scholarly journals Inhibition of activation-induced death of dendritic cells and enhancement of vaccine efficacy via blockade of MINOR

Blood ◽  
2009 ◽  
Vol 113 (13) ◽  
pp. 2906-2913 ◽  
Author(s):  
Tianhong Wang ◽  
Qiong Jiang ◽  
Camie Chan ◽  
Kevin S. Gorski ◽  
Erin McCadden ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Dendritic Cells ◽  
Vaccine Efficacy ◽  
Lentiviral Vector ◽  
Ex Vivo ◽  
Orphan Receptor ◽  
Activation Induced Cell Death ◽  
Dc Vaccines ◽  
Interfering Rna

Abstract Activation of dendritic cells (DCs) leads to cell maturation, which is accompanied by a regulated pattern of gene expression changes. Two significant and contradictory consequences of DC activation are that, although activation is necessary for maximal T-cell stimulation, it also leads to the initiation of gene expression that results ultimately in cell death. We have identified a gene, MINOR (mitogen-inducible nuclear orphan receptor), that becomes highly up-regulated on activation and whose expression leads to apoptosis in mature DCs. MINOR is a member of the Nur77 family of nuclear orphan receptors, which includes Nur77 and Nurr1. Although Nur77 and Nurr1 are expressed in macrophages and DCs, their expression levels do not change on DC activation. We thus tested the hypothesis that induction of MINOR would lead to an activation-induced cell death in DCs and that its inhibition would increase the lifespan of DCs and improve their vaccine efficacy. To block natural expression of MINOR by DCs, we generated a lentiviral vector that expresses a small interfering RNA. Our results indicate that blockade of MINOR expression dramatically decreases apoptosis in DCs and suggest that this approach may be a novel means to improve the potency of ex vivo–generated DC vaccines.

scholarly journals Dendritic Cells and Stat3 Are Essential for CD137-Induced CD8 T Cell Activation-Induced Cell Death

2010 ◽  
Vol 184 (9) ◽  
pp. 4770-4778 ◽  
Author(s):  
Benyue Zhang ◽  
Yuanyuan Zhang ◽  
Liguo Niu ◽  
Anthony T. Vella ◽  
Robert S. Mittler
Keyword(s):  
Cell Death ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Activation Induced Cell Death

Caspase-cleaved HPK1 induces CD95L-independent activation-induced cell death in T and B lymphocytes

Blood ◽  
2007 ◽  
Vol 110 (12) ◽  
pp. 3968-3977 ◽  
Author(s):  
Dirk Brenner ◽  
Alexander Golks ◽  
Mareike Becker ◽  
Wolfgang Müller ◽  
Christian R. Frey ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Cell Fate ◽  
B Lymphocytes ◽  
T And B Lymphocytes ◽  
Cell Death Pathways ◽  
Activation Induced Cell Death ◽  
Cell Death Pathway ◽  
Dependent Cell ◽  
Interfering Rna

Abstract Life and death of peripheral lymphocytes is strictly controlled to maintain physiologic levels of T and B cells. Activation-induced cell death (AICD) is one mechanism to delete superfluous lymphocytes by restimulation of their immunoreceptors and it depends partially on the CD95/CD95L system. Recently, we have shown that hematopoietic progenitor kinase 1 (HPK1) determines T-cell fate. While full-length HPK1 is essential for NF-κB activation in T cells, the C-terminal fragment of HPK1, HPK1-C, suppresses NF-κB and sensitizes toward AICD by a yet undefined cell death pathway. Here we show that upon IL-2–driven expansion of primary T cells, HPK1 is converted to HPK1-C by a caspase-3 activity below the threshold of apoptosis induction. HPK1-C se-lectively blocks induction of NF-κB–dependent antiapoptotic Bcl-2 family members but not of the proapoptotic Bcl-2 family member Bim. Interestingly, T and B lymphocytes from HPK1-C transgenic mice undergo AICD independently of the CD95/CD95L system but involving caspase-9. Knock down of HPK1/HPK1-C or Bim by small interfering RNA shows that CD95L-dependent and HPK1/HPK1-C–dependent cell death pathways complement each other in AICD of primary T cells. Our results define HPK1-C as a suppressor of antiapoptotic Bcl-2 proteins and provide a molecular basis for our understanding of CD95L-independent AICD of lymphocytes.

