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

tel-00827710, version 1 - 29 May 2013
endocytosis. Compared to the study performed by Weck and colleagues, the reduction of
antigen uptake in this study was not associated with less efficient priming. Weck at al. studied
uptake of apoptotic cells by human DCs whereas Tirapu et al. performed their experiments
with mouse DCs and soluble Ovalbumin. These different systems and antigens may explain
the functional variations observed, specifically the fact that soluble antigen and dying cells are
not engulfed via the same pathways, which are also differentially regulated by adjuvant
treatment (Burgdorf et al., 2007).
These differences highlight the importance of considering several critical parameters when
combining an antigen and an adjuvant for therapy: (i) the antigen type, (ii) the receptor(s) and
the pathway(s) engaged by the antigen, (iii) the adjuvant type and (iv) the receptor(s) and the
pathway(s) engaged by the adjuvant. The understanding of antigen presentation pathways, as
well as intracellular pathways trigerred by the adjuvant of interest, are necessary to optimize
vaccination strategies.
D. Applications in clinical studies
1) Translation into human treatments
The use of adjuvant is important in order to boost immune responses. However the pattern of
TLR expression is not always similar between mice and humans. The best example is CpG,
the ligand for TLR9. This receptor is expressed by cDCs, pDCs and B cells in mice, but only
on pDCs and B cells in humans (Kadowaki et al., 2001). From what has been discussed
regarding the potential requirement for DCs to detect antigen and adjuvant in the same time,
the different expression patterns might constitute a huge difference in overall responsiveness.
This may explain why some treatments with CpG that provided nice results in mice, were just
not as good in humans (Schmidt, 2007). These differences are crucial and must be taken in
account when developing an experimental mouse model to address questions of cross-
presentation and antigen/adjuvant delivery.
2) Manipulating DCs for vaccination
(a) Use of IFN-treated DCs
Treatment with type I IFN represents a strategy for inducing the maturation of DCs ex vivo
prior to their administration into patients, an approach often taken in the case of DC-based
vaccines. Interestingly, treatment with different cytokines ex vivo skewed the differentiation
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