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

tel-00827710, version 1 - 29 May 2013
CD8 + T cell responses are crucial for the defense against many microorganisms and cells
undergoing malignant transformation. Consequently, in-depth study of CD8 + T cell response
after immunization is critical for understanding the mechanisms underlying the impact of
multiple parameters known to influence immune response, in order to improve current
vaccination strategies. We initiated our studies by developing a tetramer-based enrichment
technique that allowed us to carefully analyze the CD8 + T cell response, both phenotypically
and functionally. We then applied these techniques to the in-depth examination of two
parameters that impact immune response: the route of immunization and the timing of
adjuvant delivery. In this section, I will first discuss the technical improvement that tetramer-
based enrichment provides for the study of CD8 + T cells. I will then return to a detailed
discussion of our results, including several hypotheses that could explain why the intradermal
immunization of cell-associated antigen generated a more robust immune response than
intravenous delivery. Finally, I will discuss the results observed regarding the timing of
adjuvant delivery and the optimization of treatments that contains a combination of adjuvant
and antigen. I will extend these considerations to other types of antigen, as well as discuss the
combination of several existing vaccine strategies and the issues raised in terms of the timing
and sequence of administration.
I. TETRAMER-BASED ENRICHMENT: A POWERFUL TOOL
A. Advantages and limitations
1) Sensitivity of the technique
The development of tetramer-based enrichment allows for the detection of rare antigen-
specific CD4 + and CD8 + T cells (Moon et al., 2007; Obar et al., 2008). This technique allows
for the study of specific T cells in naïve mice and during the first steps of T cell activation
upon immunization without transferring high numbers of TCR-transgenic T cells. The ability
to detect low numbers of circulating antigen-specific T cells also makes possible to study the
T cell response following a relatively weak antigenic stimulation, which allows for the use of
reduced antigen dose that more accurately reflects a strategy that could be adapted for human
vaccination.
In our studies, the comparison of the intradermal or intravenous routes of immunization
permitted us to determine the outcome of an immune response stimulated by a local versus
systemic dissemination of antigen. As expected, systemically disseminated antigen resulted in
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