Stimulation Of Immune Cells Research Articles

A novel therapy for melanoma developed in mice: transformation of melanoma into dendritic cells with Listeria monocytogenes.

Listeria monocytogenes is a gram-positive bacteria and human pathogen widely used in cancer immunotherapy because of its capacity to induce a specific cytotoxic T cell response in tumours. This bacterial pathogen strongly induces innate and specific immunity with the potential to overcome tumour induced tolerance and weak immunogenicity. Here, we propose a Listeria based vaccination for melanoma based in its tropism for these tumour cells and its ability to transform in vitro and in vivo melanoma cells into matured and activated dendritic cells with competent microbicidal and antigen processing abilities. This Listeria based vaccination using low doses of the pathogen caused melanoma regression by apoptosis as well as bacterial clearance. Vaccination efficacy is LLO dependent and implies the reduction of LLO-specific CD4+ T cell responses, strong stimulation of innate pro-inflammatory immune cells and a prevalence of LLO-specific CD8+ T cells involved in tumour regression and Listeria elimination. These results support the use of low doses of pathogenic Listeria as safe melanoma therapeutic vaccines that do not require antibiotics for bacterial removal.

Andosan?-An Anti-Allergic and Anti-Inflammatory Ingredient Prepared from Agaricus blazei Mushroom

Andosan™ is an extract prepared from medicinal Basidiomycetes mushrooms, mainly Agaricus blazei Murill (AbM) (82%), but it also contains Hericeum erinaceus (He) (15%) and Grifola frondosa (Gf) (3%), all of which have immunomodulating properties. Whereas He and Gf have been used in traditional Chinese and Japanese medicine against cancer, AbM originates from Brazilian rain forest and was used locally and later abroad as health food for the prevention of a range of diseases, including chronic hepatitis, diabetes and cancer. The mushrooms’ health effects are probably due to their content of A¯ÂÂ¢-glucans and other smaller immunomodulating polysaccharides and proteoglucans. These effects are mediated through their stimulation of innate immune cells, such as monocytes, NK cells and dendritic cells, and the amelioration of a skewded Th1/Th2 balance and of inflammation. Here, we give an overview of the anti-allergic effects of Andosan™ in a mouse model for allergy and anti-inflammatory effects both in vitro, in healthy individuals and in patients with inflammatory bowel diseases.

Stimulation of Innate Immune Cells Induced by Probiotics: Participation of Toll-Like Receptors

Objective: The present work aimed to study the functionality of macrophages from different locations (peritoneum, spleen and Peyer´s patches) when they were stimulated with probiotics microorganisms: Lactobacillus casei CRL 431 and Lactobacillus paracasei CNCM I-1518 or a Probiotic Fermented Milk (PFM) through Toll-Like Receptors (TLRs), prior challenged with agonists or antagonists of TLRs. Methods: BALB/c mice received in the drinking water, the probiotic bacteria (L. casei CRL 431 and L. paracasei CNCM I-1518) or the PFM. We focused our investigation mainly on the phagocytic activity of macrophages from peritoneum, spleen and Peyer’s patches and cytokine production were evaluated prior challenged with TLR2 and TLR4 agonists or antagonists. The microbicidal activity of macrophages and against an infection with Salmonella typhimurium was also studied. To assess the role of TLR in probiotic stimulation, we evaluated the phagocytic activity, cytokine production and Immunoglobin G (IgG) anti-OVA in C57BL/6 knockout mice to MyD88, TLR2 and TLR4. Results: In BALB/c mice, the best effect in the phagocytosis assay was obtained with the probiotic bacteria L. casei CRL 431, this effect was reinforced with TLR2 agonist. The production of different cytokines (IL-10 and IL-6) was improved with the probiotic treatments and this production was ameliorated with TLRs agonists. The antimicrobial activity was increased with L. casei CRL 431 and L. paracasei CNCM I-1518, TLR2 and TLR4 antagonists had a negative effect on microbicidal activity. The administration of probiotic bacteria or PFM improved the host response against S. typhimurium controlling the infection during the first hours post-infection. In C57BL/6 knockout mice, phagocytic activity was significantly diminished in comparison to wild type mice and the probiotic bacteria or PFM administration was not able to improve this activity. The IL-10 production was increased at a concentration of 108 cells/ml of L. casei CRL 431 in TLR2-/- and TLR4-/-, but not in MyD88-/- mice. The administration of probiotic bacteria or PFM did not play a stimulating effect in the systemic immune response against to OVA antigen in knockout mice. Conclusions: Probiotics modulate the different signaling pathways of innate immune cells through the TLRs. The macrophages activation depends on location of them and that different probiotic strains of Lactobacilli can evoke different intensity of responses. The data suggest that probiotic not only promote a major expression of TLRs but also use these receptors via the innate immune cells as macrophages to stimulate and modulate the immune response.

