title: Cotransplantation with myeloid-derived suppressor cells protects cell transplants: a crucial role of inducible nitric oxide synthase.
abstract: BACKGROUND
  Islet transplantation is an alternative to pancreas transplantation to cure type 1 diabetes, but both require chronic immunosuppression, which is often accompanied by deleterious side effects. The purpose of this study was to explore prolongation of islet allograft survival by cotransplantation with myeloid-derived suppressor cells (MDSCs) without requirement of immunosuppression and determine the role of inducible nitric oxide synthase (iNOS) produced by MDSCs in immune regulation.
  
  
  METHODS
  Bone marrow cells were isolated from wild-type (WT) or iNOS mice and cultured in the presence of granulocyte-macrophage colony-stimulating factor and hepatic stellate cells (HSCs), resulting in the generation of MDSCs. WT or iNOS MDSCs were cotransplanted with islet allografts under the renal capsule of diabetic recipient mice.
  
  
  RESULTS
  Addition of HSCs into DC culture promoted generation of MDSCs (instead of DCs). MDSCs had elevated expression of iNOS upon exposure to IFN-γ and inhibited T-cell responses in an MLR culture. Cotransplantation with WT MDSCs markedly prolonged survival of islet allografts, which was associated with reduced infiltration of CD8 T cells resulting from inhibited proliferative response. These effects were significantly attenuated when MDSCs were deficient in iNOS. Furthermore, iNOS MDSCs largely lost their ability to protect islet allografts.
  
  
  CONCLUSIONS
  Cotransplantation with HSC-induced MDSCs significantly extends islet allograft survival through iNOS-mediated T-cell inhibition. The results demonstrate the potential use of in vitro generated MDSCs as a novel adjunctive immunotherapy for islet transplantation.
authors.affiliation: 1 Department of General Surgery, Transplantation Center, Digestive Disease Institute, 2 Department of Immunology and 3 Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH. 4 Address correspondence to: Shiguang Qian, M.D., Department of Immunology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave., NE60, Cleveland, OH.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Arakawa
authors.forename: Jie
authors.initials: J
authors.lastname: Qin
authors.forename: Hong-Shuie
authors.initials: HS
authors.lastname: Chou
authors.forename: Sumantha
authors.initials: S
authors.lastname: Bhatt
authors.forename: Lianfu
authors.initials: L
authors.lastname: Wang
authors.forename: Dennis
authors.initials: D
authors.lastname: Stuehr
authors.forename: Arnab
authors.initials: A
authors.lastname: Ghosh
authors.forename: John J
authors.initials: JJ
authors.lastname: Fung
authors.forename: Lina
authors.initials: L
authors.lastname: Lu
authors.forename: Shiguang
authors.initials: S
authors.lastname: Qian
mesh_terms: D064591:Allografts; D000818:Animals; D006084:Graft Rejection; D006085:Graft Survival; D007167:Immunotherapy; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000637:transplantation*; D052247:Nitric Oxide Synthase Type II / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D052247:Nitric Oxide Synthase Type II