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Transplantation Research Center, Renal Division, Brigham and Women’s Hospital and Children’s Hospital Boston, Harvard Medical School, Boston, MA 02115
We have previously shown that the development of type 1 diabetes (T1D) can be prevented in nonobese diabetic (NOD) mice by reconstitution with autologous hemopoietic stem cells retrovirally transduced with viruses encoding MHC class II I-A β-chain molecules associated with protection from the disease. In this study we examined whether a blockade of the programmed death-1 (PD-1)-programmed death ligand-1 (PD-L1) pathway, a major pathway known to control diabetes occurrence, could precipitate T1D in young NOD mice following reconstitution with autologous bone marrow retrovirally transduced with viruses encoding protective MHC class II I-A β-chain molecules. In addition, we examined whether the expression of protective MHC class II alleles in hemopoietic cells could be used to prevent the recurrence of diabetes in mice with pre-existing disease following islet transplantation. Protection from the occurrence of T1D diabetes in young NOD mice by the expression of protective MHC class II I-A β-chain molecules in bone marrow-derived hemopoietic cells was resistant to induction by PD-1-PD-L1 blockade. Moreover, reconstitution of NOD mice with pre-existing T1D autologous hemopoietic stem cells transduced with viruses encoding protective MHC class II I-A β-chains allowed for the successful transplantation of syngeneic islets, resulting in the long-term reversal of T1D. Reversal of diabetes was resistant to induction by PD-1-PDL-1 blockade and depletion of CD25+ T cells. These data suggest that expression of protective MHC class II alleles in bone marrow-derived cells establishes robust self-tolerance to islet autoantigens and is sufficient to prevent the recurrence of autoimmune diabetes following islet transplantation.
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1 This work was supported in part by National Institutes of Health Grants R01AI44268 and R01AI43619 and Grant 7-04-RA-45 from the American Diabetes association (to J.I.). M.H.S. is supported by the National Institute of Allergy and Infectious Diseases (P01 AI041521 and P01 AI056299) and The Juvenile Diabetes Research Foundation Center Grant on Immunological Tolerance in Type I Diabetes. C.T. is supported in part by an American Society of Transplantation/Roche Basic Science Faculty Development Grant. M.J.A. is supported in part by The American Society of Transplantation/Wyeth Basic Science Faculty Development Grant. J.P-C. is supported by an American Diabetes Association Mentor-Based Minority Postdoctoral Fellowship. J.B. is supported in part by a grant from the Children’s A-T Project and an American Society of Transplantation Fujisawa Basic Scientist Career Development Faculty Grant.
2 Address correspondence and reprint requests to Dr. John Iacomini, Ph.D., Transplantation Research Center, Renal Division, Brigham and Women’s Hospital and Children’s Hospital Boston, Harvard Medical School, 221 Longwood Avenue, LM303, Boston, MA 02115. E-mail address: jiacomini{at}rics.bwh.harvard.edu
3 Abbreviations used in this paper: T1D, type 1 diabetes; GAD 65, glutamic acid decarboxylase 65; GVHD, graft-vs-host disease; MBP, myelin basic protein; PD-1, programmed death-1; PD-L, programmed death ligand.
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