Mesenchymal stem cells express serine protease inhibitor to evade the host immune response
- 27 January 2011
- journal article
- Published by American Society of Hematology in Blood
- Vol. 117 (4), 1176-1183
- https://doi.org/10.1182/blood-2010-06-287979
Abstract
Clinical trials using mesenchymal stem cells (MSCs) have been initiated worldwide. An improved understanding of the mechanisms by which allogeneic MSCs evade host immune responses is paramount to regulating their survival after administration. This study has focused on the novel role of serine protease inhibitor (SPI) in the escape of MSCs from host immunosurveillance through the inhibition of granzyme B (GrB). Our data indicate bone marrow–derived murine MSCs express SPI6 constitutively. MSCs from mice deficient for SPI6 (SPI6−/−) exhibited a 4-fold higher death rate by primed allogeneic cytotoxic T cells than did wild-type MSCs. A GrB inhibitor rescued SPI6−/− MSCs from cytotoxic T-cell killing. Transduction of wild-type MSCs with MigR1-SPI6 also protected MSCs from cytotoxic T cell–mediated death in vitro. In addition, SPI6−/− MSCs displayed a shorter lifespan than wild-type MSCs when injected into an allogeneic host. We conclude that SPI6 protects MSCs from GrB-mediated killing and plays a pivotal role in their survival in vivo. Our data could serve as a basis for future SPI-based strategies to regulate the survival and function of MSCs after administration and to enhance the efficacy of MSC-based therapy for diseases.Keywords
This publication has 41 references indexed in Scilit:
- Immunomodulation by Mesenchymal Stem CellsDiabetes, 2008
- Mechanisms of granule-dependent killingCell Death & Differentiation, 2007
- The role of serpinb9/serine protease inhibitor 6 in preventing granzyme B-dependent hepatotoxicityHepatology, 2007
- Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen‐induced arthritisArthritis & Rheumatism, 2007
- Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative settingBlood, 2006
- Molecular Ordering of the Caspase Activation Cascade Initiated by the Cytotoxic T Lymphocyte/Natural Killer (CTL/NK) Protease Granzyme BPublished by Elsevier BV ,2005
- Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cellsTransplantation, 2003
- A Cytosolic Granzyme B Inhibitor Related to the Viral Apoptotic Regulator Cytokine Response Modifier A Is Present in Cytotoxic LymphocytesJournal of Biological Chemistry, 1996
- Granzyme B Plays a Critical Role in Cytotoxic Lymphocyte‐induced ApoptosisImmunological Reviews, 1995
- A new microcellular cytotoxicity test based on calcein AM releaseHuman Immunology, 1993