title: 3-hydroxykynurenine suppresses CD4+ T-cell proliferation, induces T-regulatory-cell development, and prolongs corneal allograft survival.
abstract: OBJECTIVE
  IDO (indoleamine 2,3-dioxygenase) modulates the immune response by depletion of the essential amino acid tryptophan, and IDO overexpression has been shown to prolong corneal allograft survival. This study was conducted to examine the effect of kynurenines, the products of tryptophan breakdown and known to act directly on T lymphocytes, on corneal graft survival.
  
  
  METHODS
  The effects of kynurenines on T-cell proliferation and death, T-regulatory-cell development, and dendritic cell function, phenotype, and viability were analyzed in vitro. The effect of topical and systemic administration of 3-hydroxykynurenine (3HK) on orthotopic murine corneal allograft survival was examined.
  
  
  RESULTS
  T-lymphocyte proliferation was inhibited by two of the four different kynurenines: 3HK and 3-hydroxyanthranilic acid (3HAA). This effect was accompanied by significant T-cell death. Neither 3HK nor 3HAA altered dendritic cell function, nor did they induce apoptosis or pathogenicity to corneal endothelial cells. Administration of systemic and topical 3HK to mice receiving a fully mismatched corneal graft resulted in significant prolongation of graft survival (median survival of control grafts, 12 days; of treated, 19 and 15 days, respectively; P < 0.0003). While systemic administration of 3HK was associated with a significant depletion of CD4(+) T, CD8(+) T, and B lymphocytes in peripheral blood, no depletion was found after topical administration.
  
  
  CONCLUSIONS
  The production of kynurenines, in particular 3HK and 3HAA, may be one mechanism (in addition to tryptophan depletion) by which IDO prolongs graft survival. These molecules have potential as specific agents for preventing allograft rejection in patients at high rejection risk.
authors.affiliation: Department of Immunology, Division of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Zaher
authors.forename: Conrad
authors.initials: C
authors.lastname: Germain
authors.forename: Hongmei
authors.initials: H
authors.lastname: Fu
authors.forename: Daniel F P
authors.initials: DF
authors.lastname: Larkin
authors.forename: Andrew J T
authors.initials: AJ
authors.lastname: George
mesh_terms: D000287:Administration, Topical; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002460:Cell Line; D016039:Corneal Transplantation; D003713:Dendritic Cells / Q000276:immunology; D004728:Endothelium, Corneal; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: C005045:3-hydroxykynurenine; D007737:Kynurenine