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Recent studies have shown that human myeloid leukaemia cells can differentiate into dendritic cell (DC)-like cells (leukaemia-DCs) when cultured with a combination of cytokines. In the present study, we examined whether the transduction of leukaemia-DCs with OX40 ligand (OX40L), a member of the tumour necrosis factor (TNF) family, resulted in augmentation of their antigen presenting activity. Bicistronic retroviral vectors expressing both human OX40L and enhanced green fluorescent protein (EGFP) or EGFP alone were generated and used for transduction. Fresh leukaemic cells from five patients with acute myeloid leukaemia (AML) were isolated and retrovirally transduced with OX40L during the culture with a combination of cytokines from stem cell factor, fms-like tyrosine kinase (Flt)-3 ligand, granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-4 (IL-4) and TNF- α. After 7 d, the majority of cells showed DC-like morphology, and expressed higher levels of CD80, CD86 and HLA-DR than fresh leukaemic cells. The transduction efficiency was 8·5–27·2%. Leukaemia-DCs transduced with OX40L elicited higher proliferative response of allogeneic CD4+ T cells than fresh leukaemic cells, non-transduced, or mock-transduced leukaemia-DCs. Co-culture of allogeneic CD4+ T cells with OX40L-transduced leukaemia-DCs was superior in the generation of interferon (IFN)- γ producing CD4+ T cells and in production of IFN- γ. Furthermore, OX40L-transduced leukaemia-DCs could elicit significant proliferative response of human leucocyte antigen-matched T cells from the donor in allogeneic stem cell transplantation. These results indicate that retroviral transduction of leukaemia-DCs with OX40L augments their antigen presenting cell activity and thus renders them more suitable for tumour vaccines or ex vivo stimulation of leukaemia-specific T cells. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) plays an important role in the development of tumors. Immunoregulatory cells and cytokines facilitate cancer cells to avoid immune surveillance. Overexpression of immune checkpoint molecules such as CTLA-4 and PD-1/PD-L1 inhibits immune function and enables cancer cells to avoid clearance by the immune system. Thus, minimizing tumor immunosuppression could be an important strategy for cancer therapy. Currently, many immune checkpoint-targeted drugs, such as PD-1/PD-L1 inhibitors, have been approved for marketing and have shown unique advantages in the clinical treatment of cancers. The concept of "strengthening resistance to eliminate pathogenic factors" in traditional Chinese medicine (TCM) is consistent with the immunotherapy of cancer. According to previous studies, the role of TCM in tumor immunotherapy is mainly associated with the positive regulation of natural killer cells, CD8/CD4 T cells, dendritic cells, M2 macrophages, interleukin-2, tumor necrosis factor- α , and IFN- γ , as well as with the negative regulation of Tregs, myeloid-derived suppressor cells, cancer-associated fibroblasts, PD-1/PD-L1, transforming growth factor- β , and tumor necrosis factor- β. This paper summarizes the current research on the effect of TCM targeting the TME, and further introduces the research progress on studying the effects of TCM on immune checkpoints. Modern pharmacological studies have demonstrated that TCM can directly or indirectly affect the TME by inhibiting the overexpression of immune checkpoint molecules and enhancing the efficacy of tumor immunotherapy. TCM with immunomodulatory stimulation could be the key factor to achieve benefits from immunotherapy for patients with non-inflammatory, or "cold", tumors. [ABSTRACT FROM AUTHOR]

Probiotics confer immunological protection to the host through the regulation, stimulation, and modulation of immune responses. Researchers have shifted their attention to better understand the immunomodulatory effects of probiotics, which have the potential to prevent or alleviate certain pathologies for which proper medical treatment is as yet unavailable. It has been scientifically established that immune cells (T- and B-cells) mediate adaptive immunity and confer immunological protection by developing pathogen-specific memory. However, this review is intended to present the recent studies on immunomodulatory effects of probiotics. In the early section of this review, concepts of probiotics and common probiotic strains are focused on. On a priority basis, the immune system, along with mucosal immunity in the human body, is discussed in this study. It has been summarized that a number of species of Lactobacillus and Bifidobacterium exert vital roles in innate immunity by increasing the cytotoxicity of natural killer cells and phagocytosis of macrophages and mediate adaptive immunity by interacting with enterocytes and dendritic, Th1, Th2, and Treg cells. Finally, immunomodulatory effects of probiotics on proinflammatory and anti-inflammatory cytokine production in different animal models have been extensively reviewed in this paper. Therefore, isolating new probiotic strains and investigating their immunomodulatory effects on cytokine profiles in humans remain a topical issue. [ABSTRACT FROM AUTHOR]

