Antigen-encoding bone marrow terminates islet-directed memory CD8+ T-cell responses to alleviate islet transplant rejection

Coleman, Miranda A., Jessup, Claire F., Bridge, Jennifer A., Overgaard, Nana H., Penko, Daniella, Walters, Stacey, Borg, Danielle J., Galea, Ryan, Forbes, Josephine M., Thomas, Ranjeny, Coates, Patrick T. C., Grey, Shane T., Wells, James W. and Steptoe, Raymond J. (2016) Antigen-encoding bone marrow terminates islet-directed memory CD8+ T-cell responses to alleviate islet transplant rejection. Diabetes, 65 5: 1328-1340. doi:10.2337/db15-1418


Author Coleman, Miranda A.
Jessup, Claire F.
Bridge, Jennifer A.
Overgaard, Nana H.
Penko, Daniella
Walters, Stacey
Borg, Danielle J.
Galea, Ryan
Forbes, Josephine M.
Thomas, Ranjeny
Coates, Patrick T. C.
Grey, Shane T.
Wells, James W.
Steptoe, Raymond J.
Title Antigen-encoding bone marrow terminates islet-directed memory CD8+ T-cell responses to alleviate islet transplant rejection
Formatted title
Antigen-encoding bone marrow terminates islet-directed memory CD8+ T-cell responses to alleviate islet transplant rejection
Journal name Diabetes   Check publisher's open access policy
ISSN 1939-327X
0012-1797
Publication date 2016-05-01
Year available 2016
Sub-type Article (original research)
DOI 10.2337/db15-1418
Open Access Status Not yet assessed
Volume 65
Issue 5
Start page 1328
End page 1340
Total pages 13
Place of publication Alexandria, VA, United States
Publisher American Diabetes Association
Collection year 2017
Language eng
Formatted 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 antigenspecific 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Mater Research Institute-UQ (MRI-UQ)
HERDC Pre-Audit
UQ Diamantina Institute Publications
 
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