Mesenchymal Stem Cells Prevent the Rejection of Fully Allogenic Islet Grafts by the Immunosuppressive Activity of Matrix Metalloproteinase-2 and -9

  1. Yunchuan Ding1,
  2. Danmei Xu2,
  3. Gang Feng1,
  4. Andrew Bushell1,
  5. Ruth J. Muschel2 and
  6. Kathryn J. Wood1
  1. 1Transplantation Research Immunology Group, Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, U.K.;
  2. 2Department of Radiation Oncology and Biology, Radiobiology Research Institute, University of Oxford, Oxford, U.K.
  1. Corresponding author: Yunchuan Ding, yunchuan.ding{at}nds.ox.ac.uk.
  1. Y.D. and D.X. contributed equally to this article.

Abstract

OBJECTIVE Mesenchymal stem cells (MSCs) are known to be capable of suppressing immune responses, but the molecular mechanisms involved and the therapeutic potential of MSCs remain to be clarified.

RESEARCH DESIGN AND METHODS We investigated the molecular mechanisms underlying the immunosuppressive effects of MSCs in vitro and in vivo.

RESULTS Our results demonstrate that matrix metalloproteinases (MMPs) secreted by MSCs, in particular MMP-2 and MMP-9, play an important role in the suppressive activity of MSCs by reducing surface expression of CD25 on responding T-cells. Blocking the activity of MMP-2 and MMP-9 in vitro completely abolished the suppression of T-cell proliferation by MSCs and restored T-cell expression of CD25 as well as responsiveness to interleukin-2. In vivo, administration of MSCs significantly reduced delayed-type hypersensitivity responses to allogeneic antigen and profoundly prolonged the survival of fully allogeneic islet grafts in transplant recipients. Significantly, these MSC-mediated protective effects were completely reversed by in vivo inhibition of MMP-2 and MMP-9.

CONCLUSIONS We demonstrate that MSCs can prevent islet allograft rejection leading to stable, long-term normoglycemia. In addition, we provide a novel insight into the mechanism underlying the suppressive effects of MSCs on T-cell responses to alloantigen.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • See accompanying commentary, p. 1728.

    • Received March 3, 2009.
    • Accepted May 6, 2009.
  • Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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  1. Diabetes vol. 58 no. 8 1797-1806
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