Highlights • Dendritic cells with overexpression of SOCS1 are constructed with lentivirus encoding SOCS1. • SOCS1 could block maturation process of Dendritic cells through inhibition of JAK/STAT pathway signaling. • Dendritic cells with increased expression of SOCS1 could ameliorate LPS/D-GalN induced acute liver failure. Abstract Acute liver failure is a devastating clinical syndrome with extremely terrible inflammation reaction, which is still lack of effective treatment in clinic. Suppressor of Cytokine Signaling 1 protein is inducible intracellular negative regulator of Janus kinases (JAK)/signal transducers and activators of transcription (STAT) pathway that plays essential role in inhibiting excessive intracellular signaling cascade and preventing autoimmune reaction. In this paper, we want to explore whether dendritic cells (DCs) with overexpression of SOCS1 have a therapeutic effect on experimental acute liver failure. Bone marrow derived dendritic cells were transfected with lentivirus encoding SOCS1 and negative control lentivirus, thereafter collected for costimulatory molecules analysis, allogeneic Mixed Lymphocyte Reaction and Western blot test of JAK/STAT pathway. C57BL/6 mice were randomly separated into normal control and treatment groups which respectively received tail vein injection of modified DCs, negative control DCs and normal saline 12 h earlier than acute liver failure induction. Our results indicated that DCs with overexpression of SOCS1 exhibited like regulatory DCs (DCregs) with low level of costimulatory molecules and poor allostimulatory ability in vitro, which was supposed to correlate with block of JAK2/STAT1 signaling. In vivo tests, we found that infusion of modified DCs increased survival rate of acute liver failure mice and alleviate liver injury via inhibition of TLR4/HMGB1 pathway. We concluded that DCs transduced with SOCS1 gene exhibit as DCregs through negative regulation of JAK2/STAT1 pathway and ameliorated lipopolysaccharide/ d -galactosamine induced acute liver failure via inhibition of TLR4 pathway. [ABSTRACT FROM AUTHOR]

Malicious intruders on networks have been the major concerns since last one decade or more, to gain the focus of many researchers. Inspired from human immune system, Dendritic Cell Algorithm has already been implemented for intrusion detection systems. Dendritic cells are the sole of human immune system which are responsible for combining signals in the tissue and reporting to the immune system of any variation in the signal concentration. In this paper an intrusion detection system is proposed and implemented for KDD data set using probabilistic dendritic cell algorithm. Besides taking statistically derived input signal concentration, probabilistic measure based on Shanon's entropy are taken as input signal concentration to compute the output cytokines. Proposed method has shown significant improvement as compared to other existing techniques used in intrusion detection system. [ABSTRACT FROM AUTHOR]

Mast cells (MCs) produce soluble mediators such as histamine and prostaglandins that are known to influence dendritic cell (DC) function by stimulating maturation and antigen processing. Whether direct cell-cell interactions are important in modulating MC/DC function is unclear . In this paper, we show that direct contact between MCs and DCs occurs and plays an important role in modulating the immune response. Activation of MCs through FceRI cross-linking triggers the formation of stable cell-cell interactions with immature DCs that are reminiscent of the immunological synapse. Direct cellular contact differentially regulates the secreted cytokine profile, indicating that MC modulation of DC populations is influenced by the nature of their interaction. Synapse formation requires integrin engagement and facilitates the transfer of internalized MC-specific antigen from MCs to DCs. The transferred material is ultimately processed and presented by DCs and can activate T cells. The physiological outcomes of the MC-DC synapse suggest a new role for intercellular crosstalk in defining the immune response. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Traditional Chinese herbal medicine (CHM) has a long-history for treatment of various human diseases including tumors, infection, autoimmune diseases in Asian countries, especially in China, Japan, Korea and India. CHM was traditionally used as water extracts and many Chinese herbs were considered to be good for health, which can regulate immune system to protect host from diseases. With the progress of technology, the components of CHM were identified and purified, which included polysaccharides, saponins, phenolic compounds, flavonoids and so on. Recently, accumulating evidence indicates that CHM and its components can regulate immune system through targeting dendritic cells (DCs). We hereby reviewed the immunoregulatory effects of CHM on the maturation, cytokine production and function of DCs. This should help to shed light on the potential mechanism of CHM to improve the usage and clinical efficacy of CHM. Materials and methods Literatures about the effects of CHM on DCs were searched in electronic databases such as Pubmed, Google Scholar and Scopus from 2000 to 2014. ‘CHM’, ‘DC’ or ‘immune’ were used as keywords for the searches. We only reviewed literatures published in English. Results Over 600 publications were found about ‘CHM&immune’ and around 120 literatures about ‘CHM&DC’ were selected and reviewed in this paper. All publications are backed by preclinical or clinical evidences both in vitro and in vivo . Some CHM and its components promote the maturation, pro-inflammatory cytokine production and function of DCs and as the adjuvant enhance immune responses against tumor and infection. In contrast, other CHM and its components suppress the activation status of DCs to induce regulatory T cells, inhibit allergic and inflammatory responses, ameliorate autoimmune diseases, and prolong the allograft survival. A large body of evidence shows that CHM and its components regulate the activation status of DCs through TLRs, NF-κB, MAPK signaling pathways. Conclusion This review provides useful information for understanding the mechanism of CHM on the treatment of diseases, which facilitates to improve the efficacy of CHM. Based on the immunoregulatory effects of CHM on DCs, it indicated that some CHM and its components could be use to develop adjuvant to enhance antigen-specific immune responses or tolerogenic adjuvant to generate antigen-specific immune tolerance. [ABSTRACT FROM AUTHOR]

