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.
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