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Thesis Wei_v8.pdf (10.71 MB)

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TARGETING DENDRITIC CELL METABOLISM TO INDUCE IMMUNE TOLERANCE

Wei, Hsi-Ju
http://rave.ohiolink.edu/etdc/view?acc_num=case1538497998943838

Abstract Details

2019, Doctor of Philosophy, Case Western Reserve University, Biochemistry.
Tolerogenic dendritic cells (TolDCs) are actively involved in the elimination of autoreactive T cells in the thymus and quench T cell responses to self-antigens in the periphery under steady state. Normal dendritic cell (DC) maturation is influenced by both the inflammatory milieu and foreign antigens, and is required to generate an immunogenic response. These immunogenic DCs then interact with T and B cells to assist in antibody production. An imbalance between TolDCs and immunogenic DCs may instigate the development of autoimmunity and therefore, TolDCs have emerged as an expedient therapeutic target to manage autoimmunity. Although there is enough scientific evidence available depicting the development and functional utility of TolDCs in preclinical models of autoimmunity, in the absence of a more thorough understanding of TolDC biology their clinical use remains limited. This research work explores the immunomodulatory functions of TolDCs and the discovery of new possible therapeutic targets for the treatment of autoimmunity and provide three major insights. First, the protocol that we established in this thesis will help investigators to evaluate the capacity of new agents to promote the induction of TolDCs and to facilitate the effort to broaden the scope of TolDC therapeutics. Second, our data reveal that DCs are one of the principal cellular mediators of the immunomodulatory responses to the synthetic triterpenoid, CDDO-DFPA, and to related small molecules in the triterpenoid family for which we have shown efficacy in the preclinical model of multiple sclerosis. Third, we report that Nrf2 regulates DC tolerance by modulating their cytokine profile and cellular metabolism. Lastly our data show the therapeutic relevance of targeting Nrf2 signaling in the context of autoimmune disease. These data include analyses of Nrf2 function in preclinical models of multiple sclerosis (MS) and aplastic anemia (AA), and analyses of clinical specimens from patients with aplastic anemia, and together they help to further establish the therapeutic utility of TolDCs in managing clinical manifestations of these diseases. Overall, this is the first systematic research report revealing the Nrf2-dependent mechanisms of DC metabolic reprograming to generate tolerance and highlight their potential therapeutic utility in the treatment of autoimmunity.
John Letterio (Advisor)
Alex Huang (Committee Member)
Martin Snider (Committee Member)
Focco van den Akker (Committee Member)
Hung-Ying Kao (Committee Chair)
231 p.
Cellular Biology; Immunology; Medicine; Molecular Biology
Tolerogenic Dendritic Cells; Autoimmunity; Triterpenoids; Metabolism; Nrf2; Experimental Autoimmune Encephalomyelitis; Aplastic anemia;

Recommended Citations

Citations

  • Wei, H.-J. (2019). TARGETING DENDRITIC CELL METABOLISM TO INDUCE IMMUNE TOLERANCE [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1538497998943838

    APA Style (7th edition)

  • Wei, Hsi-Ju. TARGETING DENDRITIC CELL METABOLISM TO INDUCE IMMUNE TOLERANCE. 2019. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1538497998943838.

    MLA Style (8th edition)

  • Wei, Hsi-Ju. "TARGETING DENDRITIC CELL METABOLISM TO INDUCE IMMUNE TOLERANCE." Doctoral dissertation, Case Western Reserve University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1538497998943838

    Chicago Manual of Style (17th edition)

case1538497998943838
184
© 2018, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.