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Active peripheral tolerance applied to transplantation autoimmunity: revisiting an ancient concept with strategies and biotechnologies

Objective



This project is intended to develop and co-ordinate a European network of 7 partner laboratories to produce and develop novel therapeutic strategies for the prevention and the treatment of autoimmune diseases and avoidance of transplant rejection. Autoimmunity constitutes the third major pathogenetic process in developed countries after cancer and atherosclerosis. Organ and bone marrow transplantation represent the only therapeutic possibility for a variety of life threatening conditions. In both of these situations similar immune mechanisms are involved and current therapeutic approaches are essentially based on non-antigen specific immunosuppression. This strategy is insufficiently efficacious and exposes to severe side effects linked to long term over-immunosuppression and direct drug toxicity.
The aim of this collaborative project is to establish ways in which the immune response to the target antigens of the pathogenic process can be selectively inhibited, thus avoiding the hazards of long term non-specific immunosuppression. This may be achieved through peripheral tolerance defined as durable antigen specific unresponsiveness in the absence of generalized immunosuppression.
Observations made by the partner laboratories have indicated that peripheral tolerance is not only explained by deletional mechanisms. Various strategies, mainly using biological agents, will be developed to promote such peripheral tolerance and to dissect the underlying active mechanisms.
Some of these strategies will target specific mechanisms of T cell activation, others will interfere at the level of cell-cell interactions for antigen presentation or target recognition. Particular attention will be devoted to the five following steps: a) antigenic presentation, b) the delivery of activation and co-stimulatory signals to T cell precursors, c) T cell polarization towards regulatory T-cell functions including the generation of distinct cytokine-producing phenotypes, d) effector/target contact and, e) apoptosis. Taking advantage of the complementarity of technologies, animals models and biological reagents used in each laboratory, collaboration will be set up with the parallel aim of better understanding the basic mechanisms and potential clinical applications to the treatment of human autoimmune diseases and prevention of organ rejection.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Address
161,Rue De Sfvres 161
75743 Paris
France

Participants (6)

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE
France
Address
Rue Laurent Fries 1
67404 Illkirch Graffenstaden
HELLENIC PASTEUR INSTITUTE
Greece
Address
127,Vassilissis Sofias Av. 127
11521 Athens
Rijksuniversiteit Utrecht
Netherlands
Address
1,Yalelaan
3508 TD Utrecht
Stiftung Deutsches Krebsforschungszentrum
Germany
Address
280,Im Neuenheimer Feld
69009 Heidelberg
THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
United Kingdom
Address
South Parks Road
OX1 3RE Oxford
Université Libre de Bruxelles
Belgium
Address
808,Route De Lennik
1070 Bruxelles