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

• Published in: European journal of immunology Vol. 43; no. 3; pp. 734 - 746
• Main Authors: Khan, Adnan, Fu, Hongmei, Tan, Lee Aun, Harper, Jennifer E., Beutelspacher, Sven C., Larkin, Daniel F. P., Lombardi, Giovanna, McClure, Myra O., George, Andrew J. T.
• Format: Journal Article
• Language: English
• Published: 01-03-2013
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201242914

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
DC
s were transduced with a lentiviral vector expressing
CTLA
4‐
KDEL
, a fusion protein that prevents surface
CD
80/86 expression by retaining the co‐stimulatory molecules within the
ER
. In the second approach,
DC
s were transduced to express the tryptophan‐catabolising enzyme
IDO
.
CTLA
4‐
KDEL
‐expressing
DC
s induced anergy in alloreactive
T
cells and generated both
CD
4
+
CD
25
+
and
CD
4
+
CD
25
−
T
reg 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
+
DC
s lacked donor specificity. In the absence of any immunosuppressive treatment, i.v. administration of
CTLA
4‐
KDEL
‐expressing
DC
s resulted in long‐term survival of corneal allografts only when the
DC
s were capable of indirect presentation of alloantigen. This study demonstrates the therapeutic potential of
CTLA
4‐
KDEL
‐expressing
DC
s in tolerance induction.