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

作者：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^*

来源：Diabetes, 2016, 65(5): 1328-1340.

DOI：10.2337/db15-1418

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 -cells. New approaches are required to limit memory autoimmune attack of transplanted islets or replacement -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 -cell replacement therapies using patient-derived stem cells.

• 出版日期2016-5
• 单位河北医科大学