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Cell Therapy With Autologous Tolerogenic Dendritic Cells Induces Allograft Tolerance Through Interferon‐Gamma and Epstein‐Barr Virus‐Induced Gene 3
Author(s) -
Hill M.,
Thebault P.,
Segovia M.,
Louvet C.,
Bériou G.,
Tilly G.,
Merieau E.,
Anegon I.,
Chiffoleau E.,
Cuturi M.C.
Publication year - 2011
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2011.03651.x
Subject(s) - immunosuppression , medicine , immunology , immune tolerance , transplantation , blockade , dendritic cell , interferon gamma , interferon , spleen , cancer research , immune system , genetic enhancement , cd8 , t cell , biology , receptor , gene , biochemistry
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.