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Abstract
Transplantation is limited by the need for life-long pharmacological immunosuppression, which carries significant morbidity and mortality. Regulatory T cell (Treg) therapy holds significant promise as a strategy to facilitate immunosuppression minimization. Polyclonal Treg therapy has been assessed in a number of Phase I/II clinical trials in both solid organ and hematopoietic transplantation. Attention is now shifting towards the production of alloantigen-reactive Tregs (arTregs) through co-culture with donor antigen. These allospecific cells harbour potent suppressive function and yet their specificity implies a theoretical reduction in off-target effects. This review will cover the progress in the development of arTregs including their potential application for clinical use in transplantation, the knowledge gained so far from clinical trials of Tregs in transplant patients, and future directions for Treg therapy.
Highlights
Transplantation is limited by the inability to control graft alloresponses and the consequent need for life-long global pharmacological immunosuppression
We found CD137 to be upregulated rapidly on regulatory T cell (Treg), with levels peaking on day 6 after allostimulation (Fig. 1A)
Semi-direct presentation occurs when host T cells capture intact allogeneic MHC-peptide complexes presented by host antigen presenting cells (APC), and this pathway is of increasing interest in transplantation [33,34]
Summary
Transplantation is limited by the inability to control graft alloresponses and the consequent need for life-long global pharmacological immunosuppression These immunosuppressive drugs contribute to significant morbidity and mortality arising from their offtarget effects, which include life-threatening infection, cardiovascular disease, metabolic disorders, and malignancy [1,2]. Ex vivo-expansion of freshly isolated Tregs from peripheral blood is generally performed by stimulation of magnetic bead-isolated or flowsorted cells with anti-CD3/anti-CD28 beads in the presence of recombinant human IL-2 and rapamycin [8]. This leads to non-specific TCR stimulation and proliferation of polyclonally-reactive Tregs (polyTregs). Use of an enriched population of arTregs may overcome the both the requirement for high cell numbers as well as the off-target specificity of polyTregs
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