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

tel-00827710, version 1 - 29 May 2013
example, in our model we observed both the positive and negative effects of adjuvant
depending on the timing of its delivery.
While we proposed a delayed adjuvant delivery to overcome this complication, other studies
demonstrated that co-administration with antigen may lead to a more robust priming. West et
al. showed in an in vitro model that co-administration of LPS with Ovalbumin immune
complexes enhanced antigen uptake and presentation by remodeling the actin cytoskeleton. In
contrast, delayed delivery of adjuvant after antigen exposure did not promote the same effect
(West et al., 2004). Importantly, this effect is only transient and overall, a down-regulation of
antigen capture was observed upon adjuvant exposure, similar to what has been described in
our work and by other teams (Wilson et al., 2006; Weck et al., 2007). This transient
enhancement of antigen uptake has been demonstrated to be dependent on TLR-signaling.
1) Optimal timing depends on the TLR ligand
The downregulation of antigen uptake observed upon adjuvant delivery was first thought to
be due to DC maturation and be dependent on TLR trigerring. However, it appears to also
depend on the type of TLR ligand used for stimulation, despite the fact that all of them were
shown to induce DC maturation in vivo (Schwarz et al., 2003). Weck and colleagues
demonstrated that DCs matured after stimulation with TLR3 or TL4 ligands were not able to
take up apoptotic cells efficiently, as compared to DCs matured with TLR7/8 or TLR2 (Weck
et al., 2007). This dichotomy parallels the intracellular pathways engaged by TLR ligands.
TLR7/8 and TLR2 trigger a Myd88-dependent pathway, whereas TLR3 induces a TRIF-
dependent pathway. TLR4 can trigger both pathways (Figure 5). Consequently, it has been
suggested that TLR3 and TLR4 ligands could be co-administered as adjuvants for antigens
that do not need to be engulfed, such as peptide, whereas TLR7/8 or TLR2 ligands would be
used for antigens that required phagocytosis to be presented. Another possibility to work
around these heterogeneous functions is to delay the administration of TLR3 or TLR4 ligand
as previously discussed.
2) Optimal timing depends on receptor engaged
Recently, Tirapu et al. focused on the inhibition of antigen uptake following poly I:C delivery
and demonstrated that it was not actually due to TLR trigerring (Tirapu et al., 2009). Instead,
there was a competition between poly I:C and antigen to interact with scavenger receptors.
Interestingly, while poly I:C stimulation reduced uptake through scavenger receptor, it did not
affect endocytosis by mannose receptor, which is known to be crucial for Ovalbumin
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