IL-11 Protects Human Microvascular Endothelium from Alloinjury In Vivo by Induction of Survivin Expression

Kirkiles-Smith, Nancy C.; Mahboubi, Keyvan; Plescia, Janet; McNiff, Jennifer M.; Karras, James G.; Schechner, Jeffrey S.; Altieri, Dario C.; Pober, Jordan S.

doi:10.4049/jimmunol.172.3.1391

Cited by 44 publications

(25 citation statements)

References 36 publications

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“…Apoptosis in human umbilical vascular endothelial cells (HUVEC) is inhibited by angiopoeitin 1 via up-regulation of survivin expression through the forkhead-related transcription factor pathway (67). Interleukin-11 induces survivin expression in HUVEC via the signal transducer and activator of transcription-3 pathway (68) and protects human endothelial cells from graft injury caused by allogenic peripheral blood mononuclear cells (69). Furthermore, hypoxia/ischemia induces survivin expression in microvessels in the periinfarct regions in mouse brain (70), implicating survivin as a regulator of angiogenesis in ischemic brain.…”

Section: Role Of Survivin and Cytokine-regulated Expression In Vasculmentioning

confidence: 99%

Survivin, a cancer target with an emerging role in normal adult tissues

Fukuda

Pelus

2006

Molecular Cancer Therapeutics

432

360

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Survivin, an inhibitor of apoptosis protein, is highly expressed in most cancers and associated with chemotherapy resistance, increased tumor recurrence, and shorter patient survival, making antisurvivin therapy an attractive cancer treatment strategy. However, growing evidence indicates that survivin is expressed in normal adult cells, particularly primitive hematopoietic cells, T lymphocytes, polymorphonuclear neutrophils, and vascular endothelial cells, and may regulate their proliferation or survival. In preclinical animal models, targeted antisurvivin therapies show efficacy without overt toxicity. However, consequences of prolonged survivin disruption in normal cells, particularly those associated with continuous renewal, have not been clearly determined. Understanding the role of survivin in normal versus malignant cells will be important in identifying strategies that maximally disrupt survivin in cancer cells with minimal effect on normal tissues. In this review, we summarize the prognostic relevance of survivin in cancer that justifies the pursuit of antisurvivin therapies and discuss differences in survivin expression between normal and cancer cells. We subsequently review expression of survivin in normal adult tissues and evaluate preclinical antisurvivin therapies reported to date in light of emerging roles for survivin in normal physiology, particularly hematopoiesis, angiogenesis, and immune function. [Mol Cancer Ther 2006;5(5):1087 -98]

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Section: Role Of Survivin and Cytokine-regulated Expression In Vasculmentioning

confidence: 99%

Survivin, a cancer target with an emerging role in normal adult tissues

Fukuda

Pelus

2006

Molecular Cancer Therapeutics

432

360

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“…Circulating human T cells were evaluated by flow cytometry as previously described (20). In brief, heparinized retro-orbital venous samples were obtained 14 days after reconstitution, and the erythrocytes were lysed.…”

Section: Cd45ramentioning

confidence: 99%

“…PBMCs were isolated by density gradient centrifugation of leukapharesis products by using lymphocyte separation medium (Invitrogen Life Technologies). Isolated cells were stored in 10% DMSO-90% FBS at Ϫ196°C and were thawed and washed before use (20). CD4/8 ϩ T cells were isolated from PBMCs by positive selection by using Dynabeads (Dynal Biotech).…”

Section: Isolation and Culture Of Human Cellsmentioning

confidence: 99%

“…cDNA was synthesized using Taqman RT reagents (Applied Biosystems), following the manufacturer's instructions. Quantitative real-time PCR (qRT-PCR) for 4-1BBL, ICOSL, OX40L, FasL, granzyme B, and perforin and CD3⑀ was performed exactly as described (22), using primers shown in Table I or as previously described (20). Samples were analyzed by generating a standard curve from plasmids containing the PCR fragment and expressed as copy number where indicated.…”

Section: Preparation Of Rna and Cdna And Procedures For Quantitative Pcrmentioning

confidence: 99%

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Memory T Cells and Their Costimulators in Human Allograft Injury

Shiao¹,

McNiff²,

Pober

2005

The Journal of Immunology

Self Cite

105

100

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Both CD4+ and CD8+ human memory but not naive T cells respond to allogeneic human dermal microvascular endothelial cells (HDMEC) in vitro by secreting cytokines and by proliferating. Several recently identified costimulators, namely, 4-1BB ligand, ICOS ligand, and OX40 ligand, are up-regulated on cultured HDMEC in response to TNF or coculture with allogeneic T cells. Blockade of these costimulators each partially reduces IFN-γ and IL-2 secretion and proliferation of previously resting memory T cells. The effects of these costimulators are overlapping but not identical. Memory but not naive T cells are the principal effectors of microvascular injury in human skin allografts following adoptive transfer into immunodeficient mice. Furthermore, blocking 4-1BB ligand, ICOS ligand, or OX40 ligand in this model reduces human skin allograft injury and T cell effector molecule expression. These data demonstrate that human memory T cells respond to microvascular endothelial cells and can injure allografts in vivo without priming. Furthermore, several recently described costimulators contribute to these processes.

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“…There is in vivo evidence that IL-11 treatment enhanced recipient survival by suppressing cytokine production. [33][34][35] This anti-inflammatory effect is mediated by its ability to block the nuclear translocation of NFkB. In our siCD40-treated grafts, NFkB expression was downregulated and its translocation to the nucleus was blocked.…”

Section: Local Silencing Of Cd40 Changes Rejection Pattern E Ripoll Ementioning

confidence: 86%

In vivo therapeutic efficacy of intra-renal CD40 silencing in a model of humoral acute rejection

et al. 2011

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The humoral branch of the immune response has an important role in acute and chronic allograft dysfunction. The CD40/CD40L costimulatory pathway is crucial in B-and T-alloresponse. Our group has developed a new small interfering RNA (siRNA) molecule against CD40 that effectively inhibits its expression. The aim of the present study was to prevent rejection in an acute vascular rejection model of kidney transplant by intra-graft gene silencing with anti-CD40 siRNA (siCD40), associated or not with sub-therapeutic rapamycin. Four groups were designed: unspecific siRNA as control; sub-therapeutic rapamycin; siCD40; and combination therapy. Long-surviving rats were found only in both siCD40-treated groups. The CD40 mRNA was overexpressed in control grafts but treatment with siCD40 decreased its expression. Recipient spleen CD40+ B-lymphocytes were reduced in both siCD40-treated groups. Moreover, CD40 silencing reduced donor-specific antibodies, graft complement deposition and immune-inflammatory mediators. The characteristic histological features of humoral rejection were not found in siCD40-treated grafts, which showed a more cellular histological pattern. Therefore, the intra-renal effective blockade of the CD40/CD40L signal reduces the graft inflammation as well as the incidence of humoral vascular acute rejection, finally changing the type of rejection from humoral to cellular. Gene Therapy (2011) 18, 945-952;

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IL-11 Protects Human Microvascular Endothelium from Alloinjury In Vivo by Induction of Survivin Expression

Cited by 44 publications

References 36 publications

Survivin, a cancer target with an emerging role in normal adult tissues

Survivin, a cancer target with an emerging role in normal adult tissues

Memory T Cells and Their Costimulators in Human Allograft Injury

In vivo therapeutic efficacy of intra-renal CD40 silencing in a model of humoral acute rejection

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