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

tel-00827710, version 1 - 29 May 2013
vaccine to be efficient (Kleindienst and Brocker, 2003). Moreover, selective ablation of
endogenous DCs or the injection of dying, loaded DCs, rather than live cells, are enough to
abrogate the effects of a vaccine (Petersen et al., 2011). This indicates that the injected DCs
have to migrate away from the injection site and transfer antigen to resident DCs to promote
an efficient response. In parallel, knowledge about DC subsets has been expanded and
improved. The murine resident CD8α + DC subset has been identified as the most competent
for cross-presentation (den Haan et al., 2000). The human equivalent has recently been
identified and characterized by its expression of the receptor Clec9A (Crozat et al., 2010;
Poulin et al., 2010; Zhang et al., 2012). This subset is likely implicated in the engulfment of
antigens that enter the lymphoid tissue, as well as antigen that may be transferred from
peripheral, migratory DCs. From these data it made sense to enhance the delivery of antigen
directly to the CD8α + DC subset, hoping that this strategy would help to avoid the problems
of injecting ex vivo generated DCs. These antigens are targeted to the CD8α + DC subset via
conjugation to antibodies specific of CD8α + DC surface receptors such as DEC-205 or DC-
SIGN, both members of the C-type lectin receptor family (Bonifaz et al., 2002). This
approach has great interest in the field of cancer vaccines, because it can be developed on a
large scale. The existing limitation is that it must be combined with an adjuvant to trigger T
cell priming (Bonifaz et al., 2004).
(c) T cells used as cell-associated antigens
Initially, because of their role in promoting an effective immune response, DCs appeared to
be the best candidate for the development of a cellular vaccine. However it is possible that
other cell types may be used as antigen delivery vehicles. Following interesting observations
during a clinical study, T cells appeared to be a potential vehicle to deliver antigen in vivo. In
this trial, during allogeneic bone marrow transplantation, lymphocytes were infused into
patients. However, these cells had been genetically modified to express the herpes simplex
virus thymidine kinase (HSV-TK) “suicide gene”, as a security mechanism in case of an
autoreactive response against these transferred cells (Bonini et al., 1997). In this case, it was
shown that patients developed anti-HSV-TK CD4 + and CD8 + T cell responses that promoted
the elimination of the therapeutically transferred T cells; furthermore, memory T cells
targeting HSV-TK were generated (Berger et al., 2006). Due to this unexpected response, T
cells were then considered as a potential source of antigen. More than just an antigen delivery
vehicle in the context of vaccination, T cells also have some advantages as compared to DCs:
(i) these cells efficiently migrate to the lymphoid tissues allowing for the optimal localization
of antigen for phagocytosis by resident DCs and induction of a T cell response; (ii) T cells can
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