title: Cell therapy with autologous tolerogenic dendritic cells induces allograft tolerance through interferon-gamma and epstein-barr virus-induced gene 3.
abstract: Innovative therapeutic strategies are needed to diminish the impact of harmful immunosuppression in transplantation. Dendritic cell (DC)-based therapy is a promising approach for induction of antigen-specific tolerance. Using a heart allograft model in rats, we analyzed the immunoregulatory mechanisms by which injection of autologous tolerogenic DCs (ATDCs) plus suboptimal immunosuppression promotes indefinite graft survival. Surprisingly, we determined that Interferon-gamma (IFNG), a cytokine expected to be propathogenic, was threefold increased in the spleen of tolerant rats. Importantly, its blockade led to allograft rejection [Mean Survival Time (MST) = 25.6 ± 4 days], showing that IFNG plays a critical role in immunoregulatory mechanisms triggered by ATDCs. IFNG was expressed by TCRαβ(+) CD3(+) CD4(-) CD8(-) NKRP1(-)  cells (double negative T cells, DNT), which accumulated in the spleen of tolerant rats. Interestingly, ATDCs specifically induced IFNG production by DNT cells. ATDCs expressed the cytokinic chain Epstein-Barr virus-induced gene 3 (EBI3), an IL-12 family member. EBI3 blockade or knock-down through siRNA completely abolished IFNG expression in DNT cells. Finally, EBI3 blockade in vivo led to allograft rejection (MST = 36.8 ± 19.7 days), demonstrating for the first time a role for EBI3 in transplantation tolerance. Taken together our results have important implications in the rationalization of DC-based therapy in transplantation as well as in the patient immunomonitoring follow-up.
authors.affiliation: INSERM, UMR 643, Nantes, France.
authors.forename: M
authors.initials: M
authors.lastname: Hill
authors.forename: P
authors.initials: P
authors.lastname: Thebault
authors.forename: M
authors.initials: M
authors.lastname: Segovia
authors.forename: C
authors.initials: C
authors.lastname: Louvet
authors.forename: G
authors.initials: G
authors.lastname: Bériou
authors.forename: G
authors.initials: G
authors.lastname: Tilly
authors.forename: E
authors.initials: E
authors.lastname: Merieau
authors.forename: I
authors.initials: I
authors.lastname: Anegon
authors.forename: E
authors.initials: E
authors.lastname: Chiffoleau
authors.forename: M-C
authors.initials: MC
authors.lastname: Cuturi
mesh_terms: D000818:Animals; D017690:Cell Transplantation; D003713:Dendritic Cells / Q000166:cytology*; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism*; D007959:Lymphocyte Culture Test, Mixed; D018613:Microscopy, Confocal; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D014184:Transplantation, Homologous; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D014764:Viral Proteins; D007371:Interferon-gamma