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

tel-00827710, version 1 - 29 May 2013
(c) Use of other adjuvants
Poly I:C was chosen as the adjuvant for this study based on its ability to induce type I IFN
expression and secretion. Other adjuvants such as CpG, poly A:U, or TLR7 agonists could be
used to induce type I IFN production as well. The interest in using such reagents would be
that they induce type I IFN production, but via a different pathway than poly I:C. This could
allow for the distinction between actions promoted by type I IFN and the direct impact of poly
I:C on different target genes.
B. The optimal timing for adjuvant delivery depends on the nature
of antigen
For our model we focused on the study of cell-associated antigen and cross-presentation,
however, other types of antigen can be used for vaccination as described in the introduction.
Based on the implications of our results, we can attempt to predict what would be the optimal
timing for adjuvant delivery depending on the nature of antigen. Indeed, more than proposing
to consistently delay adjuvant administration after immunization, we believe that adjuvant
must be sensed by APCs at a critical time point, simultaneously with, or just after antigen
uptake. In our model, the cell-associated antigen used requires a relatively long time to be
engulfed, processed and presented, and this delay between antigen exposure and productive T
cell response allowed us to demonstrate that the timing of adjuvant delivery should be
perfectly coordinated with this kinetic. It is important to note that each of these different steps
can take up to several days, especially after local immunization. However, with another form
of antigen, such as soluble antigen, or peptide that can bind directly to the MHC complex, the
same steps are either not required or occur far more rapidly and the optimal timing for
adjuvant delivery will have to be adjusted accordingly. Using our experience will cell-
associated antigen and our knowledge about the presentation of different types of antigen, we
tried to predict the optimal timing of adjuvant delivery for each kind of antigen. These data
are summarized in Table 6. Our model used a cell-associated antigen, the antigenic form that
has the longest lag time between engulfment and time to presentation. Thus, we were able to
dissect the action(s) of the adjuvant treatment at different time points. Vaccination with a
protein antigen requires a similar set of steps except that it will disseminate more rapidly as it
is soluble, reducing the overall duration of the process. Consequently, the optimal timing for
adjuvant administration in the case of soluble antigen should be closer to the time of initial
immunization. Finally, vaccination with a peptide that is capable of direct binding and
presentation by the MHC complex would trigger an extremely rapid presentation kinetic and
Page 161 of 256