Mesenchymal stem cells prevent the rejection of fully allogenic islet grafts by the immunosuppressive activity of matrix metalloproteinase-2 and -9.
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.


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.
Ding
Yunchuan
Y
Transplantation Research Immunology Group, Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, UK. yunchuan.ding@nds.ox.ac.uk
Xu
Danmei
D
Feng
Gang
G
Bushell
Andrew
A
Muschel
Ruth J
RJ
Wood
Kathryn J
KJ
D000818:Animals; D006084:Graft Rejection / Q000517:prevention & control*; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007165:Immunosuppression Therapy / Q000379:methods*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D020778:Matrix Metalloproteinase 2 / Q000276:immunology / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000276:immunology / Q000378:metabolism*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D023001:Transplantation Tolerance / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology*
D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9