Intestinal CD14+ Macrophages Protect CD4+ T Cells From Activation-induced Cell Death via Exosomal Membrane TNF in Crohn’s Disease

2020 ◽  
Vol 14 (11) ◽  
pp. 1619-1631 ◽  
Author(s):  
Huashan Liu ◽  
Zhenxing Liang ◽  
Fengwei Wang ◽  
Xiaobin Zheng ◽  
Ziwei Zeng ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Crohn’S Disease ◽  
T Cell ◽  
Crohn's Disease ◽  
Cd4 T Cells ◽  
Ex Vivo ◽  
Cd4 T Cell ◽  
Activation Induced Cell Death ◽  
Sustained Activation

Abstract Background and aims Sustained activation of CD4+ T cells plays important roles in the pathogenesis of Crohn’s disease [CD]. Under physiologic conditions, activated T cells can be timely eliminated by a process termed activation-induced cell death [AICD], restraining T cell over-activation and preventing immunological destruction. We inquired whether defective AICD might explain CD4+ T cell over-activation in CD and investigated the underlying mechanisms. Methods CD14+ macrophages [Mφ] and CD4+ T cells were isolated from intestinal tissues or peripheral blood of controls and CD patients. An ex vivo evaluation system was employed to simulate AICD and cell apoptosis was measured by flow cytometry. Results CD4+ T cells from CD patients fail to undergo AICD in the ex vivo system. Specifically, proinflammatory type 1 helper T [Th1] and type 17 helper T [Th17] cells, rather than immunosuppressive regulatory T [Treg] cells evade AICD in CD. CD14+ Mφ in the intestinal inflammatory microenvironment of CD promote AICD resistance in CD4+ T cells via a cell-to-cell contact-independent manner. Mechanistically, CD14+ Mφ released exosomes express membrane tumour necrosis factor [TNF] which engages TNFR2 on CD4+ T cells and triggers NF-κB signalling, thereby causing AICD resistance. Importantly, clinically applicable anti-TNF antibodies effectively blocked exosomal membrane TNF-induced CD4+ T cell AICD resistance. Conclusions CD14+ Mφ participate in CD pathogenesis by inducing AICD resistance through release of exosomal membrane TNF to activate the TNFR2/NF-κB pathway in CD4+ T cells. These results present new insights into CD pathogenesis and extend mechanistic understanding of anti-TNF agents. Proposed model CD14+ Mφ in the intestinal microenvironment of CD patients maintain the sustained activation of CD4+ T cells through exosomal membrane TNF to induce apoptosis resistance via TNFR2/NF-κB signalling, which could be effectively blocked by clinically applicable anti-TNF agents.

Autocrine Activation-Induced Cell Death of T Cells By Human Peripheral Blood Monocyte-Derived CD4+ Dendritic Cells

2000 ◽  
Vol 199 (2) ◽  
pp. 115-125 ◽  
Author(s):  
Katsuaki Sato ◽  
Hitomi Nagayama ◽  
Makoto Enomoto ◽  
Kenji Tadokoro ◽  
Takeo Juji ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Dendritic Cells ◽  
Peripheral Blood ◽  
Human Peripheral Blood ◽  
Peripheral Blood Monocyte ◽  
Blood Monocyte ◽  
Activation Induced Cell Death ◽  
Human Peripheral Blood Monocyte

Inhibition of MMP-2 gene expression with small interfering RNA in rabbit vascular smooth muscle cells

2007 ◽  
Vol 293 (6) ◽  
pp. H3593-H3601 ◽  
Author(s):  
Hanna Hlawaty ◽  
Aurélie San Juan ◽  
Marie-Paule Jacob ◽  
Roger Vranckx ◽  
Didier Letourneur ◽  
...  
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Small Interfering Rna ◽  
Ex Vivo ◽  
Gelatin Zymography ◽  
Sirna Transfection ◽  
Interfering Rna

Matrix metalloproteinase-2 (MMP-2) is constitutively expressed in vascular smooth muscle cells (VSMCs). Using small interfering RNA (siRNA), we evaluated the effect of MMP-2 inhibition in VSMCs in vitro and ex vivo. Rabbit VSMCs were transfected in vitro with 50 nmol/l MMP-2 siRNA or scramble siRNA. Flow cytometry and confocal microscopy showed cellular uptake of siRNA in ∼80% of VSMCs. MMP-2 mRNA levels evaluated by real-time RT-PCR, pro-MMP-2 activity from conditioned culture media evaluated by gelatin zymography, and VSMC migration were reduced by 44 ± 19%, 43 ± 14%, and 36 ± 14%, respectively, in MMP-2 siRNA-transfected compared with scramble siRNA-transfected VSMCs ( P < 0.005 for all). Ex vivo MMP-2 siRNA transfection was performed 2 wk after balloon injury of hypercholesterolemic rabbit carotid arteries. Fluorescence microscopy showed circumferential siRNA uptake in neointimal cells. Gelatin zymography of carotid artery culture medium demonstrated a significant decrease of pro-MMP-2 activity in MMP-2 siRNA-transfected compared with scramble siRNA-transfected arteries ( P < 0.01). Overall, our results demonstrate that in vitro MMP-2 siRNA transfection in VSMCs markedly inhibits MMP-2 gene expression and VSMC migration and that ex vivo delivery of MMP-2 siRNA in balloon-injured arteries reduces pro-MMP-2 activity in neointimal cells, suggesting that siRNA could be used to modify arterial biology in vivo.