In vivo gold nanoparticle delivery of peptide vaccine induces anti-tumor immune response in prophylactic and therapeutic tumor models.

Gold nanoparticles (AuNPs) are promising vehicles for cancer immunotherapy, with demonstrated efficacy in immune delivery and innate cell stimulation. Nevertheless, their potential has yet to be assessed in the in vivo application of peptide cancer vaccines. In this study, it is hypothesized that the immune distribution and adjuvant qualities of AuNPs could be leveraged to facilitate delivery of the ovalbumin (OVA) peptide antigen and the CpG adjuvant and enhance their therapeutic effect in a B16-OVA tumor model. AuNP delivery of OVA (AuNP-OVA) and of CpG (AuNP-CpG) enhanced the efficacy of both agents and induced strong antigen-specific responses. In addition, it is found that AuNP-OVA delivery alone, without CpG, is sufficient to promote significant antigen-specific responses, leading to subsequent anti-tumor activity and prolonged survival in both prophylactic and therapeutic in vivo tumor models. This enhanced therapeutic efficacy is likely due to the adjuvant effect of peptide coated AuNPs, as they induce inflammatory cytokine release when cultured with bone marrow dendritic cells. Overall, AuNP-mediated OVA peptide delivery can produce significant therapeutic benefits without the need of adjuvant, indicating that AuNPs are effective peptide vaccine carriers with the potential to permit the use of lower and safer adjuvant doses during vaccination.

Impacts of the feed contaminant deoxynivalenol on the intestine of monogastric animals: poultry and swine.

Deoxynivalenol (DON) is one of the most prevalent cereal contaminants with major public health concerns owing to its high toxigenic potentials. Once ingested, DON first and foremost targets epithelial cells of the gastrointestinal tract, whose proper functioning, as the first line of defence, is of paramount importance for the host's health. Emerging evidences, summarized in this article, suggest that DON produces its toxicity primarily via activation of the mitogen-activated protein kinases (MAPKs) signalling pathway and alteration in the expression of genes responsible for key physiological and immunological functions of the intestinal tissue of chickens and pigs. The activation of MAPKs signalling cascade results in disruption of the gut barrier function and an increase in the permeability by reducing expression of the tight junction proteins. Exposure to DON also down-regulates the expression of multiple transporter systems in the enterocytes with subsequent impairment of the absorption of key nutrients. Other major intestinal cytotoxic effects of DON described herein are modulation of mucosal immune responses, leading to immunosupression or stimulation of local immune cells and cytokine release, and also facilitation of the persistence of intestinal pathogens in the gut. Both of the last events potentiate enteric infections and local inflammation in pigs and poultry, rendering enterocytes and the host more vulnerable to luminal toxic compounds. This review highlights the cytotoxic risks associated with the intake of even low levels of DON and also identifies gaps of knowledge that need to be addressed by future research.

Mimotope-based vaccines of Leishmania infantum antigens and their protective efficacy against visceral leishmaniasis.