This article presents abstracts for various research papers to be presented in the 27th Annual Meeting of the European Society for Dermatological Research. These research papers pertain to subjects like proinflammatory cytokines and prostaglandins' inducing maturation of potent immunostiumlatory dendritic cells, mediators that mobilize langerhans cells, antigens for the activation of T lymphocytes by skin dendritic cells and vaccination of melanoma patients with peptide-pulsed dendritic cells.

Tanshinone IIA (Tan II A) is widely used in the treatment of cardiovascular diseases as an active component of Salvia miltiorrhiza Bunge. It has been demonstrated to have pleiotropic effects for atherosclerosis. From the anti-inflammatory and immunomodulatory mechanism perspective, this paper reviewed major progresses of Tan IIA in antiatherosclerosis research, including immune cells, antigens, cytokines, and cell signaling pathways. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) play an important role in both immunological tolerance and immunity as well as in pro- and anti-inflammatory responses. Upon uptake of apoptotic cells and apoptotic bodies, DCs degrade self antigens from them and induce anti-inflammatory response and T regulatory (Treg) cells resulting in the maintenance of tolerance to self antigens. Ageing is characterized by progressive immunodeficiency, inflammation, and autoimmunity. In this paper we will review the role of DCs in inflammation and autoimmunity in human ageing and will highlight the observations that DCs from aged humans display impairment in their capacity to uptake apoptotic cells, and paradoxically induce proinflammatory response and increased reactivity to self antigen (DNA). DNA from aged is hypomethylated and hypomethylation is associated with increased immunogenecity of self DNA. [ABSTRACT FROM AUTHOR]

Psoriasis is a recurrent, chronic, immune-mediated, systemic inflammatory disease of the skin, joints, and other organic systems. After atopic dermatitis, chronic stationary psoriasis is the most common inflammatory skin disease, affecting an average of 2–4% of the world's population. The disease carries a significant burden due to its numerous comorbidities and the major impact on patients' social and emotional aspects of life. According to current knowledge, psoriasis is a multifactorial disease that occurs in genetically predisposed individuals under various environmental factors, which trigger an immune response disorder with a series of complex inflammatory cascades. The disease is initiated and maintained by mutual interaction of the innate and adaptive immune cells, primarily dendritic cells, T lymphocytes, and keratinocytes, whose leading role alternates at different stages of the disease, consisting mainly in the IL-23/Th17 pathway. Inflammatory events result in consequent epidermal and dermal changes and evolution of the characteristic psoriatic phenotype, respectively. This paper aims to present a comprehensive overview of current knowledge on psoriasis genetic and environmental etiological factors, immunopathogenesis, and the leading cellular and cytokine participants in the inflammatory pathways of this disease. [ABSTRACT FROM AUTHOR]

Background: Previous work has shown that disruption of the gene for group X secreted phospholipase A2 (sPLA2-X) markedly diminishes airway hyperresponsiveness and remodeling in a mouse asthma model. With the large number of additional sPLA2s in the mammalian genome, the involvement of other sPLA2s in the asthma model is possible – in particular, the group V sPLA2 (sPLA2-V) that like sPLA2-X is highly active at hydrolyzing membranes of mammalian cells. Methodology and Principal Findings: The allergen-driven asthma phenotype was significantly reduced in sPLA2-V-deficient mice but to a lesser extent than observed previously in sPLA2-X-deficient mice. The most striking difference observed between the sPLA2-V and sPLA2-X knockouts was the significant impairment of the primary immune response to the allergen ovalbumin (OVA) in the sPLA2-V−/− mice. The impairment in eicosanoid generation and dendritic cell activation in sPLA2-V−/− mice diminishes Th2 cytokine responses in the airways. Conclusions: This paper illustrates the diverse roles of sPLA2s in the immunopathogenesis of the asthma phenotype and directs attention to developing specific inhibitors of sPLA2-V as a potential new therapy to treat asthma and other allergic disorders. [ABSTRACT FROM AUTHOR]

