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The immunopathology of T cell-induced chronic inflammatory bowel disease

Objective

- To determine the phenotype, cytokine profile, antigen receptor repertoire and cell cycle kinetics of T cells infiltrating epithelial and lamina propria compartments of the lesion.
- To investigate the antigen processing and presentation capacity of macrophages and dendritic cells in the lesion.
- To study the involvement of cytokines in the induction and maintenance of the lesion.
- To investigate the role of B cells (immunoglobulin isotype secretion and switch), antibodies and complement in initiating and sustaining the lesion.
- To investigate intestinal epithelial cells (MHC class II expression, antigen uptake, antigen processing, macromolecular permeation).
- New therapeutic approaches (cytokine substitution, antibodies, adoptive cell transfer) for control of this disease will be tested.

Despite extensive research over several decades, the aetiologic agents and the events initiating and sustaining chronic inflammatory responses in the gut (chronic inflammatory bowel disease (IBD)), remain largely unknown. Recently a new murine model for inflammatory bowel disease (IBD) was developed in which disease development can be initiated by transplantation of limited numbers of purified CD4+ T lymphocytes into severe combined immuno deficient (scid) mice which lack immuno- competent T and B cells. Using this adoptive T cell transfer model it is now for the first time possible to analyze the individual cellular and humoral components of the immune system which initiate and sustain the pathological changes leading to the chronical inflammatory pathology of IBD. The present proposal aims to analyze these components: main research topics are mucosa infiltrating T cells (T cell receptor repertoire, lymphokine profiles, cell cycle status), B cells (immunoglobulin isotype secretion and switch), macrophages (monokine profiles) and intestinal epithelial cells (MHC class I expression, antigen uptake, antigen processing, macromolecular permeability). Examinations of the mucosal immune system in scid mice will clarify whether their colitis represents a useful model for human IBD. New therapeutic approaches (cytokine substitution, antibodies, adoptive cell transfer) for control of this disease will be tested. This model might also prove informative for the pathogenesis of the other chronic inflammatory responses mentioned above.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Københavns Universitet
Address
3,Blegdamsvej
2200 København
Denmark

Participants (3)

University of Bristol
University of Göteborg
Sweden
Address

413 45 Gøteborg
Universität Ulm
Germany
Address
8,Robert-koch-straße
89081 Ulm