title: Autologous apoptotic cells preceding transplantation enhance survival in lethal murine graft-versus-host models.
abstract: Acute graft-versus-host disease (GVHD) is induced by alloreactivity of donor T cells toward host antigens presented on antigen-presenting cells (APCs). Apoptotic cells are capable of inducing tolerance by altering APC maturation. Apoptosis can be induced by extracorporeal photopheresis (ECP). We demonstrate that the use of ECP as a prophylaxis prior to conditioning significantly improves survival (P < .0001) after bone marrow transplantation (BMT) by inhibiting the initiation phase of acute GVHD in a murine BMT model. ECP-treated autologous splenocytes resulted in immune tolerance in the host, including reduced dendritic cell activation with decreased nuclear factor-κB engagement, increased regulatory T-cell (Treg) numbers with enhanced expression of cytolytic T lymphocyte-associated antigen 4, potentiating their suppressive function. The protective effect required host production of interleukin-10 and host Tregs. Conventional T cells that entered this tolerant environment experienced reduced proliferation, as well as a reduction of tissue homing and expression of activation markers. The induction of this tolerant state by ECP was obviated by cotreatment with lipopolysaccharide, suggesting that the inflammatory state of the recipient prior to treatment would play a role in potential clinical translation. The use of prophylactic ECP may provide an alternative and safe method for immunosuppression in the bone marrow transplant setting.
authors.affiliation: Division of Blood and Marrow Transplantation, School of Medicine, Stanford University, Stanford, CA; and.
authors.forename: Mareike
authors.initials: M
authors.lastname: Florek
authors.affiliation: Division of Blood and Marrow Transplantation, School of Medicine, Stanford University, Stanford, CA; and.
authors.forename: Emanuela I
authors.initials: EI
authors.lastname: Sega
authors.affiliation: Division of Blood and Marrow Transplantation, School of Medicine, Stanford University, Stanford, CA; and.
authors.forename: Dennis B
authors.initials: DB
authors.lastname: Leveson-Gower
authors.affiliation: Division of Blood and Marrow Transplantation, School of Medicine, Stanford University, Stanford, CA; and.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Baker
authors.affiliation: Division of Blood and Marrow Transplantation, School of Medicine, Stanford University, Stanford, CA; and Division of Hematology, University Hospital, Zurich, Switzerland.
authors.forename: Antonia M S
authors.initials: AM
authors.lastname: Müller
authors.affiliation: Division of Blood and Marrow Transplantation, School of Medicine, Stanford University, Stanford, CA; and.
authors.forename: Dominik
authors.initials: D
authors.lastname: Schneidawind
authors.affiliation: Division of Blood and Marrow Transplantation, School of Medicine, Stanford University, Stanford, CA; and.
authors.forename: Everett
authors.initials: E
authors.lastname: Meyer
authors.affiliation: Division of Blood and Marrow Transplantation, School of Medicine, Stanford University, Stanford, CA; and.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Negrin
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D017209:Apoptosis; D064592:Autografts; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
chemical_list: C556062:IL10 protein, mouse; D016753:Interleukin-10