title: Modified dendritic cells coexpressing self and allogeneic major histocompatability complex molecules: an efficient way to induce indirect pathway regulation.
abstract: A feature of the tolerance that has been described in experimental models is that it can be transferred by CD4+ T cells to a naive recipient. Described is a novel approach to induce indirect pathway regulatory T cells in a rat model that exploits the natural processing and presentation of major histocompatability complex (MHC) molecules as peptide by the MHC class II molecules of the same cell. Dendritic cells (DC) coexpressing donor (AUG) and recipient (LEW) MHC molecules were rendered tolerogenic by treatment with dexamethasone. After injection into LEW animals followed by a single low dose of CTLA4-Ig, T cells were rendered unresponsive to indirectly presented AUG alloantigens, but retained direct pathway responsiveness to fully allogeneic AUG cells. The T cells from the DC-injected rats were unresponsive to (LEW x AUG)F1 stimulator cells, suggesting the presence of indirect pathway regulatory cells whose activity depended on the presence of LEW MHC molecules. Depletion of CD25+ cells from the responder population led to a marked increase in proliferation, and the T cells from the DC-injected rats inhibited the response of naive LEW T cells to (LEW x AUG)F1, but not to AUG, stimulator cells, further indicating indirect pathway-mediated regulation. Most importantly, pretreatment of LEW rats with the dexamethasone-treated DC led to the indefinite survival of AUG kidney grafts after a short course of cyclosporin to inhibit the early direct pathway response. Similarly treated AUG DC had no effect, confirming the privileged status of F1 cells in the induction of indirect pathway regulation.
authors.affiliation: Departments of Immunology, Histopatology, and Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 ONN, UK.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mirenda
authors.forename: Ivan
authors.initials: I
authors.lastname: Berton
authors.forename: Joseph
authors.initials: J
authors.lastname: Read
authors.forename: Terence
authors.initials: T
authors.lastname: Cook
authors.forename: Jennifer
authors.initials: J
authors.lastname: Smith
authors.forename: Anthony
authors.initials: A
authors.lastname: Dorling
authors.forename: Robert Ian
authors.initials: RI
authors.lastname: Lechler
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D003907:Dexamethasone / Q000494:pharmacology; D006085:Graft Survival / Q000187:drug effects; D006649:Histocompatibility Antigens / Q000096:biosynthesis*; D016030:Kidney Transplantation / Q000276:immunology*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains
chemical_list: D006649:Histocompatibility Antigens; D003907:Dexamethasone