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Regulation and manipulation of the immune response

Research project P4/29 (Research action P4)

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Description :

The main objective of this IAP is to study regulation and manipulation of the immune response. To this end three groups (ULB, ULg, VUB) collaborate on fundamental and applied projects.

When an antigen invades an organism, the first strategic choice of the immune system is between tolerance and immunity. It seems clear that besides the great sensitivity of immature T and B cells in thymus and bone marrow to negative selection, failsafe mechanisms must operate to avoid immunity against peripheral self antigens which are not present in the thymus or against developmentally regulated antigens which appear well after birth (lactation, puberty, metamorphosis, ...).
Several mechanisms have been documented including:
- clonal ignorance, as naïve lymphocytes are not adequately equipped to cross endothelial barrier;
- clonal anergy, as most non lymphoid tissues do not exhibit costimulatory molecules which are necessary to induce immunity. Costimulatory signals can be provided by other activated nearby lymphocytes or antigen presenting cells, by activation of innate immunity or by molecular signatures of the microbial world.
- regulatory T cells and immune deviation, as several groups have now clearly documented the existence of suppressor T lymphocytes which can dampen the activity of proinflammatory T lymphocytes.

Beyond the self - non self discrimination (or the danger - non danger) choice, the second decision is the regulation of the class of the immune response (cell mediated versus humoral, cytotoxic versus non cytotoxic, ...). The B cell response to thymus dependent antigens is extremely dynamic, with time modifications of the isotypic profile, the generation of somatic variants of V genes, and a stringent selection process based on affinity for antigen. The somatic hypermutation process and the affinity based selection are thought to occur in germinal centers with a second window of tolerance to eliminate new autoreactive B cells generated by mutation.

The project addresses the following questions :
- How is regulated the expression of costimulatory molecules, particularly on dendritic cells, which are the most potent activators of naïve T lymphocytes?
- Besides CD80 and CD86, what are the other costimulatory molecules used by dendritic cells?
- How is it possible to inhibit costimulatory signals in order to downmodulate inflammatory, destructive immune responses?
- What is the role of costimulatory molecules in determining the balance between Th1 and Th2 immunity?
- How can one use dendritic cells to manipulate the immune response with emphasis on the anti tumoral response? New approaches involve the use of hybrids between dendritic cells and tumor cells.
- What are the molecular mechanisms of T cell anergy to self components or to bacterial superantigens?
- What are the cellular requirements for germinal center formation (dendritic cells, B lymphocyte subsets, ...).
- What is the role of germinal centers in idiotypic dominance of memory responses?
- Are the molecular repertoires of rearranged V genes different in the primary versus the secondary B cell lineage?
- What is the role of idiotypic interactions in the selection of the secondary B cell lineage?

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