title: Dendritic cell modification as a route to inhibiting corneal graft rejection by the indirect pathway of allorecognition.
abstract: Dendritic cell (DC) modification is a potential strategy to induce clinical transplantation tolerance. We compared two DC modification strategies to inhibit allogeneic T-cell proliferation. In the first strategy, murine DCs were transduced with a lentiviral vector expressing CTLA4-KDEL, a fusion protein that prevents surface CD80/86 expression by retaining the co-stimulatory molecules within the ER. In the second approach, DCs were transduced to express the tryptophan-catabolising enzyme IDO. CTLA4-KDEL-expressing DCs induced anergy in alloreactive T cells and generated both CD4(+) CD25(+) and CD4(+) CD25(-) Treg cells (with direct and indirect donor allospecificity and capacity for linked suppression) both in vitro and in vivo. In contrast, T-cell unresponsiveness induced by IDO(+) DCs lacked donor specificity. In the absence of any immunosuppressive treatment, i.v. administration of CTLA4-KDEL-expressing DCs resulted in long-term survival of corneal allografts only when the DCs were capable of indirect presentation of alloantigen. This study demonstrates the therapeutic potential of CTLA4-KDEL-expressing DCs in tolerance induction.
authors.affiliation: Section of Molecular Immunology, Department of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.
authors.forename: Adnan
authors.initials: A
authors.lastname: Khan
authors.forename: Hongmei
authors.initials: H
authors.lastname: Fu
authors.forename: Lee Aun
authors.initials: LA
authors.lastname: Tan
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Harper
authors.forename: Sven C
authors.initials: SC
authors.lastname: Beutelspacher
authors.forename: Daniel F P
authors.initials: DF
authors.lastname: Larkin
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lombardi
authors.forename: Myra O
authors.initials: MO
authors.lastname: McClure
authors.forename: Andrew J T
authors.initials: AJ
authors.lastname: George
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D017635:Clonal Anergy / Q000276:immunology; D016039:Corneal Transplantation; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D056747:Immunomodulation / Q000235:genetics; D016086:Lentivirus / Q000235:genetics; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D009842:Oligopeptides / Q000276:immunology; D010641:Phenotype; D021382:Protein Sorting Signals; D013601:T-Lymphocytes / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014161:Transduction, Genetic; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D060908:CTLA-4 Antigen; D009842:Oligopeptides; D021382:Protein Sorting Signals; C073762:lysyl-aspartyl-glutamyl-leucine