Voie d'immunisation et séquence d'administration de l ... - TEL
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tel-00827710, version 1 - 29 May 2013 response, despite the substantial evidence that the optimal use of these components will significantly boost the immune response (Wilson et al., 2006). In this section, I have reviewed the many parameters that can influence the outcome of an immune response. These factors must all be carefully considered and examined when developing new vaccines. To efficiently address this, models that represent physiologic conditions in humans are needed, as well as the development of technologies and tools that will allow for the detailed examination of a physiological immune response, even at low levels. Indeed, as currently studied, some parameters that influence the extent of an immune response, such as adjuvant dose, T cell precursor frequency and route of administration are artificially modified in mouse models. While this can facilitate the study of the immune response and limit the variability in the results, it was just reviewed here how these manipulations can impact the outcome of the response. Thus, it is imperative to keep these parameters as close as possible to human physiology. In order to study the immune response in these “physiologic” conditions, new techniques are continually being developed, such as the tetramer-based enrichment assay. As each technique presents its own limitations, the difficulty lies in choosing the compromise between the physiologic relevance of the model and the ability to study the T cell response with the tools available. 78
tel-00827710, version 1 - 29 May 2013 Page 79 of 256 Research Plan The CD8 + T cell response is a critical component of the adaptive immune system. These cells are considered particularly important for the host response to microorganisms and cells undergoing malignant transformation. In order to carry out their effector function efficiently, these cells must be activated by DCs, presenting MHC-I-peptide complexes. For many infections and most tumors, an indirect presentation pathway (referred to as cross-priming) is utilized for the loading of antigen onto the MHC-I of DCs. Although an effective CD8 + T cell response is critical for the control of many diseases, including tumor growth, chronic viral infection and other intracellular pathogens, vaccines capable of eliciting protective CD8 + T cells have not yet been developed. In order to accomplish this goal, much work has been performed to further understand the mechanisms of cross-priming and targeting this pathway for the purpose of novel vaccination strategies. For instance, Fontana and colleagues have conducted clinical studies utilizing a cell-associated antigen - peripheral blood lymphocytes genetically modified to express tumor antigens - as a strategy for inducing tumor immunity in cancer patients (Fontana et al., 2009). Our laboratory has been interested in defining optimal strategies to cross-prime CD8 + T cells after the delivery of cell-associated antigen. However, in the development of experimental models, it has been important to prioritize establishing conditions that reflect the physiologic situation present during the vaccination of humans, particularly in terms of antigen-specific T cell frequency. In order to do this, we expanded upon a recently described tetramer-based enrichment assay that allows for the detection of low numbers of antigen-specific T cells. This strategy allowed us to work within relatively physiologic conditions, specifically in terms of T cell precursor frequency, in order to investigate the impact of two important parameters that must be taken into consideration by investigators interested in initiating adaptive immune responses during vaccination - the route of vaccination and the use of adjuvants. I. IMPACT OF THE ROUTE OF IMMUNIZATION ON CD8 + T CELL CROSS-PRIMING To mimic the administration of cell-associated antigen and study the efficacy of the resulting CD8 + T cell cross-priming, we used a well-characterized model of cross-presentation. Donor
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tel-00827710, version 1 - 29 May 2013<br />
response, <strong>de</strong>spite the substantial evi<strong>de</strong>nce that the optimal use of these components will<br />
significantly boost the immune response (Wilson <strong>et</strong> al., 2006).<br />
In this section, I have reviewed the many param<strong>et</strong>ers that can influence the outcome of an<br />
immune response. These factors must all be carefully consi<strong>de</strong>red and examined when<br />
<strong>de</strong>veloping new vaccines. To efficiently address this, mo<strong>de</strong>ls that represent physiologic<br />
conditions in humans are nee<strong>de</strong>d, as well as the <strong>de</strong>velopment of technologies and tools that<br />
will allow for the d<strong>et</strong>ailed examination of a physiological immune response, even at low<br />
levels. In<strong>de</strong>ed, as currently studied, some param<strong>et</strong>ers that influence the extent of an immune<br />
response, such as adjuvant dose, T cell precursor frequency and route of administration are<br />
artificially modified in mouse mo<strong>de</strong>ls. While this can facilitate the study of the immune<br />
response and limit the variability in the results, it was just reviewed here how these<br />
manipulations can impact the outcome of the response. Thus, it is imperative to keep these<br />
param<strong>et</strong>ers as close as possible to human physiology. In or<strong>de</strong>r to study the immune response<br />
in these “physiologic” conditions, new techniques are continually being <strong>de</strong>veloped, such as<br />
the t<strong>et</strong>ramer-based enrichment assay. As each technique presents its own limitations, the<br />
difficulty lies in choosing the compromise b<strong>et</strong>ween the physiologic relevance of the mo<strong>de</strong>l<br />
and the ability to study the T cell response with the tools available.<br />
78