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* Division of Pulmonary and Critical Care Medicine and
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109
Development of allograft rejection continues to be the major determinant of morbidity and mortality postlung transplantation. We have recently demonstrated that a population of donor-derived mesenchymal stem cells is present in human lung allografts and can be isolated and expanded ex vivo. In this study, we investigated the impact of lung resident mesenchymal stem cells (LR-MSCs), derived from allografts of human lung transplant recipients, on T cell activation in vitro. Similar to bone marrow-derived MSCs, LR-MSCs did not express MHC II or the costimulatory molecules CD80 or CD86. In vitro, LR-MSCs profoundly suppressed the proliferative capacity of T cells in response to a mitogenic or an allogeneic stimulus. The immunosuppressive function of LR-MSCs was also noted in the absence of direct cell contact, indicating that LR-MSCs mediated their effect predominantly via a soluble mediator. LR-MSCs isolated from lung transplant recipients demonstrated PGE2 secretion at baseline (385 ± 375 pg/ml), which increased in response to IL-1β (1149 ± 1081 pg/ml). The addition of PG synthesis inhibitors (indomethacin and NS-398) substantially abrogated LR-MSC-mediated immunosuppression, indicating that PGE2 may be one of the major soluble mediators impacting T cell activity. This is the first report to demonstrate that human tissue-derived MSCs isolated from an allogeneic environment have the potential to mediate immunological responses in vitro.
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.
1 This work was supported by National Institutes of Health Grants K23 HL077719 (to V.N.L.), R01 HL085149-01 (to D.J.P.), and R01 HL55397 (to D.J.P.), an American Society of Transplantation and Chest Foundation clinical research award in lung transplantation (to V.N.L.), P01 HL 89407 (to D.P.J.), Taubman Medical Research Institute (to D.P.J.), American Thoracic Society Research Award (to V.N.L.), and a Scleroderma Research Foundation award (to V.N.L. and D.J.P.).
2 L.J. and L.B. share cofirst author status.
3 Address correspondence and reprint requests to Dr. Vibha N. Lama, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, 1500 East Medical Center Drive, 3916 Taubman Center, Ann Arbor, MI 48109-0360. E-mail address: vlama{at}umich.edu
4 Abbreviations used in this paper: BOS, bronchiolitis obliterans syndrome; BAL, bronchoalveolar lavage; BM-MSC, bone marrow-derived MSC; COX, cyclooxygenase; LR-MSC, lung resident MSC; MSC, mesenchymal stem cell; Treg, regulatory T cell.
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