scholarly journals Small Molecule Inhibition of the Innate Immune Response Increases Transgene Expression

2018 ◽  
Author(s):  
Kyle Spivack ◽  
Christine Muzzelo ◽  
Christopher Neely ◽  
Julia Vanzelli ◽  
Evan Kurt ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Immune Response ◽  
Cell Proliferation ◽  
Innate Immune Response ◽  
Small Molecule ◽  
Transgene Expression ◽  
Defense Mechanism ◽  
Innate Immune ◽  
Luciferase Expression ◽  
Mcf 7

AbstractForeign molecules like plasmid DNA trigger a complex and potent innate immune response comprised of highly redundant signal transduction cascades that result in the activation of transcription factors and the production of inflammatory cytokines. Unfortunately, this defense mechanism can hinder gene therapy by inhibiting transgene expression. The goal of this study was to increase transgene expression by inhibiting key components of the innate immune response (β-catenin, NF-κB/AP1, TBK1, TLR9, and p38 MAPK) with small molecule inhibitors (iCRT-14, curcumin, BX-795, E6446, and VX-702 respectively). The effects of each drug on transgene (luciferase) expression, inflammatory cytokine (IL-6) levels, and cell viability were quantified in prostate (PC3), breast (MCF-7), and murine bladder (MB49) cancer cell lines. The β-catenin inhibitor iCRT-14 (1 μM) provided the highest enhancement of 35.5 ± 19-fold in MCF-7 cells, while the other inhibitors increased transgene expression at a more modest level (2-9 fold). The optimal concentrations of iCRT-14, curcumin, and VX-702 showed no significant effect on cell proliferation; however, optimal concentrations of BX-795 and E6446 did significantly reduce cell proliferation. Nonetheless, inhibition of the innate immune response by iCRT-14 and curcumin was confirmed by a concomitant decrease in IL-6 production in PC3 cells. These results demonstrate that these inhibitors can improve gene therapy by preventing an inflammatory innate immune response.

Hepatocyte-specific inhibitor-of-kappaB-kinase deletion triggers the innate immune response and promotes earlier cell proliferation during liver regeneration

Hepatology ◽  
2008 ◽  
Vol 47 (6) ◽  
pp. 2036-2050 ◽  
Author(s):  
Yann Malato ◽  
Leif E. Sander ◽  
Christian Liedtke ◽  
Malika Al-Masaoudi ◽  
Frank Tacke ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Proliferation ◽  
Liver Regeneration ◽  
Innate Immune Response ◽  
Specific Inhibitor ◽  
Innate Immune

scholarly journals The Challenge for Gene Therapy: Innate Immune Response to Adenoviruses

Oncotarget ◽  
2011 ◽  
Vol 2 (3) ◽  
pp. 113-121 ◽  
Author(s):  
Bart Thaci ◽  
Ilya V. Ulasov ◽  
Derek A. Wainwright ◽  
Maciej S. Lesniak
Keyword(s):  
Gene Therapy ◽  
Immune Response ◽  
Innate Immune Response ◽  
Innate Immune

scholarly journals Novel globular C1q domain-containing protein (PmC1qDC-1) participates in shell formation and responses to pathogen-associated molecular patterns stimulation in Pinctada fucata martensii

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xinwei Xiong ◽  
Chuyi Li ◽  
Zhe Zheng ◽  
Xiaodong Du
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Defense Mechanism ◽  
Innate Immune ◽  
Pinctada Fucata ◽  
Poly I:C ◽  
Shell Formation ◽  
Calcium Carbonate Precipitation ◽  
Reading Frame ◽  
Mantle Edge

