Mesenchymal stem/stromal Cells Precondition Lung monocytes/macrophages to Produce Tolerance Against Allo- And Autoimmunity in the Eye

Proc Natl Acad Sci U S A. 2016 Jan 5;113(1):158-63. doi: 10.1073/pnas.1522905113. Epub 2015 Dec 22.

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.

Keywords: corneal allotransplantation; experimental autoimmune uveitis; immune tolerance; mesenchymal stem/stromal cell; monocyte/macrophage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Animals
  • Autoimmunity / immunology*
  • CD11b Antigen / immunology
  • Cell Adhesion Molecules / genetics
  • Cornea / immunology
  • Corneal Transplantation
  • Disease Models, Animal
  • Gene Knockdown Techniques
  • Genes, MHC Class II / immunology
  • Graft Survival / immunology
  • Immune Tolerance / genetics
  • Immune Tolerance / immunology*
  • Interleukin-10 / immunology
  • Leukocyte Common Antigens / immunology
  • Lung / immunology*
  • Macrophages / immunology
  • Mesenchymal Stem Cell Transplantation
  • Mesenchymal Stem Cells / immunology*
  • Mice
  • Monocytes / immunology*
  • T-Lymphocytes, Regulatory / immunology
  • Uveitis / immunology*

Substances

  • CD11b Antigen
  • Cell Adhesion Molecules
  • Tnfaip6 protein, mouse
  • Interleukin-10
  • Leukocyte Common Antigens