Control of neuritogenic activity of PNS-specific T cells by antigen recognition and costimulation in transgenic mouse models
Project management at the University of Würzburg:
Experimental autoimmune neuritis (EAN), an animal model for the human Guillain-Barre Syndrome, is induced in rodents by immunization with peripheral nerve antigens such as P2 and P0. The model was largely developed in the rat, where T cell infiltration, inflammation and termination of the response by T cell apoptosis have been demonstrated. For a better understanding of the mechanisms underlying these different phases of EAN we plan to make use of the more advanced transgenic tools of the mouse system.A PNS-specific expression vector for the model antigen ovalbumin (OVA) has been constructed and is currently being introduced into the C57BL/6 mouse strain. T cell receptor-transgenic mouse lines expressing MHC class I and class II-restricted OVA-specific antigen receptors (OTI and OTII) will be used as a source of PNS-specific autoreactive cells in adoptive transfer experiments. The relative contribution of CD4 and CD8 T cells in the initiation and propagation of disease will thus be studied; modulation of autoreactivity by immunization with agonistic and antagonistic peptides will provide a model for the evaluation of antigen-based immunotherapy. In parallel, the role of costimulatory signals in the initiation and propagation of the inflammatory response will be investigated. Initially, non-transgenic C57BL/6 mice will be treated with monoclonal antibodies to CD28 and its ligands of the B7 family including CTLA-4. These observations will later be extended in the relevant knock out strains. The cytokine IL-2 has a dual role as a costimulating and an apoptosis-sensitizing factor involved in the termination of immune responses. The effect of IL-2 deficiency on the development of EAN will be studied in adoptive transfer experiments using IL-2 deficient mice expressing transgenic OTI and OTII receptors. These mice have been generated and are currently being characterized.We expect new insights into the initiation, propagation and termination of organ-specific autoimmunity and an assessment of the feasibility to interfere with the disease at the levels of antigen recognition and costimulation. Furthermore, susceptibility factors for glia cells and myelinated axons in the peripheral nervous system shall be characterized. This project is part of the IZKF's efforts to contribute to a better understanding and management of autoimmune diseases.
Projekt period: from 05.1999 to 04.2004
Sondermittel Land Bayern ,Granting date: 28.03.2002