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- W2053002597 abstract "Although regulatory T cells (Tregs) suppress alloimmunity, difficulties in their large-scale production and in maintaining their suppressive function after expansion have so far limited their usefulness in overcoming allograft rejection and graft-versus host disease. Here we have used our established non-human primate model to demonstrate that significant Treg expansion (up to 600-fold in 21 days) can be achieved and suppressive capacity enhanced by exposing Tregs to a short burst of sirolimus. Using an in vitro CFSE-MLR based suppression assay we show that Tregs significantly inhibit allo-proliferation of both CD4+ and CD8+ T cells (3.5 and 3.0-fold inhibition of proliferation, respectively), as well as their central memory and effector memory subpopulations (3.0-, 2.9-, 2.4- and 2.7-fold inhibition of CD4+ and CD8+ Tcm and Tem proliferation, respectively). We further show that Tregs can be combined in vitro with CTLA4-Ig to enhance the inhibition of alloproliferation that occurred with either agent alone (4.8-fold inhibition of CD8 T cell proliferation with Tregs + CTLA4Ig, compared to 3.4-fold or 2.0-fold with Tregs or CTLA4Ig alone, respectively). Importantly, we have found that the suppressive activity of ex-vivo expanded Tregs could be further enhanced by pulsing with sirolimus. Thus, while long-term culture of Tregs in the presence of sirolimus (1-1000 nM) profoundly inhibited Treg expansion (50-800 fold inhibition of expansion in the presence of 1-1000 nM sirolimus), a 48 hour pulse of sirolimus (100 nM) on days 20-21 of culture completely preserved Treg yields while significantly enhancing their suppressive function against both CD4 and CD8 alloproliferation (p< 0.01). Sirolimus pulsed Tregs (SPTs) undergo fewer rounds of proliferation in an MLR when compared with unpulsed Tregs (p = 0.015), suggesting that Treg-mediated suppression may be inversely related to their proliferative capacity. SPTs also display increased expression of CD25 (p = 0.04) and total CTLA4 (p = 0.009) compared to unpulsed Tregs, implicating signaling through both of 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 alloimmunity, in a manner amenable to large-scale ex-vivo expansion and combinatorial therapy with novel, costimulation-blockade-based immunosuppression strategies." @default.
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- W2053002597 date "2012-02-01" @default.
- W2053002597 modified "2023-09-23" @default.
- W2053002597 title "Rhesus Macaque Natural CD4 Regulatory T Cells Exhibit Decreased Proliferation But Enhanced Suppression After Pulsing with Sirolimus" @default.
- W2053002597 doi "https://doi.org/10.1016/j.bbmt.2011.12.523" @default.
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