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Regulation of immune responses: from fundamental immunology to anti-tumoral immunity

Research project P5/28 (Research action P5)

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Description :

The objective of this project is to contribute to the progress of fundamental knowledge in immunity and to elucidate the mechanisms that lead to the rejection of tumors and allografts, with the aim of developing new immunotherapy strategies. The proposed research involve five teams who have a long history of collaboration in order to take advantage of their complementary expertise in fundamental immunobiology, cancer and transplantation immunology.

The way the project was conceptualized let the different phases of immune responses - from antigen presentation to antigen synthesis and regulatory T cell generation - being approached, with a focus on the regulatory mechanisms. In the context of cancer immunity, the efforts will challenge the identification of new tools to stimulate and identify the immune anti-tumoral responses. In transplantation, we will investigate the role of two cytokines that could mediate the rejection process. For the sake of clarity and efficiency, the tasks of the respective participants are separated into 7 workpackages.

Workpackage 1 aims to identify the molecular mechanisms behind the unique characteristics of dendritic cells, the "professional" antigen presenting cells. We will make use of diverse approaches to characterize the factors essential to their maturation, their migration to the lymph nodes, their cytotoxicity and their effect on the polarization of CD4 T helper lymphocyte responses.

Workpackage 2 will deal with genetic engineering of dendritic cells targeting the best possible presentation of tumor antigens and their immunogenicity.

The objective of workpackage 3 is to generate immortal clones of tumor cells and anti-tumoral T lymphocytes, as tools to move forward in the development of new anti-tumor immunostrategies.

Workpackage 4 aims to identify new tumor antigens as a base for new cancer vaccines.

The topic of workpackage 5 is the precise characterization of immune responses in patients with tumor regression after vaccination.

Workpackage 6 will study the selection of B lymphocytes repertoires, utilizing genetically modified mice deficient in molecules involved in the differentiation of these lymphocytes or deficient in proteins selectively expressed by follicular dendritic cells creating close contacts with B lymphocytes in the lymph nodes.

The objective of workpackage 7 is to identify new mechanisms regulating the functions of T cells. We will study the changes of the membrane lipid rafts affecting the transduction of activation signal in T cells. We will also characterize the regulatory CD4 T cells in experimental in vivo models.

Workpackage 8 will study the role of IL-9 and IL-22 in allograft rejection. In these experiments, special attention will be paid to eosinophils and mastocytes, cells of innate immunity that recently appear to be implicated in transplantation.

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