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

tel-00827710, version 1 - 29 May 2013
(c) Similar pleiotropic roles of type I IFN on macrophages depending
on the timing of application
In our studies, we have focused on adjuvant and type I IFN action on DCs. The same IFN-
mediated differential effects were also observed for other cell types. In a model of
macrophage infection by Leishmania major, it was demonstrated that type I IFN could also
have conflicting effects on macrophage activity and parasite clearance (Mattner et al., 2000).
In this model, when macrophages detect parasite and IFN at the same time, macrophages are
activated and the expression of the inducible nitric oxide synthase (iNOS) is increased,
leading to Leishmania killing. If IFN are detected later than Leishmania, it also favors parasite
clearance. However, if macrophages detect IFN prior to Leishmania exposure, this activation
inhibits the expression of iNOS and, in turn, restricts Leishmania killing (Figure 55). Since
IFN are produced directly by macrophages, the authors proposed a model in which this
mechanism acts as a type of negative feedback loop, providing for the desensitization of
neighbouring macrophages if they had not yet been infected.
Figure 55. Opposite effects of type I IFN on macrophage activity depending on the sequence of
the stimuli. Leishmania major (in red) and type I IFN are administered in 3 different sequences.
iNOS, inducible nitric oxide synthase. Figure from Bogdan et al., 2004.
C. Comparison with other TLR ligands
Previous studies have already pointed out that the timing of adjuvant delivery should be
carefully determined. A deeper understanding of the mechanisms of adjuvant action is
required to both improve vaccination and further understand seemingly conflicting results.
Stimulation with TLR ligands has been shown to enhance T cell priming (Schulz et al., 2005).
However in certain contexts, the opposite effects can be observed (Wilson et al., 2006). For
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