This research proposal and training will both take place at Rockefeller University (RU), located adjacent to New York Hospital-Cornell Medical Center and the Hospital for Special Surgery. The clinical studies will take place in the fully funded RU GCRC. My short term goals in this project are to clearly demonstrate that immune-modulation by thalidomide can affect collagen synthesis in scleroderma patients. My intermediate goals are to show that selective immune enhancement can be associated with clinical benefits in some autoimmune diseases (scleroderma, sarcoidosis). My anticipated long term goals, depending on my interim results, will be to explore the factors leading to individual susceptibility to these autoimmune diseases. The immune disorder scleroderma (SSc), characterized by excessive collagen production, is resistant to immune suppressive therapy. Because SSc is associated with a Th2-type immune response, we hypothesize that an immune-modulatory intervention that causes a shift to a Th1-type immune response may alter collagen biosynthesis and thereby the disease course. We designed patient-based and in vitro studies to test this hypothesis. We will use thalidomide, an immune modulatory drug that stimulates Th1-type cytokine production in vitro and in vivo, to modulate the SSc immune response as well as to induce changes in collagen synthesis in vitro. Specifically, we will 1) establish that there is a Th2-type immune response in specific SSc tissue compartments (plasma, blood cells, skin), and 2) demonstrate the changes in these tissue compartments during thalidomide-induced Th1-type immune stimulation. We will also 3) analyze SSc skin biopsies by immunohistology for cell phenotypes and by quantitative rtPCR for procollagen mRNA expression before and after thalidomide treatment, and 4) use an in vitro collagen biosynthesis model to test the hypothesis that Thl- vs. Th2-type cytokines regulate collagen production. This study will provide new information on SSc immunopathogenesis. The resulting insights may be helpful for understanding the pathogenesis of other autoimmune disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23AR002187-01A1
Application #
6368397
Study Section
Special Emphasis Panel (ZAR1-TAS-B (M1))
Program Officer
Gretz, Elizabeth
Project Start
2001-09-01
Project End
2002-01-31
Budget Start
2001-09-01
Budget End
2002-01-31
Support Year
1
Fiscal Year
2001
Total Cost
$49,798
Indirect Cost
Name
Rockefeller University
Department
Physiology
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
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