The role of T cells in sustaining rheumatoid inflammation is incompletely understood. Many findings including the intense T cell infiltration in rheumatoid synovium, evidence of T cell activation, the association of rheumatoid arthritis (RA) with certain HLA-DR molecules, and the amelioration of disease activity with therapies that deplete T cells all argue that T cells are important. In contrast, few synovial T cells express IL2 receptors, synovial T cells do not proliferate of produce IL2 well in culture, and T cell derived cytokines are difficult to detect in the synovial environment. Thus, it has been argued that other cells are responsible for sustaining synovial inflammation. Preliminary data presented in this proposal show that synovial T cells are very effective in providing B cell help although they proliferate or produce IL2 poorly in response to mitogen. Thus, the model to be examined is that """"""""memory"""""""" T cells selectively migrate into synovium, where they differentiate in situ upon exposure to the synovial environment. It is hypothesized that these differentiated T cells produce low T concentrations of T cell cytokines, but support and sustain B cell immunoglobulin production. To examine this hypothesis, the following Specific Aims will be addressed. 1) To compare the functional capabilities of migrating blood T cells and synovial T cells in patients with RA as well as migrating T cells from normal individuals. This will involve study and comparison of the ability of these cells to proliferate in response to mitogens, the ability to produce T cell cytokines, their ability to stimulate B cell immunoglobulin production, and their surface phenotype. 2) To compare the signal-response characteristics of migrating blood T cells and synovial T cells. This will involve study of early biochemical signals generated after mitogen stimulation including the increase in intracellular calcium, inositol phosphate metabolism, and protein phosphorylation. 3) To study the mechanisms inducing the differentiation of migrating T cells into synovial tissue-like T cells. In these studies, T cells will be collected after migration across endothelium in an in vitro model. These cells will then be stimulated by mitogens, antigens, or prostaglandins to induce differentiation into the synovial cell phenotype. The unique aspect of the proposed research is the capacity to obtain cells that are likely candidates to enter the synovium from the blood and to compare them to T cells isolated from synovium. These studies will carefully define the properties of the synovial T cell and will critically test the hypothesis that synovial T cells can sustain chronic inflammation. In addition, these studies may provide important insight into the mechanisms which induce these synovial T cell functions. This will result in greater understanding of the pathogenesis of RA which may lead to the development of new therapeutic modalities.
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