title: Monocytic MDSCs regulate macrophage-mediated xenogenic cytotoxicity.
abstract: BACKGROUND
  Xenotransplantation is considered to be one of the most attractive strategies for overcoming the worldwide shortage of organs. However, many obstructions need to be overcome before it will achieve clinical use in patients. One such obstacle is the development of an effective immunosuppressive strategy. We previously reported that myeloid-derived suppressor cells (MDSCs), a heterogeneous population of progenitor and immature myeloid cells, suppress xenogenic CTL-mediated cytotoxicity. Because of their heterogeneous nature, MDSC can function via several suppressive mechanisms that disrupt both innate and adaptive immunity. Since macrophages play a pivotal role in the rejection of a xenograft, in this study, we evaluated the suppressive effects of MDSC against macrophage-mediated xenogenic rejection.
  
  
  METHODS
  To evaluate the effect of monocyte-derived MDSCs on xenogenic immune reactions, a CFSE(carboxyfluorescein diacetate, succinimidyl ester)assay was employed to assess cytotoxicity.
  
  
  RESULTS
  While, in the absence of activation, primed MDSCs had no detectable effect on macrophage-induced cytotoxicity against SEC cells, LPS-activated MDSCs were found to significantly suppress xenogenic cytotoxicity. A CFSE cytotoxicity assay revealed that MDSCs significantly suppressed macrophage-induced cytotoxicity. Furthermore, an indoleamine 2,3 dioxygenase (IDO) inhibitor, 1-methyl tryptophan (1-MT), abolished the MDSC-induced suppression of macrophage-mediated xeno-rejection, indicating that MDSCs may suppress macrophage-mediated cytotoxicity in an IDO-dependent manner.
  
  
  CONCLUSIONS
  These findings indicate that MDSCs have great potential for immunosuppressing macrophage-mediated xeno-rejection.
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan. Electronic address: ZUL06720@nifty.com.
authors.forename: Akira
authors.initials: A
authors.lastname: Maeda
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Eguchi
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Nakahata
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Pei-Chi
authors.initials: PC
authors.lastname: Lo
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Yamanaka
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Kawamura
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Rei
authors.initials: R
authors.lastname: Matsuura
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Rieko
authors.initials: R
authors.lastname: Sakai
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Asada
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Hiroomi
authors.initials: H
authors.lastname: Okuyama
authors.affiliation: Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Miyagawa
mesh_terms: D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D007165:Immunosuppression Therapy; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology*; D009569:Nitric Oxide / Q000378:metabolism; D014183:Transplantation, Heterologous; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D009569:Nitric Oxide; D014364:Tryptophan; C525396:1-methyltryptophan
keywords: Indoleamine 2,3-dioxygenase (IDO); Macrophage-mediated cytotoxicity; Myeloid-derived suppressor cells (MDSCs); Xenotransplantation