- RA is an autoimmune disease with a prevalence of 1% in western Europe and America, but with a variable frequency in other ethnic groups. The genetic susceptibility to develop RA is associated with the human immune response genes HLA-DR4. This association is thought to be due in part to an uncontrolled activation of CD4+ T cells by autoantigenic protein molecules derived from synovial joints. This proposal suggests using HLA-DR trg mice to develop a peptide-based immunomodulatory treatment aiming specifically at controlling this process. HLA-DRB*0401 and *0405 trg mice, both associated with susceptibility to RA, would be used to determine the immunogenic peptide epitopes of human autoantigenic proteins by producing antigen-specific T cell hybridomas after immunization of these mice with the human proteins. Two such human joint proteins, human collagen type II (hCII), a major constituent of synovial cartilage, and human chondrocyte glycoprotein 39 (HCgp39) can induce arthritis in the *0401 trg mouse. Forty percent of RA patients' T cells can respond to HCgp39. The HLA-DR4 trg mouse model could be an important in vivo model for testing new peptide-based immunomodulatory treatments for RA patients. Such peptides could be used to develop a narrow antigen-specific tolerance by inducing anergy or Th1/Th2 skewing, which would be much better tolerated by patients than the often very toxic treatments for RA that we know of.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR044647-04
Application #
6171580
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Gretz, Elizabeth
Project Start
1997-09-30
Project End
2001-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
4
Fiscal Year
2000
Total Cost
$258,496
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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