Induction of robust diabetes resistance and prevention of recurrent type 1 diabetes following islet transplantation by gene therapy

Chaorui Tian, Mohammed Javeed I Ansari, Jesus Paez-Cortez, Jessamyn Bagley, Jonathan Godwin, Michela Donnarumma, Mohamed H. Sayegh, John Iacomini*

*Corresponding author for this work

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6762-6769
Number of pages8
JournalJournal of Immunology
Volume179
Issue number10
DOIs
Publication statusPublished - Nov 15 2007

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ASJC Scopus subject areas

  • Immunology

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