title: Protection of islet grafts through transforming growth factor-β-induced tolerogenic dendritic cells.
abstract: In type 1 diabetes, the insulin-producing β-cells are destroyed by the immune system. One way of restoring glucose control is to transplant β-cells from a donor. Although this procedure may restore endogenous insulin production, immunosuppressive treatment is needed to prevent the recipient from rejecting the donor-derived islets. We investigated the possibilities of transient expression of the immunosuppressive cytokine transforming growth factor (TGF)-β within islets to achieve long-term graft tolerance. We found that brief expression of TGF-β prevented rejection of syngeneic islets, that there was reduction of dendritic cell (DC) activation in the graft, and that there was reduced reactivation of T cells in the graft-draining lymph nodes. In vitro exposure of bone marrow-derived DCs to TGF-β reduced expression of costimulatory molecules CD80 and CD86, as well as production of proinflammatory cytokines such as interleukin-12 p70 in DCs, but did not alter levels of major histocompatibility complex classes I and II. Furthermore, the capacity of TGF-β-treated bone marrow-derived DCs to activate both CD4(+) and CD8(+) T cells was reduced. Adding TGF-β-conditioned tolerogenic DCs to the grafted islets led to long-term survival of the graft, demonstrating that TGF-β-induced tolerogenic DCs can provide an effective means to restore immune tolerance in an already established autoimmune disease.
authors.affiliation: Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Thomas
authors.forename: F Susan
authors.initials: FS
authors.lastname: Wong
authors.forename: Paola
authors.initials: P
authors.lastname: Zaccone
authors.forename: E Allison
authors.initials: EA
authors.lastname: Green
authors.forename: Maja
authors.initials: M
authors.lastname: Wållberg
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D018664:Interleukin-12 / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D016212:Transforming Growth Factor beta; D018664:Interleukin-12