Rheumatoid arthritis (RA) is associated with the infiltration into the synovial tissues of monocytes and lymphocytes, and with the excessive proliferation of synovial fibroblasts. The causes of the monocyte migration and fibroblast proliferation are unknown. Epidemiological evidence suggests that both genetic and environmental factors contribute to the disease. Previous experiments from this laboratory have shown (i) that synovial lymphocytes from RA patients have abnormal T cell responses to the dnaJ class of bacterial heat shock proteins, and (ii) that short immunostimulatory DNA sequences (ISS) in these bacteria are potent inducers of interleukin-12 (IL-12) synthesis by monocytes, and stimulate Th1 type immune responses in vivo. Pilot experiments also suggest that DNA with ISS activity is detectable in the synovial fluids of some patients with RA. Based upon these preliminary results, the long-term goals of this component of the SCOR application are to demonstrate how exposure of normal human monocytes and fibroblasts to ISS can cause the cells to assume a phenotype capable of sustaining joint inflammation and proliferation, to characterize the ISS activity in synovial fluids, and to devise a therapy that can block the pro-inflammatory effects of ISS, without impairing general host immunity. The proposed experiments aim to answer the following specific questions: (1) Which cytokines, chemokines, and growth factors are produced by ISS activated blood and synovial monocytes? Are they the same factors that have been implicated in RA pathogenesis? (2) Can ISS stimulate synovial fibroblast proliferation and matrix metalloprotease production, and/or sensitize the fibroblasts to suboptimal concentrations of cytokines and growth factors? Do the ISS effects persist during cell passage? (3) What are the source, structures, and activities of the ISS in the synovial fluids of RA patients? (4) To what extent can immunoinhibitory DNA sequences (IIS) block the pro-inflammatory and proliferative actions of ISS delineated in Aims 1-3? How specific are IIS actions? Are these anti-inflammatory oligodeoxynucleotides active in vivo? When complete, these experiments should reveal a new mechanism for the induction and propagation of RA, and will point to new strategies for the treatment of this disabling disease.
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