PBC is an autoimmune liver disease characterized by obstruction of intrahepatic bile ducts and high titer antimitochondrial autoantibodies (AMA). The predominant autoantigen is PDC-E2. It has been demonstrated that a single dominant epitope within the mitochondrial autoantigens is engaged by both autoantibodies and autoreactive CD4+ helper T cells. In addition, precursors to autoreactive T cells to PDC-E2 are found at 100-150 fold higher frequency in target tissues (liver) than in PBMC. While there are likely multiple pathways of destruction of biliary ductules, this application will focus on the role of CD8+ T cells in PBC. Considerable advances have been made on the identification of the epitopes and fragments of the major autoantigens of PBC that are the target of humoral responses and CD4+ T cells, however, relatively little is known with regard to CD8+ responses. This takes on additional significance as PBC is characterized by extensive CD8+ infiltrates, the mitochondrial autoantigens are intracellularly localized, and the lysis of BECs in situ. Moreover, recent pilot data shows a marked increase in the frequency of PDC-E2 spectflc CD8+ T cells in the PBMC of patients with PBC as determined by an ICC assay and pCTL frequency analysis. Thus, our hypothests is that CD8+ T cells play a role in the pathogenesis of PBC. To more cleady define this role, we propose that i) identification of the autoantigen-specific epitopes recognized by MHC class I restricted CD8+ T cells in PBC; ii) determination of the precursor frequency of PDC-E2-specific CD8+ CTL in patients with PBC compared to controls, and using MHC class I tetramers, examining whether these frequencies change with stage of disease; and iii) the definition of differential responses of T cells to altered peptide ligands to identify disease-specific immune therapeutic reagents will accomplish this goal.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AI056670-03
Application #
7051449
Study Section
Special Emphasis Panel (ZRG1-MBC-1 (29))
Program Officer
Hernandez, Milton J
Project Start
2004-04-01
Project End
2007-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
3
Fiscal Year
2006
Total Cost
$27,744
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Foreman, Angela L; Lemercier, Brigitte; Lim, Annick et al. (2008) VH gene usage and CDR3 analysis of B cell receptor in the peripheral blood of patients with PBC. Autoimmunity 41:80-6