AbstractThe C1q protein, which contains the globular C1q (gC1q) domain, is involved in the innate immune response, and is found abundantly in the shell, and it participates in the shell formation. In this study, a novel gC1q domain-containing gene was identified from Pinctada fucata martensii (P. f. martensii) and designated as PmC1qDC-1. The full-length sequence of PmC1qDC-1 was 902 bp with a 534 bp open reading frame (ORF), encoding a polypeptide of 177 amino acids. Quantitative real-time PCR (qRT-PCR) result showed that PmC1qDC-1 was widely expressed in all tested tissues, including shell formation-associated tissue and immune-related tissue. PmC1qDC-1 expression was significantly high in the blastula and gastrula and especially among the juvenile stage, which is the most important stage of dissoconch shell formation. PmC1qDC-1 expression was located in the outer epithelial cells of mantle pallial and mantle edge and irregular crystal tablets were observed in the nacre upon knockdown of PmC1qDC-1 expression at mantle pallial. Moreover, the recombined protein PmC1qDC-1 increased the rate of calcium carbonate precipitation. Besides, PmC1qDC-1 expression was significantly up-regulated in the mantle pallial at 6 h and was significantly up-regulated in the mantle edge at 12 h and 24 h after shell notching. The expression level of PmC1qDC-1 in mantle edge was significantly up-regulated at 48 h after LPS stimulation and was significantly up-regulated at 12 h, 24 h and 48 h after poly I:C stimulation. Moreover, PmC1qDC-1 expression was significantly up-regulated in hemocytes at 6 h after lipopolysaccharide (LPS) and poly I:C challenge. These findings suggest that PmC1qDC-1 plays a crucial role both in the shell formation and the innate immune response in pearl oysters, providing new clues for understanding the shell formation and defense mechanism in mollusk.

scholarly journals Innate Immune Response to Tick-Borne Pathogens: Cellular and Molecular Mechanisms Induced in the Hosts

2020 ◽  
Vol 21 (15) ◽  
pp. 5437 ◽  
Author(s):  
Alessandra Torina ◽  
Sara Villari ◽  
Valeria Blanda ◽  
Stefano Vullo ◽  
Marco Pio La Manna ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Infectious Diseases ◽  
Innate Immune Response ◽  
Molecular Mechanisms ◽  
Defense Mechanism ◽  
Innate Immune ◽  
Bioactive Molecules ◽  
Host Cells ◽  
Ongoing Research

Many pathogens are transmitted by tick bites, including Anaplasma spp., Ehrlichia spp., Rickettsia spp., Babesia and Theileria sensu stricto species. These pathogens cause infectious diseases both in animals and humans. Different types of immune effector mechanisms could be induced in hosts by these microorganisms, triggered either directly by pathogen-derived antigens or indirectly by molecules released by host cells binding to these antigens. The components of innate immunity, such as natural killer cells, complement proteins, macrophages, dendritic cells and tumor necrosis factor alpha, cause a rapid and intense protection for the acute phase of infectious diseases. Moreover, the onset of a pro-inflammatory state occurs upon the activation of the inflammasome, a protein scaffold with a key-role in host defense mechanism, regulating the action of caspase-1 and the maturation of interleukin-1β and IL-18 into bioactive molecules. During the infection caused by different microbial agents, very similar profiles of the human innate immune response are observed including secretion of IL-1α, IL-8, and IFN-α, and suppression of superoxide dismutase, IL-1Ra and IL-17A release. Innate immunity is activated immediately after the infection and inflammasome-mediated changes in the pro-inflammatory cytokines at systemic and intracellular levels can be detected as early as on days 2–5 after tick bite. The ongoing research field of “inflammasome biology” focuses on the interactions among molecules and cells of innate immune response that could be responsible for triggering a protective adaptive immunity. The knowledge of the innate immunity mechanisms, as well as the new targets of investigation arising by bioinformatics analysis, could lead to the development of new methods of emergency diagnosis and prevention of tick-borne infections.

scholarly journals Innate Immune Response to Adenoviral Vectors Is Mediated by both Toll-Like Receptor-Dependent and -Independent Pathways

2007 ◽  
Vol 81 (7) ◽  
pp. 3170-3180 ◽  
Author(s):  
Jiangao Zhu ◽  
Xiaopei Huang ◽  
Yiping Yang
Keyword(s):  
Gene Therapy ◽  
Immune Response ◽  
Immune Responses ◽  
Innate Immune Response ◽  
Adenoviral Vectors ◽  
Innate Immune ◽  
Type I ◽  
Type I Ifn ◽  
Adaptive Immune ◽  
Type I Ifns