BackgroundThe development of cost-effective prophylactic strategies to prevent leishmaniasis has become a high-priority. The present study has used the phage display technology to identify new immunogens, which were evaluated as vaccines in the murine model of visceral leishmaniasis (VL). Epitope-based immunogens, represented by phage-fused peptides that mimic Leishmania infantum antigens, were selected according to their affinity to antibodies from asymptomatic and symptomatic VL dogs' sera.Methodology/Main FindingsTwenty phage clones were selected after three selection cycles, and were evaluated by means of in vitro assays of the immune stimulation of spleen cells derived from naive and chronically infected with L. infantum BALB/c mice. Clones that were able to induce specific Th1 immune response, represented by high levels of IFN-γ and low levels of IL-4 were selected, and based on their selectivity and specificity, two clones, namely B10 and C01, were further employed in the vaccination protocols. BALB/c mice vaccinated with clones plus saponin showed both a high and specific production of IFN-γ, IL-12, and GM-CSF after in vitro stimulation with individual clones or L. infantum extracts. Additionally, these animals, when compared to control groups (saline, saponin, wild-type phage plus saponin, or non-relevant phage clone plus saponin), showed significant reductions in the parasite burden in the liver, spleen, bone marrow, and paws' draining lymph nodes. Protection was associated with an IL-12-dependent production of IFN-γ, mainly by CD8+ T cells, against parasite proteins. These animals also presented decreased parasite-mediated IL-4 and IL-10 responses, and increased levels of parasite-specific IgG2a antibodies.Conclusions/SignificanceThis study describes two phage clones that mimic L. infantum antigens, which were directly used as immunogens in vaccines and presented Th1-type immune responses, and that significantly reduced the parasite burden. This is the first study that describes phage-displayed peptides as successful immunogens in vaccine formulations against VL.

Hyperoxygenation attenuated a murine model of atopic dermatitis through raising skin level of ROS.

Atopic dermatitis (AD) is a chronic inflammatory skin disease resulting from excessive stimulation of immune cells. Traditionally, reactive oxygen species (ROS) have been implicated in the progression of inflammatory diseases, but several opposing observations suggest the protective role of ROS in inflammatory disease. Recently, we demonstrated ROS prevented imiquimod-induced psoriatic dermatitis through enhancing regulatory T cell function. Thus, we hypothesized AD might also be attenuated in elevated levels of ROS through tissue hyperoxygenation, such as by hyperbaric oxygen therapy (HBOT) or applying an oxygen-carrying chemical, perfluorodecalin (PFD). Elevated levels of ROS in the skin have been demonstrated directly by staining with dihydroethidum as well as indirectly by immunohistochemistry (IHC) for indoleamine 2,3-dioxygenase (IDO). A murine model of AD was developed by repeated application of a chemical irritant (1% 2,4-dinitrochlorobenzene) and house dust mite (Dermatophagoide farinae) extract on one ear of BALB/c mice. The results showed treatment with HBOT or PFD significantly attenuated AD, comparably with 0.1% prednicarbate without any signs of side effects, such as telangiectasia. The expressions of interleukin-17A and interferon-γ were also decreased in the AD lesions by treatment with HBOT or PFD. Enhanced expression of IDO and reduced level of hypoxia-inducible factor-1α, in association with increased frequency of FoxP3+ regulatory T cells in the AD lesions, might be involved in the underlying mechanism of oxygen therapy. Taken together, it was suggested that tissue hyperoxygenation, by HBOT or treatment with PFD, might attenuate AD through enhancing skin ROS level.

Stimulation of innate immune cells by light-activated TLR7/8 agonists.

The innate immune response is controlled, in part, by the synergistic interaction of multiple Toll-like receptors (TLRs). This multi-receptor cooperation is responsible for the potent activity of many vaccines, but few tools have been developed to understand the spatio-temporal elements of TLR synergies. In this Communication, we present photo-controlled agonists of TLR7/8. By strategically protecting the active agonist moiety based on an agonist-bound crystal structure, TLR activity is suppressed and then regained upon exposure to light. We confirmed NF-κB production upon light exposure in a model macrophage cell line. Primary cell activity was confirmed by examining cytokine and cell surface marker production in bone-marrow-derived dendritic cells. Finally, we used light to activate dendritic cell sub-populations within a larger population.

