title: Combining autologous dendritic cell therapy with CD3 antibodies promotes regulatory T cells and permanent islet allograft acceptance.
abstract: Cell therapy and the use of mAbs that interfere with T cell effector functions constitute promising approaches for the control of allograft rejection. In the current study, we investigated a novel approach combining administration of autologous tolerogenic dendritic cells with short-term treatment with CD3-specific Abs. Permanent acceptance of pancreatic islet allografts was achieved in mice treated with the combination therapy the day before transplantation but not in recipients treated with either therapy alone. The combination treatment induced a marked decrease in T cells infiltrating the allografts and a sustained reduction of antidonor responses. Importantly, CD4(+)Foxp3(+) regulatory T cells appeared to play a crucial role in the long-term graft acceptance. Their frequency increased significantly in the spleen, draining lymph nodes, and transplanted islets and remained elevated over the long term; they exhibited increased donor-specific suppressive functions; and their removal at the time of transplantation abrogated the therapeutic effect of the combined therapy. These results support the therapeutic potential of protocols combining autologous dendritic cells and low-dose CD3 Abs, both currently in clinical development, and that act in synergy to control allogeneic immune responses and favor graft survival in a full-mismatch situation.
authors.affiliation: Institut Necker-Enfants Malades - INSERM U1151, 75015 Paris, France; Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; and.
authors.forename: Marije C
authors.initials: MC
authors.lastname: Baas
authors.affiliation: Institut Necker-Enfants Malades - INSERM U1151, 75015 Paris, France; Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; and.
authors.forename: Chantal
authors.initials: C
authors.lastname: Kuhn
authors.affiliation: Institut Necker-Enfants Malades - INSERM U1151, 75015 Paris, France; Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; and.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Valette
authors.affiliation: Institut Necker-Enfants Malades - INSERM U1151, 75015 Paris, France; Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; and.
authors.forename: Claire
authors.initials: C
authors.lastname: Mangez
authors.affiliation: Institute of Transplantation Urology-Nephrology, INSERM UMR-S 1064, Center for Research in Transplantation and Immunology, 44093 Nantes, France.
authors.forename: Mercedes Segovia
authors.initials: MS
authors.lastname: Duarte
authors.affiliation: Institute of Transplantation Urology-Nephrology, INSERM UMR-S 1064, Center for Research in Transplantation and Immunology, 44093 Nantes, France.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Hill
authors.affiliation: Institut Necker-Enfants Malades - INSERM U1151, 75015 Paris, France; Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; and.
authors.forename: Alix
authors.initials: A
authors.lastname: Besançon
authors.affiliation: Institut Necker-Enfants Malades - INSERM U1151, 75015 Paris, France; Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; and.
authors.forename: Lucienne
authors.initials: L
authors.lastname: Chatenoud
authors.affiliation: Institute of Transplantation Urology-Nephrology, INSERM UMR-S 1064, Center for Research in Transplantation and Immunology, 44093 Nantes, France.
authors.forename: Maria-Cristina
authors.initials: MC
authors.lastname: Cuturi
authors.affiliation: Institut Necker-Enfants Malades - INSERM U1151, 75015 Paris, France; Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; and sylvaine.you@inserm.fr.
authors.forename: Sylvaine
authors.initials: S
authors.lastname: You
mesh_terms: D064591:Allografts; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017252:CD3 Complex / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation*; D000939:Epitopes / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D056747:Immunomodulation / Q000187:drug effects / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000379:methods; D051379:Mice; D023421:Models, Animal; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology*; D023001:Transplantation Tolerance / Q000187:drug effects / Q000276:immunology; D014182:Transplantation, Autologous
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D000939:Epitopes