Gene delivery of indoleamine 2,3‐dioxygenase prolongs cardiac allograft survival by shaping the types of T‐cell responses

Yu, Guang; Dai, Hong; Chen, Jie; Duan, Lihua; Gong, Min; Liu, Li; Xiong, Ping; Wang, Cong Yi; Fang, Min; Gong, Feili

doi:10.1002/jgm.1201

Cited by 39 publications

(38 citation statements)

References 30 publications

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“…Heterotopic cardiac transplantation and assessment of allograft function were conducted as described previously. 24 Briefly, the cardiac allograft was transplanted in the abdominal cavity by anastomosing the aorta and pulmonary artery of the graft end-to-side to the recipient's aorta and vena cava, respectively. Allograft function was assessed by daily palpation of the abdomen.…”

Section: Antibodies and Reagentsmentioning

confidence: 99%

“…Tissue sections were also double stained for CD4 and IL-17 for analysis of in situ allograft-infiltrating CD4 þ IL-17 þ T cells using the established techniques. 22,24 To identify the cell types of infiltrates in the allogeneic or syngeneic cardiac grafts, we stained tissue sections for CD4, CD8, Gr-1, or F4/ 80 by immunohistochemical staining method. Briefly, after deparaffinization and rehydration, the sections were treated with 3% H 2 O 2 followed by blocking with 10% goat serum in PBS.…”

Section: Histological and Immunohistochemical Analysesmentioning

confidence: 99%

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High-mobility group box 1 promotes early acute allograft rejection by enhancing IL-6-dependent Th17 alloreactive response

Duan

Wang

Chen

et al. 2011

Laboratory Investigation

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Previously, we reported that extracellular high-mobility group box 1 (HMGB1) functions as an innate alarmin implicated in cardiac allograft acute rejection. We now present evidence suggesting that HMGB1 is pivotal in inducing interleukin-17 (IL-17)-producing alloreactive T cells by stimulating dendritic cells secretion of IL-6. Those IL-17 þ T cells are likely to be the major effector cells responsible for the early stage of cardiac allograft rejection through mediating an influx of neutrophils into allografts, and therefore, blockade of IL-17A significantly prolonged murine cardiac allograft survival. In contrast to the classical model for a dominant role of IFN-g þ -Th1 cells have in acute allograft rejection, our data suggest that IFN-g þ -Th1 cells are responsible for the late stage of graft destruction by inducing monocyte infiltration when IL-17 þ T-cell response recedes. Blockade of HMGB1 significantly decreased splenic alloreactive Th17 cells and IFN-g-producing CD8 þ T cells in the recipients, leading to less infiltration of neutrophils along with lower IL-6 and IL-17 expression levels in the grafts as well as prolongation of cardiac allograft survival. Together, these data support a novel model in which HMGB1 induces IL-17-producing alloreactive T cells to mediate early stage of allograft rejection, whereas IFN-g-producing alloreactive Th1 cells provoke graft destruction after Th17 response recedes.

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Section: Antibodies and Reagentsmentioning

confidence: 99%

Section: Histological and Immunohistochemical Analysesmentioning

confidence: 99%

High-mobility group box 1 promotes early acute allograft rejection by enhancing IL-6-dependent Th17 alloreactive response

Duan

Wang

Chen

et al. 2011

Laboratory Investigation

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“…Most literature supports this view, however there have been reports of IDO overexpression causing modulation of T regs populations in other model systems. 43 Because we did not perform in vivo analysis of CD4 + CD25…”

Section: Ido Modulates Inhibitor Formation L Liu Et Almentioning

confidence: 99%

Indoleamine 2,3-dioxygenase attenuates inhibitor development in gene-therapy-treated hemophilia A mice