CLINICAL TRIALS OF A THIRD-GENERATION RECOMBINANT ONCOLYTIC HSV-1 IN RECURRENT GLIOBLASTOMA AND OLFACTORY NEUROBLASTOMA PATIENTS

BACKGROUND: Genetically engineered, conditionally replicating herpes simplex viruses type 1 (HSV-1) are promising therapeutic agents for cancer. We have developed a triple-mutated, third-generation oncolytic HSV-1, G47Δ, by introducing an additional genetic mutation in the viral genome of G207, a second-generation HSV-1 used in multiple clinical trials for glioblastoma in the US. In preclinical studies, G47Δ exhibited better stimulation of human antitumor immune cells, better growth properties leading to higher virus yields and increased cytopathic effect in vitro, better antitumor efficacy in various mouse cancer models, and preserved safety in HSV-1-sensitive mice compared with G207. METHODS: Clinical-grade G47Δ has been manufactured at the GMP Vector Production Facility at the Institute of Medical Science, the University of Tokyo. The first-in-man clinical trial of G47Δ started in 2009. It is an open-label, single-armed, phase I-IIa study in patients with a single lesion of recurrent glioblastoma. For each patient, G47Δ is administered stereotactically into the tumor, twice within 14 days. RESULTS: So far, the treatment has been well tolerated by patients. Clinical observations in some patients hint the efficacy of G47Δ for glioblastoma, which warrants further clinical development for glioblastoma as well as for other cancer. This first trial teaches us that conventional methods for efficacy evaluation such as RECIST and WHO criteria may not be adequate for oncolytic virus therapy. Also, a conventional dose escalation scheme for anti-cancer drugs may not be suited for designing phase I trials for oncolytic virus therapy. Because the extent of viral replication and the strength of immune responses vary considerably among patients, a preferred means of treatment using oncolytic HSV-1 may be repeating local injections until the cancer is cured. In the new clinical trial that started in 2013 for recurrent olfactory neuroblastoma, the patients receive repeated intratumoral G47Δ administration every 4 weeks until the shrinkage of the tumor or the patient is judged to have progressive disease. CONCLUSIONS: G47Δ is considered to be efficacious not only for brain tumors but for a variety of solid cancer. We aim that oncolytic virus therapy using G47Δ become a standard therapeutic option for brain tumor and cancer patients in the near future. SECONDARY CATEGORY: n/a.

Integrated Nanoplasmonic Sensing for Cellular Functional Immunoanalysis Using Human Blood

Localized surface plasmon resonance (LSPR) nanoplasmonic effects allow for label-free, real-time detection of biomolecule binding events on a nanostructured metallic surface with simple optics and sensing tunability. Despite numerous reports on LSPR bionanosensing in the past, no study thus far has applied the technique for a cytokine secretion assay using clinically relevant immune cells from human blood. Cytokine secretion assays, a technique to quantify intercellular-signaling proteins secreted by blood immune cells, allow determination of the functional response of the donor’s immune cells, thus providing valuable information about the immune status of the donor. However, implementation of LSPR bionanosensing in cellular functional immunoanalysis based on a cytokine secretion assay poses major challenges primarily owing to its limited sensitivity and a lack of sufficient sample handling capability. In this paper, we have developed a label-free LSPR biosensing technique to detect cell-secreted tumor necrosis factor (TNF)-α cytokines in clinical blood samples. Our approach integrates LSPR bionanosensors in an optofluidic platform that permits trapping and stimulation of target immune cells in a microfluidic chamber with optical access for subsequent cytokine detection. The on-chip spatial confinement of the cells is the key to rapidly increasing a cytokine concentration high enough for detection by the LSPR setup, thereby allowing the assay time and sample volume to be significantly reduced. We have successfully applied this approach first to THP-1 cells and then later to CD45 cells isolated directly from human blood. Our LSPR optofluidics device allows for detection of TNF-α secreted from cells as few as 1000, which translates into a nearly 100 times decrease in sample volume than conventional cytokine secretion assay techniques require. We achieved cellular functional immunoanalysis with a minimal blood sample volume (3 μL) and a total assay time 3 times shorter than that of the conventional enzyme-linked immunosorbent assay (ELISA).

