: Novel approaches for treatment of autoimmune diseases are emerging, as we better understand the molecular mechanisms of autoimmunity. A shift from nonspecific treatment with associated toxicity to specific, targeted molecular therapies is sorely needed. Our therapeutic approach focuses on targeting the IgG protection receptor FcRn, which plays a very restricted role in immune system. We believe that the blockade of FcRn-mediated protection will have a substantial effect on antibody responses, IgG homeostasis, and the modulation of autoimmune diseases with autoantibody etiology. To facilitate the extrapolation to humans, we will use humanized mouse models for therapeutic evaluation. Our experimental design is to first test potential therapeutic approaches for their ability to inhibit the binding of IgG to the human (hu) huFcRn in vitro. We will then test them in vivo in mice that lack mouse FcRn but transgenically co-express huFcRn and hu?2m. Our long-term goal is to determine whether we can use the same therapeutic approaches to ameliorate arthritis and systemic lupus erythematosus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AR049695-01
Application #
6584997
Study Section
Special Emphasis Panel (ZRG1-F07 (20))
Program Officer
Gretz, Elizabeth
Project Start
2003-02-01
Project End
2005-01-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
1
Fiscal Year
2003
Total Cost
$49,864
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Petkova, Stefka B; Konstantinov, Konstantin N; Sproule, Thomas J et al. (2006) Human antibodies induce arthritis in mice deficient in the low-affinity inhibitory IgG receptor Fc gamma RIIB. J Exp Med 203:275-80
Petkova, Stefka B; Akilesh, Shreeram; Sproule, Thomas J et al. (2006) Enhanced half-life of genetically engineered human IgG1 antibodies in a humanized FcRn mouse model: potential application in humorally mediated autoimmune disease. Int Immunol 18:1759-69
Akilesh, Shreeram; Petkova, Stefka; Sproule, Thomas J et al. (2004) The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease. J Clin Invest 113:1328-33