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Gene delivery of indoleamine 2,3‐dioxygenase prolongs cardiac allograft survival by shaping the types of T‐cell responses
Author(s) -
Yu Guang,
Dai Hong,
Chen Jie,
Duan Lihua,
Gong Min,
Liu Li,
Xiong Ping,
Wang CongYi,
Fang Min,
Gong Feili
Publication year - 2008
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.1201
Subject(s) - foxp3 , indoleamine 2,3 dioxygenase , mixed lymphocyte reaction , immunology , transfection , transplantation , il 2 receptor , flow cytometry , biology , t cell , medicine , cancer research , immune system , gene , tryptophan , biochemistry , amino acid
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‐γ 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. Copyright © 2008 John Wiley & Sons, Ltd.