title: Antigen-encoding bone marrow terminates islet-directed memory CD8+ T-cell responses to alleviate islet transplant rejection.
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.
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, AUSTRALIA.
authors.forename: Miranda A
authors.initials: MA
authors.lastname: Coleman
authors.affiliation: Discipline of Medicine, University of Adelaide, Adelaide SA, AUSTRALIA Department of Anatomy & Histology, Flinders University, SA, AUSTRALIA.
authors.forename: Claire F
authors.initials: CF
authors.lastname: Jessup
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, AUSTRALIA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Bridge
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, AUSTRALIA.
authors.forename: Nana H
authors.initials: NH
authors.lastname: Overgaard
authors.affiliation: Discipline of Medicine, University of Adelaide, Adelaide SA, AUSTRALIA.
authors.forename: Daniella
authors.initials: D
authors.lastname: Penko
authors.affiliation: Garvan Institute of Medical Research, Sydney, NSW, AUSTRALIA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Walters
authors.affiliation: Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, AUSTRALIA.
authors.forename: Danielle J
authors.initials: DJ
authors.lastname: Borg
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, AUSTRALIA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Galea
authors.affiliation: Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, AUSTRALIA.
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Forbes
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, AUSTRALIA.
authors.forename: Ranjeny
authors.initials: R
authors.lastname: Thomas
authors.affiliation: Discipline of Medicine, University of Adelaide, Adelaide SA, AUSTRALIA.
authors.forename: Patrick T C
authors.initials: PT
authors.lastname: Coates
authors.affiliation: Garvan Institute of Medical Research, Sydney, NSW, AUSTRALIA.
authors.forename: Shane T
authors.initials: ST
authors.lastname: Grey
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, AUSTRALIA.
authors.forename: James W
authors.initials: JW
authors.lastname: Wells
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, QLD, AUSTRALIA. r.steptoe@uq.edu.au.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Steptoe