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Mechanisms of selective immunosuppressive effects of indoleamine 2, 3-dioxygenase and borrelidin

University of British Columbia

Indoleamine 2, 3-dioxygenase (IDO), a tryptophan degrading enzyme, is a potent immunomodulatory factor that has been considered as a promising candidate in down-regulating alloimmune responses. IDO expression generates a tryptophan-deficient environment that selectively induces apoptosis in immune cells but not in primary skin cells. However, the mechanism(s) underlying these selective effects of IDO is not elucidated. In this doctoral research project, we hypothesize that different sensitivity of immune cells versus skin cells to IDO-induced tryptophan-deficient environment is due to the differential activity of general control non-derepressible-2 (GCN2) kinase stress-responsive pathway and its inhibitor, protein IMPACT homolog, in these cells. Considering the selective effect of tryptophan-deficiency on immune cells, we also proposed that borrelidin, a small molecule agent that mimics the effects of amino acid deprivation, may provide potential therapy for acute lymphoblastic leukemia (ALL) via its selective apoptotic effects. To this end, we investigated whether borrelidin selectively inhibits the proliferation of malignant ALL cell lines and studied the mechanism by which this drug acts. Three specific objectives were accomplished in this study. We first showed that in the presence of IDO, higher activation of GCN2 in immune cells leads to apoptosis and is due to the very low or undetectable expression of IMPACT in these cells. Our gain- and loss-of-function findings suggest that high expression of IMPACT in non-immune cells acts as a protective mechanism against IDO-induced apoptosis. In the next phase, in order to stably express IDO in grafts to prolong their survival, a pure population of IDO-expressing bystander fibroblasts was generated using two simple yet effective lentiviral-based approaches. Finally, borrelidin was used as a novel strategy in treating ALL. We showed that borrelidin treatment potently and selectively inhibits proliferation, induces apoptosis and mediates G₁ arrest in ALL cell lines and that borrelidin treatment in these cells is correlated with activation of the GCN2 pathway. The findings presented in this thesis collectively demonstrate the mechanism of IDO action and pave the way towards application of IDO as an immunosuppressive factor in development of long-lasting non-rejectable allografts. Our findings also reveal the potential application of borrelidin in treating ALL.

Text

2011-08-15

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/36674

Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/