ABSTRACT Recombinant adenoviral vectors have been widely used for gene therapy applications and as vaccine vehicles for treating infectious diseases such as human immunodeficiency virus disease. The innate immune response to adenoviruses represents the most significant hurdle in clinical application of adenoviral vectors for gene therapy, but it is an attractive feature for vaccine development. How adenovirus activates innate immunity remains largely unknown. Here we showed that adenovirus elicited innate immune response through the induction of high levels of type I interferons (IFNs) by both plasmacytoid dendritic cells (pDCs) and non-pDCs such as conventional DCs and macrophages. The innate immune recognition of adenovirus by pDCs was mediated by Toll-like receptor 9 (TLR9) and was dependent on MyD88, whereas that by non-pDCs was TLR independent through cytosolic sensing of adenoviral DNA. Furthermore, type I IFNs were pivotal in innate and adaptive immune responses to adenovirus in vivo, and type I IFN blockade diminished immune responses, resulting in more stable transgene expression and reduction of inflammation. These findings indicate that adenovirus activates innate immunity by its DNA through TLR-dependent and -independent pathways in a cell type-specific fashion, and they highlight a critical role for type I IFNs in innate and adaptive immune responses to adenoviral vectors. Our results that suggest strategies to interfere with type I IFN pathway may improve the outcome of adenovirus-mediated gene therapy, whereas approaches to activate the type I IFN pathway may enhance vaccine potency.

scholarly journals Innate Immune Response Induced by Baculovirus Attenuates Transgene Expression in Mammalian Cells

2013 ◽  
Vol 88 (4) ◽  
pp. 2157-2167 ◽  
Author(s):  
C. Ono ◽  
A. Ninomiya ◽  
S. Yamamoto ◽  
T. Abe ◽  
X. Wen ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Mammalian Cells ◽  
Transgene Expression ◽  
Innate Immune ◽  
Expression In Mammalian Cells

scholarly journals Tetrasubstituted imidazoles as incognito Toll-like receptor 8 a(nta)gonists

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yi Yang ◽  
Adam Csakai ◽  
Shuangshuang Jiang ◽  
Christina Smith ◽  
Hiromi Tanji ◽  
...  
Keyword(s):  
Immune Response ◽  
Side Effects ◽  
Inflammatory Response ◽  
Innate Immune Response ◽  
Small Molecule ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Tlr Agonists ◽  
Small Molecule Modulators ◽  
Tetrasubstituted Imidazoles

AbstractSmall-molecule modulators of TLR8 have drawn much interests as it plays pivotal roles in the innate immune response to single-stranded RNAs (ssRNAs) derived from viruses. However, their clinical uses are limited because they can invoke an uncontrolled, global inflammatory response. The efforts described herein culminate in the fortuitous discovery of a tetrasubstituted imidazole CU-CPD107 which inhibits R848-induced TLR8 signaling. In stark contrast, CU-CPD107 shows unexpected synergistic agonist activities in the presence of ssRNA, while CU-CPD107 alone is unable to influence TLR8 signaling. CU-CPD107’s unique, dichotomous behavior sheds light on a way to approach TLR agonists. CU-CPD107 offers the opportunity to avoid the undesired, global inflammation side effects that have rendered imidazoquinolines clinically irrelevant, providing an insight for the development of antiviral drugs.

Oral Immune Activation by Disgust and Disease-Related Pictures

2015 ◽  
Vol 29 (3) ◽  
pp. 119-129 ◽  
Author(s):  
Richard J. Stevenson ◽  
Deborah Hodgson ◽  
Megan J. Oaten ◽  
Luba Sominsky ◽  
Mehmet Mahmut ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Innate Immune Response ◽  
Negative Control ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Immune Markers ◽  
Before And After ◽  
Secondary Analyses ◽  
Image Set

Abstract. Both disgust and disease-related images appear able to induce an innate immune response but it is unclear whether these effects are independent or rely upon a common shared factor (e.g., disgust or disease-related cognitions). In this study we directly compared these two inductions using specifically generated sets of images. One set was disease-related but evoked little disgust, while the other set was disgust evoking but with less disease-relatedness. These two image sets were then compared to a third set, a negative control condition. Using a wholly within-subject design, participants viewed one image set per week, and provided saliva samples, before and after each viewing occasion, which were later analyzed for innate immune markers. We found that both the disease related and disgust images, relative to the negative control images, were not able to generate an innate immune response. However, secondary analyses revealed innate immune responses in participants with greater propensity to feel disgust following exposure to disease-related and disgusting images. These findings suggest that disgust images relatively free of disease-related themes, and disease-related images relatively free of disgust may be suboptimal cues for generating an innate immune response. Not only may this explain why disgust propensity mediates these effects, it may also imply a common pathway.

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