T cell targeted interventions for experimental autoimmunity

Ariana Barbera Betancourt

    Research output: ThesisDoctoral thesis 2 (Research NOT UU / Graduation UU)

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    Abstract

    Autoimmune diseases are chronic conditions caused by a loss of tolerance to self-antigens due to inappropriate activation of the immune system. Rheumatoid arthritis (RA) is a chronic inflammatory disease where the inadequate activation of T cells with pro-inflammatory characteristics leads to synovial hyperplasia and joint inflammation. In spite of excellent results in patients responding to biological therapies approved for the treatment of these patients, only partial responses have been achieved and a continuous treatment is required. In the case of type 1 diabetes (T1D), no drugs have been approved to halt the autoimmune process that causes the destruction of insulin producing β cells. There is an increasing understanding that pro-inflammatory responses directed to self-antigens become chronic in autoimmune diseases because regulatory mechanisms fail to control them. As autoimmune disorders are T-cell driven, therapies that initiate the deletion of effector T (Teff) cells, skew their pro-inflammatory profile or induce a regulatory phenotype in auto-antigen specific T cells, seem promising. The research described in this thesis focuses on two approaches aimed to restore a proper balance between pathogenic and regulatory T cells in the context of two autoimmune diseases. The first part describes the regulatory properties of a peptide from heat shock protein of 60 kDa (HSP-60) in the context of RA. The second part focuses on the effect of the pharmacological inhibition of p110δ alone or in combination with abatacept to restore the balance between diabetogenic and regulatory T cells in the context of T1D. P110δ is the main phosphoinositide 3-kinases (PI3K) isoform expressed in leukocytes that triggers antigen-specific immune responses. These enzymes have the ability to control essential functions for cells like: proliferation, differentiation, growth, survival and intracellular trafficking.
    Original languageEnglish
    Awarding Institution
    • Utrecht University
    Supervisors/Advisors
    • van Eden, Willem, Primary supervisor
    • Broere, Femke, Co-supervisor
    • van Roon, Joel, Co-supervisor, External person
    Award date26 Sept 2017
    Publisher
    Publication statusPublished - 26 Sept 2017

    Keywords

    • Autoimmune diseases
    • T cells
    • bystander suppression
    • heat shock proteins
    • p110δ

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