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tel-00827710, version 1 - 29 May 2013 of monocytes into DCs with varying phenotypes and functions. Activation of monocytes with IL-4, IFNα, TNF or IL-15 gave rise to different populations of DCs with diverse phenotypes. That could explain the different efficiencies of these cells in mounting CD8 + T cell responses (Paquette et al., 1998; Dubsky et al., 2007). (b) Side effects of type I IFN treatment on DCs Not all type I IFN effects on DCs promote a well-regulated immune response. Autoimmune disorders have been observed in melanoma patients undergoing treatment with type I IFN. One hypothesis is that IFN induced in vivo maturation of DCs that have taken up self-antigen and this led to an autoimmune response (Rizza et al., 2010). (c) Targeting DCs with specific antigens It was previously introduced that the type of antigen and thus the type of receptor implicated for antigen uptake plays a role in the efficiency of the subsequent immune response. One promising approach for vaccination development is to target antigens to a specific subset of DCs by coupling them with antibodies directed against DC-specific cell-surface molecules. The CD8α + DC subset has been the most studied thus far, due to its specialization for cross- priming. Antibodies coupled to Ovalbumin and targeting different receptors, DEC-205, Clec9A and Clec12A were tested. Interestingly it was observed that the outcome of the response and the requirement for adjuvant depends on which receptor was targeted. DEC-205 and Clec9A are effective targets to promote cytotoxic T cell responses, while Clec12A was shown to be inefficient (Lahoud et al., 2011). Addition of adjuvant is always required to induce a CD8 + T cell response. In contrast, a potent humoral response can be obtained upon targeting of antigen to Clec9A in the absence of adjuvant (Figure 56). Since Clec9A expression is restricted to CD8α + DCs and pDCs, this observation may be due to a longer persistence of antigen coupled to antibody in the blood because fewer cells are available that can endocytosed it, allowing for a sustained presentation on MHC-II. 170

tel-00827710, version 1 - 29 May 2013 Figure 56. Immune responses generated after targeting of antigen to the same DC subset via different receptors. Tfh, follicular helper T cells. Figure from Caminschi et al., 2012. 3) Context of vaccination Patients that are chronically infected with Hepatitis C virus (HCV) do not display type I IFN production in the liver, which is the organ targeted by the virus. Yet a significant amount of type I IFN was found circulating in the blood of these patients (Mihm et al., 2004). This raises questions regarding the maturation state of DCs, as well as the reactivity of other cell types in this system, when therapeutic vaccination is considered for treatment. Indeed, several trials are currently underway to test vaccine candidates. As an example, IC41 which is a synthetic peptide containing several CD8 + and CD4 + epitopes formulated with the adjuvant poly-L- arginine was tested in chronic HCV patients. The effectiveness of this antigen in combination with the topical application of the TLR7 ligand imiquimod was also examined (Klade et al., 2012). The results obtained from the trial were encouraging, although not as good as expected. In the light of our results regarding the timing of type I IFN production, we can identify several caveats in this type of approach. Indeed, if DCs were already completely matured or impaired in their function prior to vaccination, we may have observed an inefficient response against the virus (Ryan and O'Farrelly, 2011). Most likely, several approaches must be combined in this case to create an environment that allows for the development of a response against the peptide vaccine. Moreover, adding yet another type I IFN-inducer as an adjuvant (such as imiquimod) in chronic HCV patients will probably not Page 171 of 256

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