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.

Project Start
2001-09-01
Project End
2002-08-31
Budget Start
Budget End
Support Year
4
Fiscal Year
2001
Total Cost
$150,001
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Wu, Christina C N; Hayashi, Tomoko; Takabayashi, Kenji et al. (2007) Immunotherapeutic activity of a conjugate of a Toll-like receptor 7 ligand. Proc Natl Acad Sci U S A 104:3990-5
Albani, Salvatore; Prakken, Berent (2006) T cell epitope-specific immune therapy for rheumatic diseases. Arthritis Rheum 54:19-25
Holderbaum, D; Malvitz, T; Ciesielski, C J et al. (2005) A newly described hereditary cartilage debonding syndrome. Arthritis Rheum 52:3300-4
Giannoni, Francesca; Barnett, Joellen; Bi, Kun et al. (2005) Clustering of T cell ligands on artificial APC membranes influences T cell activation and protein kinase C theta translocation to the T cell plasma membrane. J Immunol 174:3204-11
Prakken, Berent J; Samodal, Rodrigo; Le, Tho D et al. (2004) Epitope-specific immunotherapy induces immune deviation of proinflammatory T cells in rheumatoid arthritis. Proc Natl Acad Sci U S A 101:4228-33
de Kleer, Isme M; Wedderburn, Lucy R; Taams, Leonie S et al. (2004) CD4+CD25bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis. J Immunol 172:6435-43
Lu, Desheng; Zhao, Yandong; Tawatao, Rommel et al. (2004) Activation of the Wnt signaling pathway in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 101:3118-23
Sen, Malini; Cheng, Yu-Ho; Goldring, Mary B et al. (2004) WISP3-dependent regulation of type II collagen and aggrecan production in chondrocytes. Arthritis Rheum 50:488-97
Wu, Christina C N; Lee, Jongdae; Raz, Eyal et al. (2004) Necessity of oligonucleotide aggregation for toll-like receptor 9 activation. J Biol Chem 279:33071-8
Leake, John A D; Albani, Salvatore; Kao, Annie S et al. (2004) Acute disseminated encephalomyelitis in childhood: epidemiologic, clinical and laboratory features. Pediatr Infect Dis J 23:756-64

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