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• W2790985847 abstract "Regulatory T cells expressing CD4, CD25, and the transcription factor FoxP3 (Treg) play a critical role in suppressing immune reactions and maintaining tolerance. Murine studies have demonstrated that Treg suppress graft-versus-host disease (GVHD) without limiting the graft-versus-tumor effect. However, challenges in Treg isolation and ex vivoexpansion have hampered clinical utilization of these cells. Recently, in vivo activation through the death receptor 3 (DR3) pathway using an agonistic antibody (4C12) has been shown to selectively expand Treg in healthy mice (Kim, BS et al. Blood. 2015 Jul 23;126(4):546-57). We found that treatment of healthy donor mice (C57Bl/6 background) with a fusion protein incorporating the endogenous ligand of DR3, TL1A-Ig (Pelican Therapeutics/Heat Biologics), also leads to an expansion of Treg (mean 24.4% of splenic CD4+cells on day 7 of treatment regimen). This effect was enhanced when low dose IL-2 was included in the treatment regimen (mean 30.1% of splenic CD4+ cells on day 7). Using mice expressing luciferase under control of the FoxP3 promotor, bioluminescent imaging revealed peak Treg expansion (2- to 6-fold increase in luminescence) on day 7, with return to near baseline around 2-3 weeks. Similar kinetics were noted with flow cytometric analysis of peripheral blood. We further characterized the expanded Treg from various tissues on the day of peak expansion. Treatment with 4C12 or TL1A-Ig, with or without low dose IL-2, led to significant upregulation of ICOS, KLRG-1, PD-1, CD103, and Ki-67, but not Lag3 or CD62L, on splenic Treg. Treg from lymph nodes and peripheral blood showed similar enhancement of activation. Despite reported expression of DR3 by invariant natural killer T cells, no expansion of this population was noted following treatment with either 4C12 or TL1A-Ig, with or without IL-2. Further, we found in a major mismatch model of GVHD (C57Bl/6 into Balb/C) that donor treatment with TL1A-Ig led to a significant reduction in GVHD development in recipients (P < .01 for survival, P < .01 for GVHD score and P < .05 for weight loss). The addition of IL-2 to the donor treatment regimen led to a significant improvement in recipient GVHD score as compared to TL1A-Ig alone, but no additional benefit was noted in regard to weight loss or survival. These data demonstrate that, similar to the DR3 agonistic antibody 4C12, treatment with the TL1A-Ig fusion protein leads to expansion and activation of regulatory T cells and provide insight into the mechanism by which donor treatment leads to a reduction in GVHD in recipients." @default.
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• W2790985847 date "2018-03-01" @default.
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• W2790985847 title "Treatment of Donors with Death Receptor 3 Agonistic Fusion Protein TL1A-Ig (with and Without Low Dose IL-2) Leads to Regulatory T Cell Expansion and Activation with Reduction in Graft-Versus-Host Disease" @default.
• W2790985847 doi "https://doi.org/10.1016/j.bbmt.2017.12.148" @default.
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