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UBC Theses and Dissertations

Borrelidin, a threonyl-tRNA synthetase inhibitor, is a potent immunosuppressive and anti-inflammatory agent Ogloff, Nadya

Abstract

Excessive or dysregulated immune responses require clinical intervention to prevent tissue damage and organ dysfunction. Unfortunately, many of these clinical interventions have undesired side effects; therefore, development of novel therapeutic agents with different mechanisms of action would be immensely beneficial. Mounting evidence in in vitro and in vivo studies implicate amino acid deprivation (AAD) as a key natural mechanism by which the body regulates immune responses and suppresses immune cell activation and function. However, the role of aminoacyl-tRNA synthetase (aaRS) inhibitors in regulating immune responses is largely unknown. Since inhibitors of aaRSs limit the cell’s availability to specific amino acids and thereby creating an amino acid limiting environment, a deeper investigation of aaRS inhibitorinduced amino acid deprivation and its ability to regulate immune cell function is needed. We hypothesized that aminoacyl tRNA synthetase inhibitors might represent a novel class of immunosuppressive and/or anti-inflammatory agents that act as pharmacomimetics of amino acid deprivation. Two specific aims were accomplished in this study. We first showed that borrelidin is a potent inhibitor of T-cell proliferation, activation and cytokine production. As compared with other primary cells and cell lines, we determined borrelidin is most effective at suppressing Tcells. We then showed borrelidin potently suppresses lipopolysaccharide (LPS) induced- release of inflammatory cytokines such as TNF alpha (TNFα) from primary splenocytes and suppression of TNFα occurs at the level of protein synthesis. In both T-cells and macrophages, intracellular staining and flow cytometry identified that borrelidin promotes activation of the general control non-derepressible 2 (GCN2) stress response pathway and inhibition of the mammalian target of rapamycin (mTOR) pathway. iii The findings presented in this thesis collectively demonstrate that borrelidin is a potent immunosuppressive and anti-inflammatory agent. These findings help us to better understand the role of aminoacyl-tRNA synthetase inhibitors in regulating immune function.

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