- Rheumatoid arthritis and related animal models are inflammatory diseases of the joints mediated by activated synovial cells and infiltrating bone marrow-derived cells. The long-term goal of research of the investigators is to eradicate the arthritic inflammation by somatic gene transfer. They hypothesize that intra-articular Fas-ligand gene transfer may convert an otherwise inflammatory joint into an immune privileged organ by inducing apoptosis of activated synovial cells and by deleting antigen-specific lymphocytes. To test this hypothesis they have developed four specific aims: 1). To study Fas-mediated apoptosis in the arthritic synovium following adenoviral vector-mediated FasL gene transfer. The kinetics of apoptosis of both fibroblast-like synoviocytes and bone marrow-derived synovial cells will be studied; 2) to determine the frequencies and functions of collagen-specific lymphocytes in arthritic animals injected with FasL virus. Intra-articular expression of FasL may induce type II collagen-specific immune tolerance by selectively depleting collagen-specific lymphocytes. Thus, intra-articular injection of FasL virus may prevent the development of arthritis in other joints. This will be investigated by determining the frequencies and functions of collagen-specific TH1, TH2 and B cells in and outside of the arthritic synovium; 3) to determine the frequencies and functions of vector-specific lymphocytes in arthritic animals injected with FasL virus. Intra-articular FasL gene transfer may also induce apoptosis of vector-specific lymphocytes and help diminish the immune barrier impeding viral vector-mediated gene therapy. This will be investigated by examining the frequencies and functions of vector-specific lymphocytes in and outside of the arthritis joints and by monitoring the lengths and levels of transgene expression in vivo; 4) to study FasL gene transfer in spontaneous autoimmune arthritis. If FasL gene transfer eliminates activated synovial cells that mediate arthritic inflammation, it should be effective in diminishing arthritis regardless of its etiology or initiating antigens so long as the disease is mediated by activated synovial cells expressing the Fas molecule. To test this theory, they will study FasL gene therapy in a spontaneous arthritis model in which systemic autoimmunity leads to joint-specific inflammation. Information generated from these studies may help elucidate the mechanisms by which FasL gene transfer diminishes autoimmune arthritis and may lead to the development of a novel strategy for treatment of autoimmune arthritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR044914-01
Application #
2454518
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1998-04-01
Project End
2002-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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