Poster Board III-484
During graft-versus-host disease (GVHD), donor T cells become activated and migrate to tissue sites. Previously, we demonstrated a crucial role for the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) in GVHD regulation. Here, we show that upon arrival in the colon, activated donor T cells produced IFN-γ that upregulated IDO, causing T cell anergy and apoptosis. IDO induces GCN2 kinase, upregulating a T cell stress response implicated in IDO immunosuppression. Donor T cells did not require GCN2 kinase to respond to IDO, suggesting toxic IDO metabolites, and not tryptophan depletion, were responsible for suppression. When exogenous metabolites were administered, GVHD lethality was reduced. To determine if IDO could be induced pre-transplantation for enhanced GVHD suppression, we first determined whether antigen presenting cells (APCs) or epithelial cells were primarily responsible for IDO expression and subsequent GVHD suppression. Recipients with wild-type vs. IDO−/− APCs had increased survival, regardless of epithelial cell expression of IDO, suggesting that APCs were suitable targets for inducing IDO. Administration of an agonist to toll-like receptor (TLR)-7/8, a receptor expressed primarily on APCs, induced IDO and reduced injury in the colon, and ameliorated lethality. We conclude that IDO upregulation may have therapeutic potential for preventing GVHD in the clinic.
Mellor:NewLink Genetics, Inc.: Consultancy, Intellectual property interests in the therapeutic use of IDO and IDO inhibitors and receive consulting income and research support from NewLink Genetics, Inc., Research Funding. Munn:NewLink Genetics, Inc: Consultancy, Intellectual property interests in the therapeutic use of IDO and IDO inhibitors and receive consulting income and research support from NewLink Genetics, Inc, Patents & Royalties, Research Funding.
Asterisk with author names denotes non-ASH members.