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* Transplantation Research Center, Children’s Hospital and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115;
Department of Medicine, San Raffaele Scientific Institute, Milan, Italy;
Department of Pathology, Ospedale di Circolo and Department of Human Morphology, University of Insubria, Varese, Italy;
Department of Pathology, Division of Hematopathology, Brigham and Women’s Hospital, Boston, MA 02115;
¶ Department of Pathology, Massachusetts General Hospital, Boston, MA 02114;
|| Stem Cell Therapy Program, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia; and
# Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610
Human clinical trials in type 1 diabetes (T1D) patients using mesenchymal stem cells (MSC) are presently underway without prior validation in a mouse model for the disease. In response to this void, we characterized bone marrow-derived murine MSC for their ability to modulate immune responses in the context of T1D, as represented in NOD mice. In comparison to NOD mice, BALB/c-MSC mice were found to express higher levels of the negative costimulatory molecule PD-L1 and to promote a shift toward Th2-like responses in treated NOD mice. In addition, transfer of MSC from resistant strains (i.e., nonobese resistant mice or BALB/c), but not from NOD mice, delayed the onset of diabetes when administered to prediabetic NOD mice. The number of BALB/c-MSC trafficking to the pancreatic lymph nodes of NOD mice was higher than in NOD mice provided autologous NOD-MSC. Administration of BALB/c-MSC temporarily resulted in reversal of hyperglycemia in 90% of NOD mice (p = 0.002). Transfer of autologous NOD-MSC imparted no such therapeutic benefit. We also noted soft tissue and visceral tumors in NOD-MSC-treated mice, which were uniquely observed in this setting (i.e., no tumors were present with BALB/c- or nonobese resistant mice-MSC transfer). The importance of this observation remains to be explored in humans, as inbred mice such as NOD may be more susceptible to tumor formation. These data provide important preclinical data supporting the basis for further development of allogeneic MSC-based therapies for T1D and, potentially, for other autoimmune disorders.
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 is supported in part by National Institutes of Health P01 AI-41521, Juvenile Diabetes Research Foundation (JDRF) Grant 4-2007-1065, JDRF R&D Grant 4-2007-1065, and by the Scott and Heidi Schuster Foundation (M.H.S.). P.F. is the recipient of an American Society of Transplantation-JDRF Faculty Grant and a JDRF-Career Development Award. R.A. is the recipient of a JDRF Regular Grant.
2 P.F. and M.J. contributed equally to this work and are considered coauthors for this publication.
3 Address correspondence and reprint requests to Dr. Reza Abdi or Dr. Paolo Fiorina, Transplantation Research Center/Division of Nephrology, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115. E-mail addresses: rabdi{at}rics.bwh.harvard.edu and paolo.fiorina{at}childrens.harvard.edu
4 Abbreviations used in this paper: MSC, mesenchymal stem cells; BM, bone marrow; DC, dendritic cell; NOR, nonobese resistant; P4, passage 4; PLN, pancreatic lymph node; T1D, type 1 diabetes; Treg, T regulatory cell.
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