scholarly journals Insights Into Dendritic Cells in Cancer Immunotherapy: From Bench to Clinical Applications

2021 ◽  
Vol 9 ◽  
Author(s):  
Ahmed Salah ◽  
Hao Wang ◽  
Yanqin Li ◽  
Meng Ji ◽  
Wen-Bin Ou ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Cancer Immunotherapy ◽  
Ex Vivo ◽  
Induced Pluripotent Stem Cell ◽  
Genetically Engineered ◽  
Blood Monocytes ◽  
Pulsed Dc ◽  
Dc Vaccines ◽  
Induced Pluripotent

Dendritic cells (DCs) are efficient antigen-presenting cells (APCs) and potent activators of naïve T cells. Therefore, they act as a connective ring between innate and adaptive immunity. DC subsets are heterogeneous in their ontogeny and functions. They have proven to potentially take up and process tumor-associated antigens (TAAs). In this regard, researchers have developed strategies such as genetically engineered or TAA-pulsed DC vaccines; these manipulated DCs have shown significant outcomes in clinical and preclinical models. Here, we review DC classification and address how DCs are skewed into an immunosuppressive phenotype in cancer patients. Additionally, we present the advancements in DCs as a platform for cancer immunotherapy, emphasizing the technologies used for in vivo targeting of endogenous DCs, ex vivo generated vaccines from peripheral blood monocytes, and induced pluripotent stem cell-derived DCs (iPSC-DCs) to boost antitumoral immunity.

scholarly journals Activation-Induced Cell Death of Dendritic Cells Is Dependent on Sphingosine Kinase 1

2016 ◽  
Vol 7 ◽  
Author(s):  
Anja Schwiebs ◽  
Olga Friesen ◽  
Elisabeth Katzy ◽  
Nerea Ferreirós ◽  
Josef M. Pfeilschifter ◽  
...  
Keyword(s):  
Cell Death ◽  
Dendritic Cells ◽  
Sphingosine Kinase ◽  
Sphingosine Kinase 1 ◽  
Activation Induced Cell Death

Phase I study of immunotherapy for advanced ROR1+ malignancies with autologous ROR1-specific chimeric antigen receptor-modified (CAR)-T cells.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. TPS79-TPS79 ◽  
Author(s):  
Jennifer M Specht ◽  
Sylvia Lee ◽  
Cameron Turtle ◽  
Carolina Berger ◽  
Josh Veatch ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
Phase I Study ◽  
Lentiviral Vector ◽  
Tumor Regression ◽  
Ex Vivo ◽  
Orphan Receptor ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T

TPS79 Background: CAR-T cells have demonstrated marked tumor regression in patients (pts) with hematologic malignancies. ROR1, a tyrosine kinase orphan receptor, is expressed in triple negative breast cancers (TNBC) and non-small cell lung cancers (NSCLC) and is a novel candidate for CAR-T cell therapy. ROR1-specific CAR-T cells are engineered with lentiviral vector encoding ROR1 scFv/4-1BB/CD3ζ and a truncated EGFR molecule to permit elimination of ROR1 CAR-T cells in case of toxicity. Methods: NCT02706362 is a phase I study evaluating the safety and anti-tumor activity of adoptively transferred autologous ROR1 CAR-T cells in pts with advanced ROR1+ TNBC and NSCLC. Eligibility criteria include: metastatic TNBC or NSCLC; measurable disease; prior standard therapy with no maximum on number of prior regimens; tumor ROR1 expression > 20% by IHC; KPS > 70%; age ≥18; negative pregnancy test for women of childbearing potential; informed consent; adequate organ function. Exclusions are: active autoimmune disease or uncontrolled infection, HIV seropositive status, contraindication to cyclophosphamide, anticipated survival < 3 months, and/or untreated CNS metastases. After screening, leukapheresis is performed, CD8+ and CD4+ T cells are selected, then transduced with the ROR1+ CAR lentivirus and expanded. Lymphodepletion with cyclophosphamide and fludarabine is followed 36-96 hours later by infusion of ROR1 CAR-T cells in escalating doses (3.3 x 105/kg - 1 x 107/kg cells with defined CD8+ and CD4+ composition). Pts are treated in cohorts of 2 to determine cell dose associated with an estimated toxicity rate of < 25%. Primary aim is to determine the maximum tolerated dose (MTD) and safety of ex vivo expanded ROR1 CAR-T cells. Secondary aims include persistence and phenotype of transferred T cells, trafficking of T cells to tumor site, in vivo function, and preliminary antitumor activity of ROR1 CAR-T cells by RECIST 1.1. Dose escalation is determined by CRM algorithm with minimum of 21-day interval following infusion between pts. Preliminary estimates of efficacy will be obtained among all pts and those treated at estimated MTD. Six of 30 pts have been enrolled with no DLTs observed. Clinical trial information: NCT02706392.

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