DC- Tcell interaction in CIA

Rheumatoid arthritis (RA) represents a chronic inflammatory disease which appears to depend on immunlogically mediated events. The critical interaction initiating and perhaps perpetuating RA is the presentation of unknown arthritogenic antigen(s) to autoreactive T cells. Although the target auto-antigen(s) for disease initiation or maintenance of RA in man remain unknown, candidate RA auto-antigens, among those type II collagen, have been identified. Dendritic cells (DC) represent most potent antigen presenting cells that seem to crucially involved in both, self-tolerance towards tissue auto-antigens as well as in the initiation and perpetuation of autoimmune responses. For RA, however, little is known about the anatomical location and sequence of events for self-antigen presentation and priming of auto-reactive T cells, e.g. the role of secondary lymphoid structures vs. the synovial tissue as site of inflammation and tissue destruction. We therefore plan to analyze DC - T cell interactions in the murine model of collagen-induced arthritis (CIA) both in vitro and in vivo. A more detailed knowledge about the sequential events during self-antigen presentation in CIA will provide the basis for specifically designed therapeutic approaches. In particular we consider the use of cell based therapies such as regulatory (CD4+CD25+) T cells, or tolerogenic immature DC that have been shown to actively interfere with pathogeneic mechanism of inflammatory diseases as a novel promising, curative approach.

Rheumatoid arthritis (RA) represents a chronic inflammatory disease which appears to depend on immunologically mediated events. Critical for the initiation and perhaps perpetuation of RA is the presentation of unknown arthritogenic antigen(s) to autoreactive T cells by professional antigen presenting cells (APC). The question, which type of APC is responsible for the presentation of autoantigen(s) and the subsequent activation of autoreative T cells in RA, is still under debate. In addition, our knowledge concerning the specific site of antigen presentation and the spatio-temporal sequence of events during self-antigen presentation and T cell priming in RA is limited. Thus, the aim of this project was to define the major APC type involved in RA using the murine collagen-induced arthritis (CIA) model and to analyze the spatio-temporal interaction of T cells and antigen presenting cells (APC). Phenotypic analysis of the joint draining (dr) lymph nodes (LN) in comparison to non-draining (non-dr) LN by flow cytometry revealed a signifcant on average 1.6-fold increases in absolute cell numbers in drLN as compard to non-drLN or spleen 10 weeks post immunization. This was mainly due to an increase in activated B cells and to a lesser extent in dendritic cells (DC) and monocytes. DC in the drLN, on the other hand, displayes phenoypic characteristics of an immunosuppressive DC subset. Immunofluorescence analysis of cryo-sections of LN and spleen in addition revealed active B cell migration in the drLN. In summary our study demonstrates a prominent role of tissue draining lymphoid organs in the immunopathogenesis of CIA where B cells and monocytes seem to play a prominent role in the inflammatory process. New techniques were developed in the course of this study and will allow to perform similar investigations of the inflamed synovial tissue in parallel. These studies will help to further clarify the interaction between tissue- draining secondary lymphoid organs and the target synovial tissue in RA.