My career goal is to develop treatments for patients with devastating clinical immune disorders. During the time of this award, with Dr. Lawrence Steinman as my mentor I propose to develop selective immune therapy for an animal model of rheumatoid arthritis (RA). RA is a chronic autoimmune inflammatory synovitis affecting 1 percent of the world population. Using collagen-induced arthritis (CIA) in mice as a model for RA and DNA vaccination as a tool for generating and modulating immune responses, I propose to answer several questions pertaining to therapeutic immunization against CIA. I will also develop and study peptide pulsed peripheral monocytes for therapy of CIA and autoimmunity. I will address the following specific aims: (1) Can we protect against CIA by injection of DNA encoding: (a) the Vbeta8.2 region of the T-cell receptor, (b) collagen or collagen peptide, and (c) tandem DNA constructs encoding collagen, collagen peptide, or Vbeta8 TCR plus Th2 promoting cytokines including IL-4, IL-10, and TGF-beta? (2) We will examine the mechanisms of DNA vaccine-mediated protection against CIA using (a) cytokine assays, (b) flow cytometry, (c) soluble tetrameric major histocompatibility complex class II-peptide complexes, (d) T cell proliferation assays, (e) bone marrow chimeric mice, and (f) DNA microarrays. (3) Can we protect against CIA by injection of collagen peptide pulsed peripheral monocytes? These experiments will be carried out at the Stanford University Beckman Center. During the course of the proposed award period the candidate will continue to practice clinical Rheumatology on a 10 percent basis and take formal coursework in immunology and the ethical conduct of research. The overall goal of the proposed training program is to prepare this candidate to establish an independent laboratory in an academic division of Rheumatology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AR002133-02
Application #
6374338
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Gretz, Elizabeth
Project Start
2000-09-30
Project End
2005-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
2
Fiscal Year
2001
Total Cost
$113,292
Indirect Cost
Name
Stanford University
Department
Neurology
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Günther, Claudia; Kind, Barbara; Reijns, Martin A M et al. (2015) Defective removal of ribonucleotides from DNA promotes systemic autoimmunity. J Clin Invest 125:413-24
Hueber, Wolfgang; Tomooka, Beren H; Zhao, Xiaoyan et al. (2007) Proteomic analysis of secreted proteins in early rheumatoid arthritis: anti-citrulline autoreactivity is associated with up regulation of proinflammatory cytokines. Ann Rheum Dis 66:712-9
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
Kanter, Jennifer L; Narayana, Sirisha; Ho, Peggy P et al. (2006) Lipid microarrays identify key mediators of autoimmune brain inflammation. Nat Med 12:138-43
Robinson, William H (2006) Antigen arrays for antibody profiling. Curr Opin Chem Biol 10:67-72
Ho, Peggy P; Higgins, John P; Kidd, Brian A et al. (2006) Tolerizing DNA vaccines for autoimmune arthritis. Autoimmunity 39:675-82
Weng, Kevin C; Kanter, Jennifer L; Robinson, William H et al. (2006) Fluid supported lipid bilayers containing monosialoganglioside GM1: a QCM-D and FRAP study. Colloids Surf B Biointerfaces 50:76-84
Hueber, Wolfgang; Kidd, Brian A; Tomooka, Beren H et al. (2005) Antigen microarray profiling of autoantibodies in rheumatoid arthritis. Arthritis Rheum 52:2645-55
Ho, Peggy P; Fontoura, Paulo; Platten, Michael et al. (2005) A suppressive oligodeoxynucleotide enhances the efficacy of myelin cocktail/IL-4-tolerizing DNA vaccination and treats autoimmune disease. J Immunol 175:6226-34
Hueber, Wolfgang; Zeng, Defu; Sharpe, Orr et al. (2004) Characterization of novel antigens recognized by serum autoantibodies from anti-CD1 TCR-transgenic lupus mice. Eur J Immunol 34:1654-62

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