The perpetuation of rheumatoid synovitis will be studied in the context of an autologous mixed lymphocyte reaction (AMLR) model. We have recently observed a similarity between the lymphokines produced in the AMLR and in the rheumatoid joint: Both show IL-3 like activity (defined by mast cell growth factor (MCGF), colony stimulating factor (CSF), and stimulation of IL-3 dependent cell lines) and both contain low amounts of IL-2 and IFN-gamma. The relatively restricted lymphokine profiles of these two situations suggest that they may share a similar pathogenesis. Studies of lymphokines secreted into synovial fluid or into medium in an AMLR are complicated by the presence of inhibitors, local degradation, and absorption. Therefore, we propose to study the production of lymphokines in these two systems at the mRNA level. Messenger RNA levels of various cytokines in RA synovium and in AMLR cells will be measured using riboprobe protection assays. In addition, in situ hybridization will be performed on AMLR cells and tissue sections of rheumatoid synovium to determine the phenotype and local environment of cytokine secreting cells in the joint. These studies will also be extended to other forms of chronic inflammatory arthritis. In addition, the unique IL-3 like activity produced in the inflamed joint will be characterized. Preliminary data has already shown that at least two factors are responsible for the activity (i.e. MCGF and CSF), and that these factors are distinct from IL -3. We plan to identify and clone those activities from a human synovial cDNA library.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AR039576-04
Application #
3457111
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1988-07-01
Project End
1992-03-02
Budget Start
1991-07-01
Budget End
1992-03-02
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Firestein, G S; Boyle, D L; Yu, C et al. (1994) Synovial interleukin-1 receptor antagonist and interleukin-1 balance in rheumatoid arthritis. Arthritis Rheum 37:644-52
Elices, M J; Tsai, V; Strahl, D et al. (1994) Expression and functional significance of alternatively spliced CS1 fibronectin in rheumatoid arthritis microvasculature. J Clin Invest 93:405-16
Firestein, G S; Paine, M M; Boyle, D L (1994) Mechanisms of methotrexate action in rheumatoid arthritis. Selective decrease in synovial collagenase gene expression. Arthritis Rheum 37:193-200
Alvaro-Gracia, J M; Yu, C; Zvaifler, N J et al. (1993) Mutual antagonism between interferon-gamma and tumor necrosis factor-alpha on fibroblast-like synoviocytes: paradoxical induction of IFN-gamma and TNF-alpha receptor expression. J Clin Immunol 13:212-8
Morales-Ducret, J; Wayner, E; Elices, M J et al. (1992) Alpha 4/beta 1 integrin (VLA-4) ligands in arthritis. Vascular cell adhesion molecule-1 expression in synovium and on fibroblast-like synoviocytes. J Immunol 149:1424-31
Broide, D H; Paine, M M; Firestein, G S (1992) Eosinophils express interleukin 5 and granulocyte macrophage-colony-stimulating factor mRNA at sites of allergic inflammation in asthmatics. J Clin Invest 90:1414-24
Firestein, G S; Paine, M M (1992) Stromelysin and tissue inhibitor of metalloproteinases gene expression in rheumatoid arthritis synovium. Am J Pathol 140:1309-14
Tsai, V; Firestein, G S; Arend, W et al. (1992) Cytokine-induced differentiation of cultured nonadherent macrophages. Cell Immunol 144:203-16
Firestein, G S; Berger, A E; Tracey, D E et al. (1992) IL-1 receptor antagonist protein production and gene expression in rheumatoid arthritis and osteoarthritis synovium. J Immunol 149:1054-62
Broide, D H; Firestein, G S (1991) Endobronchial allergen challenge in asthma. Demonstration of cellular source of granulocyte macrophage colony-stimulating factor by in situ hybridization. J Clin Invest 88:1048-53

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