Journal
AMERICAN JOURNAL OF TRANSPLANTATION
Volume 12, Issue 6, Pages 1441-1457Publisher
WILEY
DOI: 10.1111/j.1600-6143.2011.03963.x
Keywords
immunosuppression; regulatory T cells; sirolimus
Categories
Funding
- Yerkes
- National Primate Research Center [RR00165]
- NIH [2U19 AI051731, 2P01 AI044644, R01 AI34495, HL 56067, P01 CA 067493]
- Burroughs Wellcome Fund Career Award in the Biomedical Sciences
- JDRF [1-2008-594, 1U01AI079223-01A1, 5 U19 AI051731]
- [5K08 AI065822]
- [1R01 HL095791]
- [2U24 RR018109]
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Although regulatory T cells (Tregs) suppress allo-immunity, difficulties in their large-scale production and in maintaining their suppressive function after expansion have thus far limited their clinical applicability. Here we have used our nonhuman primate model to demonstrate that significant ex vivo Treg expansion with potent suppressive capacity can be achieved and that Treg suppressive capacity can be further enhanced by their exposure to a short pulse of sirolimus. Both unpulsed and sirolimus-pulsed Tregs (SPTs) are capable of inhibiting proliferation of multiple T cell subpopulations, including CD4+ and CD8+ T cells, as well as antigen-experienced CD28+CD95+ memory and CD28-CD95+ effector subpopulations. We further show that Tregs can be combined in vitro with CTLA4-Ig (belatacept) to lead to enhanced inhibition of allo-proliferation. SPTs undergo less proliferation in a mixed lymphocyte reaction (MLR) when compared with unpulsed Tregs, suggesting that Treg-mediated suppression may be inversely related to their proliferative capacity. SPTs also display increased expression of CD25 and CTLA4, implicating signaling through these molecules in their enhanced function. Our results suggest that the creation of SPTs may provide a novel avenue to enhance Treg-based suppression of allo-immunity, in a manner amenable to large-scale ex vivo expansion and combinatorial therapy with novel, costimulation blockade-based immunosuppression strategies.
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