title: IDO expressing dendritic cells suppress allograft rejection of small bowel transplantation in mice by expansion of Foxp3+ regulatory T cells.
abstract: BACKGROUND
  Indoleamine 2,3-dioxygenase (IDO), the enzyme that catalyzes the first and rate-limiting step of tryptophan catabolism, suppresses T-cell responses by tryptophan depletion and accumulation of kynurenine metabolites. IDO prevents allograft rejection in various transplantations.
  
  
  METHODS
  Dendritic cells (DC) highly expressing IDO (IDO(+) DC) were cultured through transduction of adenovirus vectors carrying the IDO sequence. IDO(+) DC were incubated with CD4(+) CD25(-) T cells to detect T cell proliferation. The effects of IDO(+) DC and 3-Hydroxyanthranilic acid (3-HAA) were verified in an allogeneic murine small bowel transplantation (SBT) model. Foxp3(+) Treg cells of recipient mice were detected by flow cytometry and cytokines in plasma were determined by ELISA.
  
  
  RESULTS
  IDO(+) DC effectively suppressed proliferation of CD4(+) CD25(-) T cells in vitro, and this effect could be enhanced by adding 3-HAA. In the SBT transplantation model, both 3-HAA (P < 0.05) and IDO(+) DC (P < 0.01) prolonged the survival time of transplanted mice. Mice treated with IDO(+) DC achieved longer mean survival time than 3-HAA administrated mice (11.5d vs. 18.5d). Grafts from IDO(+) DC, 3-HAA and combination treatment group showed reduced inflammation and minimal architectural distortion. IFN-γ production was significantly inhibited by IDO(+) DC and 3-HAA (P<0.05). The expression of IL-2 was slightly lower with 3-HAA or IDO(+) DC treatment. However, IL-10 was higher in 3-HAA, IDO(+) DC and combination treatment groups, while TGF-β was elevated in all non-control groups.
  
  
  CONCLUSIONS
  IDO(+) DC plus 3-HAA has an immunoprotective role and represents a potential strategy to suppress acute rejection and prolong survival of grafts in SBT.
authors.affiliation: Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.
authors.forename: Fang Tao
authors.initials: FT
authors.lastname: Xie
authors.affiliation: Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.
authors.forename: Ji Sen
authors.initials: JS
authors.lastname: Cao
authors.affiliation: Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Qi
authors.affiliation: Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China. Electronic address: dxc01tj@gmail.com.
authors.forename: Xiang Chen
authors.initials: XC
authors.lastname: Dai
mesh_terms: D015095:3-Hydroxyanthranilic Acid / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D007421:Intestine, Small / Q000637:transplantation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016377:Organ Transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D019076:Transgenes / Q000235:genetics
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D015095:3-Hydroxyanthranilic Acid
keywords: 3-hydroxyanthranilic acid (3-HAA); Immune tolerance; Indoleamine 2,3-dioxygenase (IDO); Regulatory T cells (treg); Small bowel transplantation