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

tel-00827710, version 1 - 29 May 2013
molecules that are known to induce type I IFN production, including TLR and RLR ligands,
are currently being tested for their effectiveness and feasibility as candidate adjuvants.
(b) TLR3 and RLR ligands
Doubled stranded RNA (dsRNA) is a potent activator of innate immune cell activity
following engagement with endosomal TLR3, as well as cytosolic ribonucleic acid helicases
RIG-I and Mda5 (Alexopoulou et al., 2001; Kato et al., 2006). Poly I:C is a synthetic dsRNA
analog that is known to be detected by TLR3 and Mda5. In this case, the size of this ligand is
critical, as long dsRNA is required for optimal activation of Mda5. Several derivatives of poly
I:C have been developed to limit toxicity and modify the downstream biological effects
(Nicodemus and Berek, 2010). Poly ICLC corresponds to poly I:C complexed with poly-L-
lysine and carboxymethylcellulose, allowing for a prolonged effect in vivo. This complexe is
actively used in clinical trials under the brand name Hiltonol ® . Ampligen ® (polyI: polyC12U)
is another modified dsRNA obtained by the addition of uridine in the sequence leading to
occasional base pair mismatches and a more rapid metabolism in vivo, which serves to limit
its toxicity. Ampligen appears to act only through TLR3. TLR3 expression, and therefore
stimulation, is not uniform and is likely different in specific tissue microenvironments. TLR3
is expressed in some subsets of cDCs, macrophages, and NK cells as well as non-immune
cells such as fibroblasts and epithelial cells. Additionally, RLRs are expressed in different cell
types, although the RLR expression profile has not yet been detailed thoroughly. The
signaling pathways triggering type I IFN production upon TLR3 or RLR engagement are
different and will be described later in this introduction. TLR3 stimulation has been
demonstrated to act on DCs by stimulating IL-12 and type I IFN secretion, as well as
upregulating antigen presentation (Schulz et al., 2005). Mda5 appears to be more involved in
the response of non-hematopoietic cells by stimulating their production of type I IFN (Longhi
et al., 2009). The activation of both TLR3 and Mda5 pathways by poly I:C serves to strongly
enhance the Th1 and CD8 + T cell response, better than either one of the two pathways alone.
Thus far, the combination of TLR3 action directly on DCs and bystander Mda5 action mainly
on non-hematopoietic cells appears to be the best way to boost the CD8 + T cell response.
(c) TLR7 and TLR8 ligands
TLR7 and TLR8 are also endosomal PRRs, responsible for detecting single stranded RNAs
(Diebold et al., 2004). These PAMPs are not particularly stable because they are quickly
degraded by RNases in the environment. Thus, they do not make for good adjuvants unless
they are modified or formulated with another component that confers an increased stability.
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