Autonomic regulation of cellular immune function

The nervous system and the immune system (IS) are two integrative systems that work together to detect threats and provide host defense, and to maintain/restore homeostasis. Cross-talk between the nervous system and the IS is vital for health and well-being. One of the major neural pathways responsible for regulating host defense against injury and foreign antigens and pathogens is the sympathetic nervous system (SNS). Stimulation of adrenergic receptors (ARs) on immune cells regulates immune cell development, survival, proliferative capacity, circulation, trafficking for immune surveillance and recruitment, and directs the cell surface expression of molecules and cytokine production important for cell-to-cell interactions necessary for a coordinated immune response. Finally, AR stimulation of effector immune cells regulates the activational state of immune cells and modulates their functional capacity. This review focuses on our current understanding of the role of the SNS in regulating host defense and immune homeostasis. SNS regulation of IS functioning is a critical link to the development and exacerbation of chronic immune-mediated diseases. However, there are many mechanisms that need to be further unraveled in order to develop sound treatment strategies that act on neural-immune interaction to resolve or prevent chronic inflammatory diseases, and to improve health and quality of life.

Effects of Aging on Influenza Virus Infection Dynamics

The consequences of influenza virus infection are generally more severe in individuals over 65 years of age (the elderly). Immunosenescence enhances the susceptibility to viral infections and renders vaccination less effective. Understanding age-related changes in the immune system is crucial in order to design prophylactic and immunomodulatory strategies to reduce morbidity and mortality in the elderly. Here, we propose different mathematical models to provide a quantitative understanding of the immune strategies in the course of influenza virus infection using experimental data from young and aged mice. Simulation results suggested a central role of CD8(+) T cells for adequate viral clearance kinetics in young and aged mice. Adding the removal of infected cells by natural killer cells did not improve the model fit in either young or aged animals. We separately examined the infection-resistant state of cells promoted by the cytokines alpha/beta interferon (IFN-α/β), IFN-γ, and tumor necrosis factor alpha (TNF-α). The combination of activated CD8(+) T cells with any of the cytokines provided the best fits in young and aged animals. During the first 3 days after infection, the basic reproductive number for aged mice was 1.5-fold lower than that for young mice (P < 0.05). The fits of our models to the experimental data suggest that the increased levels of IFN-α/β, IFN-γ, and TNF-α (the "inflammaging" state) promote slower viral growth in aged mice, which consequently limits the stimulation of immune cells and contributes to the reported impaired responses in the elderly. A quantitative understanding of influenza virus pathogenesis and its shift in the elderly is the key contribution of this work.

Neural progenitor cells from human induced pluripotent stem cells generated less autogenous immune response

The breakthrough development of induced pluripotent stem cells (iPSCs) raises the prospect of patient-specific treatment for many diseases through the replacement of affected cells. However, whether iPSC-derived functional cell lineages generate a deleterious immune response upon auto-transplantation remains unclear. In this study, we differentiated five human iPSC lines from skin fibroblasts and urine cells into neural progenitor cells (NPCs) and analyzed their immunogenicity. Through co-culture with autogenous peripheral blood mononuclear cells (PBMCs), we showed that both somatic cells and iPSC-derived NPCs do not stimulate significant autogenous PBMC proliferation. However, a significant immune reaction was detected when these cells were co-cultured with allogenous PBMCs. Furthermore, no significant expression of perforin or granzyme B was detected following stimulation of autogenous immune effector cells (CD3(+)CD8(-) T cells, CD3(+)CD8(+) T cells or CD3(-)CD56(+) NK cells) by NPCs in both PBMC and T cell co-culture systems. These results suggest that human iPSC-derived NPCs may not initiate an immune response in autogenous transplants, and thus set a base for further preclinical evaluation of human iPSCs.

