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

tel-00827710, version 1 - 29 May 2013
(a) Efficiency of adjuvant physically linked with antigen
Despite differences in antigen formulation, it is clear that antigen physically linked with its
adjuvant generally gives very good results, as the two molecules are most likely sensed at the
same time by APCs (Wille-Reece et al., 2005; Huleatt et al., 2007). This effect was
highlighted in the work of Nierkens and colleagues in which they studied the adjuvant effect
of CpG in a tumor model. B16-OVA tumor-bearing mice were treated with cryoablation,
which provided an instant antigen source for DCs and this was combined with injections of
CpG at various time points surrounding the antigen injection. They observed that the
strongest adjuvant effect was obtained when CpG was administered concurrently with
cryoablation (Nierkens et al., 2008). As cryoablation leads to the generation of soluble, as
well as cell-associated antigen, they chose to study soluble Ovalbumin to mimic antigen
quickly released after cryoablation. In these conditions, they demonstrated that the most
efficient response correlated with a colocalization between soluble antigen and CpG in the
same cellular compartment. This is also in accordance with studies demonstrating that antigen
and danger signals have to be detected by the same cell to induce an optimal response (Kratky
et al., 2011; Sporri and Reis e Sousa, 2005). Moreover, Blander and Medzhitov even suggest
that antigen and danger signals have to be delivered into the same compartment (Blander and
Medzhitov, 2006) in order to observe efficient priming, although these results remain
controversial (Yates and Russell, 2005).
Lastly, an additional advantage of adjuvant that is physically linked to its antigen is that the
amount of adjuvant necessary is lower, as it is directly targeted to the effector APC. In
conditions using lower adjuvant doses, less side effects of adjuvant were observed
(Nicodemus and Berek, 2010).
(b) Importance of non-hematopoietic cells
In several studies, it has been observed that the most robust response was obtained when co-
detection of adjuvant and antigen was made by the same APCs. However, in some cases, the
non-hematopoietic cells were also demonstrated to be crucial for the adjuvant effect of a
molecule. Longhi et al. studied the adjuvant effect of poly I:C on the CD4 + T cell response
and they demonstrated in bone-marrow chimeras that type I IFN production by hematopoietic
cells, as well as stromal cells, was required for the most effective T cell response (Longhi et
al., 2009).
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