seven classes: IFNα, IFNβ, IFNε, IFNκ, IFNω, IFNδ and IFNτ. By
contrast, type II IFN corresponds to a single protein, IFNγ. Type III IFN was identified only
recently and this family is composed of three IFNλ proteins.
Here I will focus only on type I IFN molecules. While they were initially identified due to
antiviral properties, they also can act to defend against other pathogens such as bacteria,
parasites, fungi and their microbially-derived products (Bogdan et al., 2004). Several
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