Skip to main navigation Skip to search Skip to main content

Antigen-Encoding Bone Marrow Terminates Islet-Directed Memory CD8+ T-Cell Responses to Alleviate Islet Transplant Rejection

  • Miranda Coleman
  • , Claire F. Jessup
  • , Jennifer A. Bridge
  • , Nana Haahr Overgaard
  • , Daniella Penko
  • , Stacey Walters
  • , Danielle J. Borg
  • , Ryan Galea
  • , Josephine M. Forbes
  • , Ranjeny Thomas
  • , Patrick T. C. Coates
  • , Shane T. Grey
  • , James W. Wells
  • , Raymond Steptoe
    • University of Adelaide
    • Garvan Institute of Medical Research
    • University of Queensland

    Research output: Contribution to journalJournal articleResearchpeer-review

    840 Downloads (Orbit)

    Abstract

    Islet-specific memory T cells arise early in type 1 diabetes (T1D), persist for long periods, perpetuate disease, and are rapidly reactivated by islet transplantation. As memory T cells are poorly controlled by “conventional” therapies, memory T cell–mediated attack is a substantial challenge in islet transplantation, and this will extend to application of personalized approaches using stem cell–derived replacement β-cells. New approaches are required to limit memory autoimmune attack of transplanted islets or replacement β-cells. Here, we show that transfer of bone marrow encoding cognate antigen directed to dendritic cells, under mild, immune-preserving conditions, inactivates established memory CD8+ T-cell populations and generates a long-lived, antigen-specific tolerogenic environment. Consequently, CD8+ memory T cell–mediated targeting of islet-expressed antigens is prevented and islet graft rejection alleviated. The immunological mechanisms of protection are mediated through deletion and induction of unresponsiveness in targeted memory T-cell populations. The data demonstrate that hematopoietic stem cell–mediated gene therapy effectively terminates antigen-specific memory T-cell responses, and this can alleviate destruction of antigen-expressing islets. This addresses a key challenge facing islet transplantation and, importantly, the clinical application of personalized β-cell replacement therapies using patient-derived stem cells.
    Original languageEnglish
    JournalDiabetes
    Volume65
    Issue number5
    Pages (from-to)1328-1340
    ISSN0012-1797
    DOIs
    Publication statusPublished - 2016

    UN SDGs

    This output contributes to the following UN Sustainable Development Goals (SDGs)

    1. SDG 3 - Good Health and Well-being
      SDG 3 Good Health and Well-being

    Fingerprint

    Dive into the research topics of 'Antigen-Encoding Bone Marrow Terminates Islet-Directed Memory CD8+ T-Cell Responses to Alleviate Islet Transplant Rejection'. Together they form a unique fingerprint.

    Cite this