T cell–mediated vascular dysfunction of human allografts results from IFN-γ dysregulation of NO synthase

Koh, Kian Peng; Wang, Yinong; Yi, Tai; Shiao, Stephen L.; Lorber, Marc I.; Sessa, William C.; Tellides, George; Pober, Jordan S.

doi:10.1172/jci21767

Cited by 92 publications

(75 citation statements)

References 54 publications

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“…It is generally understood that IFN-g plays a central role in acute allografts in acute allograft rejection [33][34]. Although the exact pathogenesis of CAV remains to be established, previous studies have suggested that CAV is primarily an immune system-mediated disease and have demonstrated that the pivotal role of IFN-g in triggering the pathological changes associated with CAV [35][36][37]. Our in vitro and in vivo findings indeed confirm that CCR5 blockade in combination with rapa can inhibit the production of IFN-g and attenuate T cell proliferative responses and reduce the size of the effector T cell pool.…”

Section: Foxp3mentioning

confidence: 99%

Retracted: CCR5 blockade in combination with rapamycin prolongs cardiac allograft survival in mice

Zhang

et al. 2009

Clinical and Experimental Immunology

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SummaryBoth chemokine receptor 5 (CCR5) blockade and rapamycin (rapa) are effective in modulating transplant immunity and led to prolonged allograft survival, yet a great many grafts were ultimately lost to acute rejection. In this study we examined the inhibition of CCR5 in combination with the treatment with rapa in cardiac transplantation. Fully major histocompatibility complexmismatched murine cardiac allograft models were randomized to five groups. They were administered with anti-CCR5 antibody or control antibody and rapa or phosphate-buffered saline (PBS), respectively. An additional group was treated with anti-CCR5 antibody, rapa and anti-CD25 antibody. Allograft rejection was investigated by flow cytometric analyses and enzyme-linked immunospot assay. Allografts treated with anti-CCR5 antibody plus rapa showed significantly prolonged survival (83 Ϯ 3 days, P < 0·001) compared with control antibody plus PBS-treated allografts (6 Ϯ 1 days). Treatment with anti-CCR5 monoclonal antibody (mAb) plus rapa inhibited significantly the progression of chronic rejction. Further analysis of donor hearts in the anti-CCR5 antibody plus rapa-treated group demonstrated increased infiltration of CD4 + CD25 + forkhead box P3 + regulatory T cells, and depletion of CD25 + cells resulted in acute rejection of allografts in 18 Ϯ 1 day. CCR5 blockade in combination with rapa is effective in preventing acute and chronic rejection in a robust murine model. This effect is mediated by CD25 + T cell recruitment and control of T lymphocyte proliferation.

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Section: Foxp3mentioning

confidence: 99%

Retracted: CCR5 blockade in combination with rapamycin prolongs cardiac allograft survival in mice

Zhang

et al. 2009

Clinical and Experimental Immunology

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“…We tested humanized BMA031: GZ-αβTCR for its efficacy to specifically target (activated) αβ T cells in vitro and in vivo in two model systems (hu-PBL-and hu-HSC-NSG), both suitable to study human T cells in context with human allograft rejection. 19,20,[38][39][40] GZ-αβTCR significantly modulated hu CD45 + CD3 + cells in peripheral blood, spleen and BM. Single application downmodulated T-cell numbers only transiently, with a T-cell decline similar to what was reported for type I diabetes patients following anti-CD3 mAb therapy (Teplizumab), which was described as transient margination.…”

Section: Discussionmentioning

confidence: 94%

Selective, efficient modulation of activated CD4+ αβT cells by the novel humanized antibody GZ-αβTCR targeting human αβTCR

Blank

Welker

Haarer

et al. 2014

Bone Marrow Transplant

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Allograft rejection and immunosuppression are two major issues in transplantation medicine. The specific targeting of alloreactive T cells, the initiators and promoters of allograft rejection, would be a promising strategy to reduce unwanted T-cell responses and side effects of lifelong immunosuppression. The novel humanized monoclonal antibody GZ-αβTCR, specific for the human αβT-cell receptor, was tested in vitro and in vivo for its specificity and efficacy to modulate the αβT-cell compartment. GZ-αβTCR moderately induced apoptosis in resting αβT cells in vitro, an effect considerably amplified in activated T cells. A single dose of GZ-αβTCR significantly reduced human CD45 + CD3 + T cells in vivo, with a preferential modulation of CD4 + αβT cells. Importantly, naive T cells, the T-cell subset from which alloreactivity emanates, were significantly reduced. Simultaneously, a significant, compensatory increase of γδ T cells was observed in vitro and in vivo in both humanized mouse models examined. GZ-αβTCR did not induce cytokines and was well tolerated. Thus, specificity and high efficacy make GZ-αβTCR a powerful tool to selectively eliminate putatively detrimental T-cell subsets, a major goal in transplantation medicine. At the same time, GZ-αβTCR spares γδ and natural killer cells, thus leaving the recipient's immune system competent for cell-mediated immunoregulation and cell-mediated immunity.

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“…In allograft arteries, agonist-induced vasodilation is severely compromised by IFN-g-mediated inhibition of eNOS expression (19,44). Thus, biological processes that support vasodilation through the induction of NO production in ECs have the potential to preserve lumen diameter and maintain blood flow through allograft arteries.…”

Section: Discussionmentioning

confidence: 99%

Induction of Endothelial Nitric Oxide Synthase Expression by IL-17 in Human Vascular Endothelial Cells: Implications for Vascular Remodeling in Transplant Vasculopathy

Liu

Lee

McManus

et al. 2012

The Journal of Immunology

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IL-17 is a signature cytokine of Th17 cells, a recently described subset of effector CD4 T cells implicated in the development of several pathologies. We have examined the role of IL-17 in regulating endothelial NO synthase (eNOS) expression in human vascular endothelial cells (ECs) because of the key role of eNOS in determining the pathological outcome of immune-mediated vascular diseases. In cultured ECs, IL-17 increased expression of eNOS, eNOS phosphorylation at Ser1177, and NO production. The induction of eNOS expression by IL-17 was prevented by the pharmacological inhibition of NF-κB, MEK, and JNK, as well as by small interfering RNA-mediated gene silencing of these signaling pathways. The expression of IL-17 was then examined by immunohistochemistry in human arteries affected by transplant vasculopathy (TV), a vascular condition that is a leading reflection of chronic heart transplant rejection. IL-17 was expressed by infiltrating leukocytes in the intima of arteries with TV, and the majority of IL-17–positive cells were T cells. The number of IL-17–positive cells was not correlated with the intima/media ratio, but was negatively correlated with the amount of luminal occlusion. There was also a significant positive correlation between the number of IL-17–positive cells and the density of eNOS-expressing luminal ECs in arteries with TV. Altogether, these findings show that IL-17 induces the expression of eNOS in human ECs and that this may facilitate outward expansion of arteries afflicted with TV.

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T cell–mediated vascular dysfunction of human allografts results from IFN-γ dysregulation of NO synthase

Cited by 92 publications

References 54 publications

Retracted: CCR5 blockade in combination with rapamycin prolongs cardiac allograft survival in mice

Retracted: CCR5 blockade in combination with rapamycin prolongs cardiac allograft survival in mice

Selective, efficient modulation of activated CD4+ αβT cells by the novel humanized antibody GZ-αβTCR targeting human αβTCR

Induction of Endothelial Nitric Oxide Synthase Expression by IL-17 in Human Vascular Endothelial Cells: Implications for Vascular Remodeling in Transplant Vasculopathy

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