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

tel-00827710, version 1 - 29 May 2013
the type I IFN that are produced upon adjuvant delivery on immune response. These findings
remain preliminary and additional work is needed to confirm our results. Nevertheless, we
convincingly demonstrated that poly I:C acts at the level of antigen uptake and cross-
presentation by cDCs (II). When adjuvant is delivered early, it leads to DC maturation,
resulting in the downregulation of antigen uptake; DC migration to lymph nodes, which
removes DCs that engulf antigen from the site of injection; and/or DC death, which also may
explain the disappearance of cross-presenting DCs. The combination of these effects creates
an environment that is no longer optimal for cross-presentation. In contrast, if adjuvant
stimulation occurred with a short delay, once DCs have engulfed antigen, the beneficial
effects of adjuvant on maturation and migration to the lymph nodes could act to effectively
promote cross-priming.
Following from these results, we returned to our comparison between the two routes of
immunization and optimal timing of adjuvant delivery. Poly I:C acts on antigen uptake, DC
maturation and antigen presentation, and it is clear that the kinetics of these steps vary
depending on the route of immunization (Figure 32). As adjuvant delivery should be well
coordinated with antigen uptake and presentation in order to enhance these processes, this
may explain why the optimal timing for its delivery is delayed upon i.d. immunization. Taken
these data together, we propose the following model to explain the differential impact of
adjuvant delivery, with regards to the route of immunization (Figure 49). Systemic
dissemination (represented by i.v. injection) of cell-associated antigen allows for capture and
cross-presentation within one day. Within this kinetic, administration of poly I:C on day 1
post-immunization serves to stimulate cross-presenting DCs and enhances priming (Figure
49A). In contrast, localized delivery of cell-associated antigen, as seen with i.d.
immunization, requires three days for efficient antigen uptake and presentation.
Consequently, administration of poly I:C on day 1 results in “pre-mature” DCs, which are
unable to cross-present cell-associated antigen (Figure 49B). If instead, adjuvant
administration is performed on day 3 post-immunization, there has been sufficient time for
uptake and cross-presentation and the pro-maturation/pro-migration effects of the adjuvant
result in the enhancement of cross-priming (Figure 49C).
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