Gene delivery of indoleamine 2,3-dioxygenase prolongs cardiac allograft survival by shaping the types of T-cell responses.
BACKGROUND
We investigated the hypothesis that overexpression of indoleamine 2,3-dioxygenase (IDO) by a cardiac allograft may result in a survival advantage of the allograft by creating a tolerogenic microenvironment.


METHODS
An adenoviral vector encoding for murine IDO cDNA (AdIDO) was transfected into murine allogeneic cardiac allografts, and transplantation was performed for evaluation of the effects of local AdIDO transfection on allograft survival. Intragraft IDO expression and lymphocytes infiltration were measured by immunohistochemical and histological analysis. Quantitative polymerase chain reaction assays, mixed lymphocyte reaction and flow cytometric analysis were employed to determine the expression of mRNA for Foxp3, IDO, pro-inflammatory cytokines, allogeneic T-cell proliferation and the proportion of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) from graft-infiltrating lymphocytes and splenocytes of recipients, respectively.


RESULTS
Cardiac allografts transfected with AdIDO showed a significant prolonged survival compared to the control groups. Hearts treated with AdIDO exhibited considerable up-regulation of IDO expression, whereas contained significantly reduced transcript levels for interleukin (IL)-2, interferon-gamma and IL-17. These T cells isolated from allografts pre-treated with AdIDO displayed a dramatic reduction of proliferation capacity to alloantigen stimuli and had a significant higher proportion of Tregs compared to the control, as demonstrated by an increase of Foxp3 expression in allografts pre-treated with AdIDO compared to control groups.


CONCLUSIONS
Overexpression of IDO significantly delays cardiac allograft acute rejection by shaping the types of T-cell responses elicited by alloantigen stimuli.
Yu
Guang
G
Department of Immunology, Laboratory of Transplantation, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
Dai
Hong
H
Chen
Jie
J
Duan
Lihua
L
Gong
Min
M
Liu
Li
L
Xiong
Ping
P
Wang
Cong-Yi
CY
Fang
Min
M
Gong
Feili
F
D000256:Adenoviridae; D000818:Animals; D049109:Cell Proliferation; D018076:DNA, Complementary / Q000235:genetics; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006085:Graft Survival / Q000235:genetics*; D016027:Heart Transplantation / Q000276:immunology / Q000379:methods*; D007150:Immunohistochemistry; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016038:Skin Transplantation / Q000379:methods; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D014184:Transplantation, Homologous
D018076:DNA, Complementary; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase