Hematopoietic stem cell transplant is the only curative therapy for a variety of malignant and non-malignant hematologic disorders and has the potential to treat a variety of other difficult diseases. Unfortunately, the procedure carries a high risk of graft versus host disease (GVHD), limiting its efficacy and wider application. GVHD occurs when antigen disparity between donor and host leads donor T cells to become activated and proliferate. They then migrate to the liver, skin, lung, and gut and mediate tissue damage. By uncovering the positive and negative regulatory pathways in GVHD biology, new therapeutic targets can be identified. Data presented here establishes indoleamine 2,3-dioxygenase (IDO), an immunosuppressive enzyme in the tryptophan metabolism pathway, as a major regulator of GVHD. IDO-deficient recipients of bone marrow transplant suffered accelerated GVHD lethality, with pathology concentrated in the colon. IFN-γ produced by donor T cells highly upregulated colon IDO; in its absence, donor T cells underwent more proliferation and less apoptosis, leading to increased disease severity and lethality. Tryptophan depletion was not central to these effects, as T cells lacking the sensor for tryptophan were suppressed by IDO. Accordingly, treatment of transplant recipients with kynurenines, the downstream metabolites of tryptophan breakdown, ameliorated disease. IDO expressed by antigen presenting cells (APCs) was responsible for its T cell suppressive effects. By targeting APCs using a TLR agonist, IDO could be upregulated in the colon before transplantation, and this upregulation was sufficient to diminish GVHD. This work identifies IDO as a potent modulator of GVHD. This finding is then used to develop two clinically relevant therapeutic strategies for GVHD treatment and prevention.
University of Minnesota Ph.D. dissertation. June 2009. Major: Microbiology, Immunology and Cancer Biology. Advisor: Bruce Blazar. 1 computer file (PDF); x, 124 pages.
Jasperson, Lisa Kristine.
Indoleamine 2,3-dioxygenase: a potent regulator of graft versus host disease with potential therapeutic applications..
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