TY - JOUR
T1 - Therapeutic polyclonal human CD8+ CD25+ Fox3+ TNFR2+ PD-L1+ regulatory cells induced ex-vivo
AU - Horwitz, David A.
AU - Pan, Stephanie
AU - Ou, Jing Ni
AU - Wang, Julie
AU - Chen, Maogen
AU - Gray, J. Dixon
AU - Zheng, Song Guo
N1 - Funding Information:
This study was supported in part by grants from the National Institutes of Health ( R43 AI084359 ) to ExCell Therapeutics, LLC, the Arthritis Foundation , Southern California Chapter , Athelos-Neostem Inc. , the Treadwell Foundation and funds from a Schwab Charitable Trust (ExCell Therapeutics, LLC, the donor).
PY - 2013/12
Y1 - 2013/12
N2 - We report that polyclonal CD8regs generated in one week ex-vivo with anti-CD3/28 beads and cytokines rapidly developed suppressive activity in vitro sustained by TGF-β. In immunodeficient mice, these CD8regs demonstrated a markedly protective, IL-10 dependent activity against a xeno-GVHD. They expressed IL-2Rα/β, Foxp3, TNFR2, and the negative co-stimulatory receptors CTLA-4, PD-1, PD-L1 and Tim-3. Suppressive activity in vitro correlated better with TNFR2 and PD-L1 than Foxp3. Blocking studies suggested that TNF enhanced PD-L1 expression and the suppressive activity of the CD8regs generated. Unlike other polyclonal CD4 and CD8 Tregs, these CD8regs preferentially targeted allogeneic T cells, but they lacked cytotoxic activity against them even after sensitization. Unlike CD4regs, these CD8regs could produce IL-2 and proliferate while inhibiting target cells. If these CD8regs can persist in foreign hosts without impairing immune surveillance, they could serve as a practical remission-inducing product for the treatment of autoimmune diseases, graft. versus-host disease, and allograft rejection.
AB - We report that polyclonal CD8regs generated in one week ex-vivo with anti-CD3/28 beads and cytokines rapidly developed suppressive activity in vitro sustained by TGF-β. In immunodeficient mice, these CD8regs demonstrated a markedly protective, IL-10 dependent activity against a xeno-GVHD. They expressed IL-2Rα/β, Foxp3, TNFR2, and the negative co-stimulatory receptors CTLA-4, PD-1, PD-L1 and Tim-3. Suppressive activity in vitro correlated better with TNFR2 and PD-L1 than Foxp3. Blocking studies suggested that TNF enhanced PD-L1 expression and the suppressive activity of the CD8regs generated. Unlike other polyclonal CD4 and CD8 Tregs, these CD8regs preferentially targeted allogeneic T cells, but they lacked cytotoxic activity against them even after sensitization. Unlike CD4regs, these CD8regs could produce IL-2 and proliferate while inhibiting target cells. If these CD8regs can persist in foreign hosts without impairing immune surveillance, they could serve as a practical remission-inducing product for the treatment of autoimmune diseases, graft. versus-host disease, and allograft rejection.
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U2 - 10.1016/j.clim.2013.08.007
DO - 10.1016/j.clim.2013.08.007
M3 - Article
C2 - 24211847
AN - SCOPUS:84887335883
SN - 1521-6616
VL - 149
SP - 450
EP - 463
JO - Clinical Immunology
JF - Clinical Immunology
IS - 3 PB
ER -