Liu

Mah

et al. 2009

Gene Ther

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A serious impediment to gene and protein replacement therapy in hemophilia A is the development of inhibitors. Mechanisms responsible for inhibitor development include T-cell-dependent adaptive immune responses and the CD28-B7 signaling pathway that eventually leads to the formation of antibodies directed against factor VIII (FVIII). Indoleamine 2,3-dioxygenase (IDO) is a potent immunosuppressive enzyme that can inhibit T-cell responses and induce T-cell apoptosis by regulation of tryptophan metabolism. Kynurenine, one of the metabolites of tryptophan, has been implicated as an immune modulator. Here we hypothesize that co-delivery of the genes for FVIII and IDO can attenuate inhibitor formation. Using transposon-based gene delivery, we observed long-term therapeutic FVIII expression and significantly reduced inhibitor titers when the genes were codelivered. Co-expression of FVIII and IDO in the liver was associated with increased plasma kynurenine levels, an inhibition of T-cell infiltration and increased apoptosis of T cells within the liver. These experiments suggest that modulation of tryptophan catabolism through IDO expression provides a novel strategy to reduce inhibitor development in hemophilia gene/protein therapy.

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“…19 After day 7 of transplantation, the skin allografts were excised and fixed in 4% paraformaldehyde. Serial sections (5 mm in thickness) were prepared using a microtome and stained with hematoxylin/eosin for the analysis of pathological changes.…”

Section: Skin Allograft Histologymentioning

confidence: 99%

“…Heterotopic heart transplantation was performed as previously reported. 19 The pulsation of heart grafts was monitored daily by two independent observers without prior knowledge of the treatment protocol.…”

Section: Splenic Stromal Cells and Allograft Protection L Liu Et Al 34mentioning

confidence: 99%

Indoleamine 2,3-dioxygenase and regulatory dendritic cells contribute to the allograft protection induced by infusion of donor-specific splenic stromal cells

et al. 2010

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It has been reported that splenic stromal cells (SSCs) are capable of directly supporting the development of CD11c lo CD45RB 1 IL-10-producing dendritic cells (DCs) from lineage-negative c-kit 1 progenitor cells in the absence of exogenous cytokines. In vitro, DCs that differentiate on stromal cells suppress mixed leukocyte reaction responses and induce primary alloreactive CD41 T cells to differentiate into IL-10-producing Tr1 cells. However, the precise mechanisms by which these SSCs exert their regulatory functions in vivo remain undefined. Furthermore, their possible contribution to the development of allograft transplantation tolerance has yet to be examined. Here, we have used both murine skin and cardiac allograft transplantation models to explore whether in vivo alloresponses can be regulated by infusion with donor-derived SSCs and to investigate the possible mechanisms by which SSCs exert regulatory effects to prevent allograft rejection. We show that intravenous SSC infusion prolonged murine skin allograft survival. The prolonged graft survival is associated with augmentation of the generation of regulatory DC subsets and CD4 Foxp31 regulatory T cells (Tregs), as well as upregulation of the production of suppressive cytokines IL-10 and transforming growth factor (TGF)-b. Moreover, we found that indoleamine 2,3-dioxygenase and SSC-derived regulatory DCs contribute to allograft protection by infusion of donor-specific SSCs. Our data suggest that donor-derived SSCs could be used as a therapeutic target to promote transplantation tolerance.

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Gene delivery of indoleamine 2,3‐dioxygenase prolongs cardiac allograft survival by shaping the types of T‐cell responses

Abstract: Overexpression of IDO significantly delays cardiac allograft acute rejection by shaping the types of T-cell responses elicited by alloantigen stimuli.

Cited by 39 publications

References 30 publications

High-mobility group box 1 promotes early acute allograft rejection by enhancing IL-6-dependent Th17 alloreactive response

High-mobility group box 1 promotes early acute allograft rejection by enhancing IL-6-dependent Th17 alloreactive response

Indoleamine 2,3-dioxygenase attenuates inhibitor development in gene-therapy-treated hemophilia A mice

Indoleamine 2,3-dioxygenase and regulatory dendritic cells contribute to the allograft protection induced by infusion of donor-specific splenic stromal cells

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