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

Adnan Khan; Hongmei Fu; Lee Aun Tan; Jennifer E. Harper; Sven C. Beutelspacher; Daniel F. P. Larkin; Giovanna Lombardi; Myra O. McClure; Andrew J. T. George

doi:10.1002/eji.201242914

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

Adnan Khan, Hongmei Fu, Lee Aun Tan, Jennifer E. Harper, Sven C. Beutelspacher, Daniel F. P. Larkin, Giovanna Lombardi, Myra O. McClure, Andrew J. T. George^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

20 Citations (Scopus)

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.

Original language	English
Pages (from-to)	734-746
Number of pages	13
Journal	European Journal of Immunology
Volume	43
Issue number	3
DOIs	https://doi.org/10.1002/eji.201242914
Publication status	Published - Mar 2013

Keywords

Corneal transplantation
Dendritic cells
Gene therapy
Tolerance induction
Transplantation tolerance
REGULATORY T-CELLS
MOUSE BONE-MARROW
NF-KAPPA-B
INDOLEAMINE 2,3-DIOXYGENASE
ANTIGEN PRESENTATION
TRYPTOPHAN CATABOLISM
ALLOGRAFT-REJECTION
LENTIVIRAL VECTORS
INTERFERON-GAMMA
LYMPH-NODES

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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.",

keywords = "Corneal transplantation, Dendritic cells, Gene therapy, Tolerance induction, Transplantation tolerance, REGULATORY T-CELLS, MOUSE BONE-MARROW, NF-KAPPA-B, INDOLEAMINE 2,3-DIOXYGENASE, ANTIGEN PRESENTATION, TRYPTOPHAN CATABOLISM, ALLOGRAFT-REJECTION, LENTIVIRAL VECTORS, INTERFERON-GAMMA, LYMPH-NODES",

author = "Adnan Khan and Hongmei Fu and Tan, {Lee Aun} and Harper, {Jennifer E.} and Beutelspacher, {Sven C.} and Larkin, {Daniel F. P.} and Giovanna Lombardi and McClure, {Myra O.} and George, {Andrew J. T.}",

year = "2013",

month = mar,

doi = "10.1002/eji.201242914",

language = "English",

volume = "43",

pages = "734--746",

journal = "European Journal of Immunology",

issn = "0014-2980",

publisher = "Wiley-VCH Verlag",

number = "3",

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TY - JOUR

T1 - Dendritic cell modification as a route to inhibiting corneal graft rejection by the indirect pathway of allorecognition

AU - Khan, Adnan

AU - Fu, Hongmei

AU - Tan, Lee Aun

AU - Harper, Jennifer E.

AU - Beutelspacher, Sven C.

AU - Larkin, Daniel F. P.

AU - Lombardi, Giovanna

AU - McClure, Myra O.

AU - George, Andrew J. T.

PY - 2013/3

Y1 - 2013/3

N2 - 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.

AB - 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.

KW - Corneal transplantation

KW - Dendritic cells

KW - Gene therapy

KW - Tolerance induction

KW - Transplantation tolerance

KW - REGULATORY T-CELLS

KW - MOUSE BONE-MARROW

KW - NF-KAPPA-B

KW - INDOLEAMINE 2,3-DIOXYGENASE

KW - ANTIGEN PRESENTATION

KW - TRYPTOPHAN CATABOLISM

KW - ALLOGRAFT-REJECTION

KW - LENTIVIRAL VECTORS

KW - INTERFERON-GAMMA

KW - LYMPH-NODES

U2 - 10.1002/eji.201242914

DO - 10.1002/eji.201242914

M3 - Article

SN - 0014-2980

VL - 43

SP - 734

EP - 746

JO - European Journal of Immunology

JF - European Journal of Immunology

IS - 3

ER -

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

Abstract

Keywords

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