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Dendritic cell modification as a route to inhibiting corneal graft rejection by the indirect pathway of allorecognition.

Authors
  • Khan, Adnan1
  • Fu, Hongmei
  • Tan, Lee Aun
  • Harper, Jennifer E
  • Beutelspacher, Sven C
  • Larkin, Daniel F P
  • Lombardi, Giovanna
  • McClure, Myra O
  • George, Andrew J T
  • 1 Section of Molecular Immunology, Department of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom. , (United Kingdom)
Type
Published Article
Journal
European Journal of Immunology
Publisher
Wiley (John Wiley & Sons)
Publication Date
March 2013
Volume
43
Issue
3
Pages
734–746
Identifiers
DOI: 10.1002/eji.201242914
PMID: 23212959
Source
Medline
License
Unknown

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.

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