title: Tolerogenic Donor-Derived Dendritic Cells Risk Sensitization In Vivo owing to Processing and Presentation by Recipient APCs.
abstract: Modification of allogeneic dendritic cells (DCs) through drug treatment results in DCs with in vitro hallmarks of tolerogenicity. Despite these observations, using murine MHC-mismatched skin and heart transplant models, donor-derived drug-modified DCs not only failed to induce tolerance but also accelerated graft rejection. The latter was inhibited by injecting the recipient with anti-CD8 Ab, which removed both CD8(+) T cells and CD8(+) DCs. The discrepancy between in vitro and in vivo data could be explained, partly, by the presentation of drug-modified donor DC MHC alloantigens by recipient APCs and activation of recipient T cells with indirect allospecificity, leading to the induction of alloantibodies. Furthermore, allogeneic MHC molecules expressed by drug-treated DCs were rapidly processed and presented in peptide form by recipient APCs in vivo within hours of DC injection. Using TCR-transgenic T cells, Ag presentation of injected OVA-pulsed DCs was detectable for ≤ 3 d, whereas indirect presentation of MHC alloantigen by recipient APCs led to activation of T cells within 14 h and was partially inhibited by reducing the numbers of CD8(+) DCs in vivo. In support of this observation when mice lacking CD8(+) DCs were pretreated with drug-modified DCs prior to transplantation, skin graft rejection kinetics were similar to those in non-DC-treated controls. Of interest, when the same mice were treated with anti-CD40L blockade plus drug-modified DCs, skin graft survival was prolonged, suggesting endogenous DCs were responsible for T cell priming. Altogether, these findings highlight the risks and limitations of negative vaccination using alloantigen-bearing "tolerogenic" DCs.
authors.affiliation: Medical Research Council Centre for Transplantation, King's College London, Guy's Hospital, London SE1 9RT, United Kingdom.
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Smyth
authors.forename: Kulachelvy
authors.initials: K
authors.lastname: Ratnasothy
authors.forename: Aurelie
authors.initials: A
authors.lastname: Moreau
authors.forename: Sally
authors.initials: S
authors.lastname: Alcock
authors.forename: Pervinder
authors.initials: P
authors.lastname: Sagoo
authors.forename: Lucy
authors.initials: L
authors.lastname: Meader
authors.forename: Yakup
authors.initials: Y
authors.lastname: Tanriver
authors.forename: Matthew
authors.initials: M
authors.lastname: Buckland
authors.forename: Robert
authors.initials: R
authors.lastname: Lechler
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lombardi
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007519:Isoantigens / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D016038:Skin Transplantation / Q000276:immunology; D014019:Tissue Donors; D014180:Transplantation
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007519:Isoantigens; D011948:Receptors, Antigen, T-Cell; D023201:CD40 Ligand
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