Abstract

Current concepts of rheumatoid arthritis (RA) pathogenesis indicate that the disease is not caused by a single genetic defect, infection, or autoimmune reaction, but rather by improper control of host immune, inflammatory, and proliferative responses within the joints. This revised application for a Specialized Center for Research (SCOR) in RA focuses on this central theme. It contains four projects. Each concerns a molecular defect that may contribute to immune dysregulation and pannus formation in RA. Furthermore, each project aims to develop a therapeutic strategy to correct how bacterial and host-derived immunostimulatory DNA sequences can induce normal T1-type immune responses within the joints, and will demonstrate how ISS action might be interrupted therapeutically. Project 2: """"""""The Synovium as an Immune Underprivileged Site"""""""" (Thomas J. Kipps, M.D. PhD. Project Leader) aims to delineate how the proteolytic environment within the joint prevents deletion of activated immune cells, and will devise gene therapeutic strategies to correct the defect. Project 3 """"""""Immune Deviation Induced by Gene Vaccination: Applications to Arthritis"""""""" (Mary P. Corr, M.D. Project Leader) aims to deviate pro-inflammatory Th1 immune responses toward a less inflammatory Th2 phenotype by the creation of an """"""""immunologic window"""""""" through genetic engineering of DNA vaccines. Project 4: """"""""Properties of Shared Epitope-Specific T Cells in RA"""""""" (Salvatore Albani. M.D. Project Leader will discriminate the functional properties of isolated T cells from RA patients that recognize the shared epitope and will explore how pharmacological invention can change their frequency or function. The four projects will be supported by an Administrative Core (Dennis A. Carson, M.D. Director), that will coordinate the research and monitor its progress, and by a centralized Research Resources Core (Gary S. Firestein, M.D. Director), that will collect and distribute patient samples, and provide assistance with the evaluation of animal models. When completed, the experiments proposed in the SCOR will demonstrate how specific molecular abnormalities can promote the development of chronic arthritis, and will describe specific approaches for therapeutic intervention.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center (P50)
Project #
5P50AR044850-03
Application #
6171376
Study Section
Special Emphasis Panel (ZAR1-AAA-C (O2))
Program Officer
Freeman, Julia B
Project Start
1998-09-28
Project End
2003-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
3
Fiscal Year
2000
Total Cost
$1,074,215
Indirect Cost

  Institution

Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093

  Publications

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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