title: Mesenchymal stem/stromal cells precondition lung monocytes/macrophages to produce tolerance against allo- and autoimmunity in the eye.
abstract: Intravenously administered mesenchymal stem/stromal cells (MSCs) engraft only transiently in recipients, but confer long-term therapeutic benefits in patients with immune disorders. This suggests that MSCs induce immune tolerance by long-lasting effects on the recipient immune regulatory system. Here, we demonstrate that i.v. infusion of MSCs preconditioned lung monocytes/macrophages toward an immune regulatory phenotype in a TNF-α-stimulated gene/protein (TSG)-6-dependent manner. As a result, mice were protected against subsequent immune challenge in two models of allo- and autoimmune ocular inflammation: corneal allotransplantation and experimental autoimmune uveitis (EAU). The monocytes/macrophages primed by MSCs expressed high levels of MHC class II, B220, CD11b, and IL-10, and exhibited T-cell-suppressive activities independently of FoxP3(+) regulatory T cells. Adoptive transfer of MSC-induced B220(+)CD11b(+) monocytes/macrophages prevented corneal allograft rejection and EAU. Deletion of monocytes/macrophages abrogated the MSC-induced tolerance. However, MSCs with TSG-6 knockdown did not induce MHC II(+)B220(+)CD11b(+) cells, and failed to attenuate EAU. Therefore, the results demonstrate a mechanism of the MSC-mediated immune modulation through induction of innate immune tolerance that involves monocytes/macrophages.
authors.affiliation: Department of Ophthalmology, Seoul National University Hospital, Seoul 110-744, Korea; Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, Seoul 110-744, Korea;
authors.forename: Jung Hwa
authors.initials: JH
authors.lastname: Ko
authors.affiliation: Department of Ophthalmology, Seoul National University Hospital, Seoul 110-744, Korea; Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, Seoul 110-744, Korea;
authors.forename: Hyun Ju
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Ophthalmology, Seoul National University Hospital, Seoul 110-744, Korea; Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, Seoul 110-744, Korea;
authors.forename: Hyun Jeong
authors.initials: HJ
authors.lastname: Jeong
authors.affiliation: Department of Ophthalmology, Seoul National University Hospital, Seoul 110-744, Korea; Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, Seoul 110-744, Korea;
authors.forename: Mee Kum
authors.initials: MK
authors.lastname: Kim
authors.affiliation: Department of Ophthalmology, Seoul National University Hospital, Seoul 110-744, Korea; Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, Seoul 110-744, Korea;
authors.forename: Won Ryang
authors.initials: WR
authors.lastname: Wee
authors.affiliation: Transplantation Research Institute, Seoul National University College of Medicine, Seoul 110-744, Korea;
authors.forename: Sun-Ok
authors.initials: SO
authors.lastname: Yoon
authors.affiliation: Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine at Scott & White, Temple, TX 76502.
authors.forename: Hosoon
authors.initials: H
authors.lastname: Choi
authors.affiliation: Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine at Scott & White, Temple, TX 76502 prockop@medicine.tamhsc.edu jooyounoh77@gmail.com.
authors.forename: Darwin J
authors.initials: DJ
authors.lastname: Prockop
authors.affiliation: Department of Ophthalmology, Seoul National University Hospital, Seoul 110-744, Korea; Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, Seoul 110-744, Korea; prockop@medicine.tamhsc.edu jooyounoh77@gmail.com.
authors.forename: Joo Youn
authors.initials: JY
authors.lastname: Oh
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D039481:CD11b Antigen / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000235:genetics; D003315:Cornea / Q000276:immunology; D016039:Corneal Transplantation; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D005802:Genes, MHC Class II / Q000276:immunology; D006085:Graft Survival / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000276:immunology; D008168:Lung / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D051379:Mice; D009000:Monocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014605:Uveitis / Q000276:immunology*
chemical_list: D039481:CD11b Antigen; D015815:Cell Adhesion Molecules; C513057:Tnfaip6 protein, mouse; D016753:Interleukin-10; D017493:Leukocyte Common Antigens
keywords: corneal allotransplantation; experimental autoimmune uveitis; immune tolerance; mesenchymal stem/stromal cell; monocyte/macrophage