The broad, long-term objective of this proposal is to use autoantibody profiling to guide the selection of DNA tolerizing vaccines for the treatment of an animal model of primary biliary cirrhosis (PBC) called experimental autoimmune cholangitis (EAC). We will test the hypothesis that large-scale, parallel detection of autoantibody profiles can be used to explore epitope spreading, the role played by a subset of inflammatory cytokines in the initiation and propagation of autoimmunity, and ultimately in selection of antigen-specific tolerizing therapies. We will use biochemical, immunological, and molecular biological techniques to validate and extend our ongoing protein array platform in exploring three specific aims in this proposal: (i.) to construct a PBC autoantigen microarray suitable for the identification of human and murine autoantibodies. This array will be used to identify dominant B cell epitopes in the EAC model, and to determine the precise ordering of epitope spreading in EAC. (ii.) to determine whether interleukin-4 (IL-4) and interferon-gamma (IFNy) are required for the development of EAC. An imbalance between Thl and Th2 lymphocytes is thought to play an important role in some autoimmune diseases, and IL-4 and IFN3' represent critical cytokines in the pathogenesis of autoimmunity. (iii.) to employ DNA vaccination to prevent and treat EAC using cDNAs encoding autoantigens identified using protein microarrays developed in the first aim. The results of this proposal will determine the long-term usefulness of the newly described EAC animal model of PBC. Successful treatment of EAC using plasmids encoding prominent autoantigens may herald an era of customized, antigen- or tissue- specific tolerizing therapy in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AR049328-01
Application #
6561923
Study Section
Special Emphasis Panel (ZAR1-RJB-A (O1))
Program Officer
Gretz, Elizabeth
Project Start
2002-09-23
Project End
2004-05-31
Budget Start
2002-09-23
Budget End
2003-05-31
Support Year
1
Fiscal Year
2002
Total Cost
$79,499
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Teo, Pearline Zhaoying; Utz, Paul J; Mollick, Joseph A (2012) Using the allergic immune system to target cancer: activity of IgE antibodies specific for human CD20 and MUC1. Cancer Immunol Immunother 61:2295-309
Kattah, Nicole H; Kattah, Michael G; Utz, Paul J (2010) The U1-snRNP complex: structural properties relating to autoimmune pathogenesis in rheumatic diseases. Immunol Rev 233:126-45
Graham, Kareem L; Lee, Lowen Y; Higgins, John P et al. (2010) Treatment with a toll-like receptor inhibitory GpG oligonucleotide delays and attenuates lupus nephritis in NZB/W mice. Autoimmunity 43:140-55
Thibault, Donna L; Graham, Kareem L; Lee, Lowen Y et al. (2009) Type I interferon receptor controls B-cell expression of nucleic acid-sensing Toll-like receptors and autoantibody production in a murine model of lupus. Arthritis Res Ther 11:R112
Kattah, Michael G; Coller, John; Cheung, Regina K et al. (2008) HIT: a versatile proteomics platform for multianalyte phenotyping of cytokines, intracellular proteins and surface molecules. Nat Med 14:1284-9
Chan, Steven M; Olson, Janelle A; Utz, Paul J (2006) Single-cell analysis of siRNA-mediated gene silencing using multiparameter flow cytometry. Cytometry A 69:59-65
Balboni, Imelda; Chan, Steven M; Kattah, Michael et al. (2006) Multiplexed protein array platforms for analysis of autoimmune diseases. Annu Rev Immunol 24:391-418
Kattah, Michael G; Alemi, Golnaz R; Thibault, Donna L et al. (2006) A new two-color Fab labeling method for autoantigen protein microarrays. Nat Methods 3:745-51
Paniagua, Ricardo T; Sharpe, Orr; Ho, Peggy P et al. (2006) Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis. J Clin Invest 116:2633-42
Graham, Kareem L; Vaysberg, Maria; Kuo, Annie et al. (2006) Autoantigen arrays for multiplex analysis of antibody isotypes. Proteomics 6:5720-4

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