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

Mesenchymal stem/stromal cells precondition lung monocytes/macrophages to produce tolerance against allo- and autoimmunity in the eye.

Author information

1
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;
2
Transplantation Research Institute, Seoul National University College of Medicine, Seoul 110-744, Korea;
3
Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine at Scott & White, Temple, TX 76502.
4
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.
5
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.

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

PMID:
26699483
PMCID:
PMC4711840
DOI:
10.1073/pnas.1522905113
[Indexed for MEDLINE]
Free PMC Article

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