LEUKOTRIENE RECEPTOR ANTAGONISTS IN DIFFERENT PHENOTYPES OF BRONCHIAL ASTHMA

Cysteinyl leukotrienes which are products of lipoxygenase pathway of arachidonic acid metabolism play an important role in all phenotypes of bronchial asthma (BA). They are involved in immune and non-immune stimulation of different cells and inflammatory mechanisms in BA. Leukotrienes cause bronchoconstriction, increase vascular permeability and bronchial mucosa oedema, stimulate mucus secretion. Knowledge of leukotriene as inflammation mediators has allowed development leukotriene receptor antagonists and their implementation in clinical practice. Antiinflammatory properties of leukotriene receptor antagonists facilitate achievement asthma control while using both as monotherapy in mild asthma and in combinations with other antiasthmatic drugs in more severe disease. Currently, ongoing research of asthma phenotypes could define certain phenotypes with more important role of leukotrienes.

The bispecific immunoligand ULBP2‐aCEA redirects natural killer cells to tumor cells and reveals potent anti‐tumor activity against colon carcinoma

NKG2D, an activating receptor expressed on NK cells and T cells, is critically involved in tumor immunosurveillance. In this study, we explored the potential therapeutic utility of the NKG2D ligand ULBP2 for the treatment of colon carcinoma. To this end we designed a fusion protein consisting of human ULBP2 and an antibody-derived single chain targeting the tumor carcinoembryonic antigen (CEA). The bispecific recombinant fusion protein re-directed NK cells towards malignant cells by binding to both, tumor cells and NK cells, and triggered NK cell-mediated target cell killing in vitro. Moreover, tumor growth was significantly delayed in a syngeneic colon carcinoma mouse model in response to immunoligand treatment. The anti-tumor activity could be attributed to the stimulation of immune cells with an elevated expression of the activation marker CD69 on NK, T and NKT cells and the infiltration of CD45+ immune cells into the solid tumor. In summary, it was demonstrated that immunoligands provide specific tumor targeting by NK cells and exert anti-tumor activity in vitro and in vivo. This technology represents a novel immunotherapeutic strategy for solid tumors with the potential to be further developed for clinical applications.

Activation of Protein Tyrosine Phosphatase Non-Receptor Type 2 by Spermidine Exerts Anti-Inflammatory Effects in Human THP-1 Monocytes and in a Mouse Model of Acute Colitis

BackgroundSpermidine is a dietary polyamine that is able to activate protein tyrosine phosphatase non-receptor type 2 (PTPN2). As PTPN2 is known to be a negative regulator of interferon-gamma (IFN-γ)-induced responses, and IFN-γ stimulation of immune cells is a critical process in the immunopathology of inflammatory bowel disease (IBD), we wished to explore the potential of spermidine for reducing pro-inflammatory effects in vitro and in vivo.MethodsHuman THP-1 monocytes were treated with IFN-γ and/or spermidine. Protein expression and phosphorylation were analyzed by Western blot, cytokine expression by quantitative-PCR, and cytokine secretion by ELISA. Colitis was induced in mice by dextran sodium sulfate (DSS) administration. Disease severity was assessed by recording body weight, colonoscopy and histology.ResultsSpermidine increased expression and activity of PTPN2 in THP-1 monocytes and reduced IFN-γ-induced phosphorylation of signal transducer and activator of transcription (STAT) 1 and 3, as well as p38 mitogen-activated protein kinase (MAPK) in a PTPN2 dependent manner. Subsequently, IFN-γ-induced expression/secretion of intracellular cell adhesion molecule (ICAM)-1 mRNA, monocyte chemoattractant protein (MCP)-1, and interleukin (IL)-6 was reduced in spermidine-treated cells. The latter effects were absent in PTPN2-knockdown cells. In mice with DSS-induced colitis, spermidine treatment resulted in ameliorated weight loss and decreased mucosal damage indicating reduced disease severity.ConclusionsActivation of PTPN2 by spermidine ameliorates IFN-γ-induced inflammatory responses in THP-1 cells. Furthermore, spermidine treatment significantly reduces disease severity in mice with DSS-induced colitis; hence, spermidine supplementation and subsequent PTPN2 activation may be helpful in the treatment of chronic intestinal inflammation such as IBD.

LOW-DOSE RECOMBINANT VACCINE ANTIGEN DELIVERY BY ENGINEERED OUTER MEMBRANE VESICLES

The use of engineered antigen carriers to optimize the immune response to recombinant subunit vaccines has seen great advances in recent years. Optimization can take several forms, such as facilitating stimulation of certain immune cells or amplifying the adjuvancy effect of the vaccine formulation. In this paper, we applied dose/response analysis to demonstrate the ability of outer membrane vesicle (OMV) antigen carriers derived from engineered Escherichia coli to produce strong antigen-specific immune responses to a model antigen at a significantly decreased antigen load compared to an industry standard alum-based control. Inflammopathology and histological analysis of extended studies further supported a capacity to enhance immune cell recruitment locally at the injection site while decreasing inflammation and eliminating injection site scaring. The results indicate a strong potential for OMV-based vaccines as recombinant antigen delivery vehicles, affording strong immunogenicity at low doses with a broadly applicable platform for recombinant subunit antigen inclusion.

The Resolusion of Ethyl (S)-Nipecotate and the New Synthesis of Ethyl-1- (2-Thiopheneacetyl)-3-Piperidine Carboxylate

The optically pure ethyl nipecotate is an important drug intermediates. It was used for a variety of synthesis of APIs and pharmaceutical intermediates. In this paper we launched a study of the split of ethyl nipecotate. An efficient resolution of (±)-nipecotic acid has been achieved by the fractional crystallization with good yield and high enatio. The compound (S)-ethyl-1-(2-thiopheneacetyl)-3-piperidine-carboxylate is an investigational immune potentiating agent targeting direct stimulation of immune cells, useful for the prevention of infectious diseases in livestock.

DsDNA ASCs for caspase 8-mediated apoptosis

dsDNA ASCs for caspase 8-mediated apoptosis

Nucleic Acid Scavenging Polymers Inhibit Extracellular DNA-Mediated Innate Immune Activation without Inhibiting Anti-Viral Responses

Toll-like receptor (TLR) family members, 3, 7 and 9 are key components in initiation and progression of autoimmune disorders such as systemic lupus erythematosus (SLE). These TLRs are often referred to as nucleic acid-sensing TLRs based on their ability to recognize DNAs or RNAs produced by pathogens or damaged cells. During autoimmune disease progression these receptors recognize self nucleic acids as well as self nucleic acid-containing complexes and contribute to inflammatory cytokine production and subsequent enhancement of serum autoantibody levels. We have recently discovered that nucleic-acid scavenging polymers (NASPs) can neutralize the proinflammatory effects of nucleic acids. Here, we begin to explore what effects such NASPs have on normal immune function. We show that such NASPs can inhibit TLR activation without affecting nucleic acid-independent T cell activation. Moreover, we observe that stimulation of immune cells by encapsulated nucleic acids, such as those found in viral particles, is unaffected by NASPs. Thus NASPs only limit the activation of the immune system by accessible extra-cellular nucleic acid and do not engender non-specific immune suppression. These important findings suggest that NASPs represent a new approach toward anti-inflammatory drug development as these agents can potentially be utilized to block overt autoimmune disorders and inflammation while allowing normal immune responses to occur.