Abstract: The CD40L/CD40 signalling pathway is critically involved in the final stage of the maturation of DCs. This paper reports the identification and functional characterization of CD40L and CD40 from Atlantic salmon (Salmo salar). Salmon CD40L is a type II membrane-bound protein with a TNF homology domain in its extracellular C-terminal region, while CD40 is a type I membrane-bound receptor with a sequence pattern of four cysteine-rich domains in its extracellular N-terminal region. The salmon CD40L and CD40 were widely expressed, particularly in immune tissues, and while CD40L expression was induced by in vitro stimulation of HKLs with PHA and ConA, CpG increased CD40 expression. A CD40L construct was overexpressed in the CHSE-214 cell line and co-cultivation of the CD40L-CHSE transfectants with HKL induced a rapid and long-lasting upregulation of important costimulatory molecules like CD40, CD83, B7-H1 and the cytokines IL-12p40, IL-10, IL-1β and IFNs, which all are involved in T-helper cell responses. Furthermore, the CD40L transfected cells increased the percentage of HKLs expressing surface MHCIIβ but unlike other APC maturation stimuli, like CpG, they did not reduce the capacity to internalise antigen. Our results provide the first evidence for the existence of a functional CD40L mediated costimulatory pathway in Atlantic salmon. [Copyright &y& Elsevier]

Abstract: Rheumatic autoimmune diseases have been associated with accelerated atherosclerosis and various types of vasculopathies. Atherosclerosis is an inflammatory condition which starts as a “response to injury” favoring endothelial dysfunction which is associated with increased expression of adhesion molecules, pro-inflammatory cytokines, pro-thrombotic factors, oxidative stress upregulation and abnormal vascular tone modulation. Endothelial dysfunction in rheumatic autoimmune diseases involves innate immune responses, including macrophages and dendritic cells expression of scavenger and toll-like receptors for modified or native LDL as well as neutrophil and complement activation, and dysregulation of adaptive immune responses, including proliferation of autoreactive T-helper-1 lymphocytes and defective function of dendritic and regulatory T cells. Specific differences for endothelial function among different disorders include: a) increased amounts of pro-atherogenic hormones, decreased amounts of anti-atherogenic hormones and increased insulin resistance in rheumatoid arthritis; b) autoantibodies production in systemic lupus erythematosus and antiphospholipid syndrome; c) smooth muscle cells proliferation, destruction of internal elastic lamina, fibrosis and coagulation and fibrinolytic system dysfunction in systemic sclerosis. Several self-antigens (i.e. high density lipoproteins, heat shock proteins, β2-glycoprotein1) and self-molecules modified by oxidative events (i.e. low density lipoproteins and oxidized hemoglobin) have been identified as targets of autoimmune responses. Endothelial dysfunction leads to accelerated atherosclerosis in rheumatoid arthritis, systemic lupus erythematosus and spondyloarthropaties whereas obliterative vasculopathy is associated with systemic sclerosis. In this paper, we will briefly review the most relevant information upon endothelial dysfunction and inflammatory mechanisms in atherosclerosis and we will summarize the similarities and differences in vascular disease patterns underlying different rheumatic autoimmune diseases. [Copyright &y& Elsevier]

Probiotic bacteria have been shown to modulate immune responses and could have therapeutic effects in allergic and inflammatory disorders. However, little is known about the signalling pathways that are engaged by probiotics. Dendritic cells (DCs) are antigen-presenting cells that are involved in immunity and tolerance. Monocyte-derived dendritic cells (MoDCs) and murine DCs are different from human gut DCs; therefore, in this study, we used human DCs generated from CD34+ progenitor cells (hematopoietic stem cells) harvested from umbilical cord blood; those DCs exhibited surface antigens of dendritic Langerhans cells, similar to the lamina propria DCs in the gut. We report that both a novel probiotic strain isolated from faeces of exclusively breast-fed newborn infants, Lactobacillus paracasei CNCM I-4034, and its cell-free culture supernatant (CFS) decreased pro-inflammatory cytokines and chemokines in human intestinal DCs challenged with Salmonella. Interestingly, the supernatant was as effective as the bacteria in reducing pro-inflammatory cytokine expression. In contrast, the bacterium was a potent inducer of TGF-β2 secretion, whereas the supernatant increased the secretion of TGF-β1 in response to Salmonella. We also showed that both the bacteria and its supernatant enhanced innate immunity through the activation of Toll-like receptor (TLR) signalling. These treatments strongly induced the transcription of the TLR9 gene. In addition, upregulation of the CASP8 and TOLLIP genes was observed. This work demonstrates that L. paracasei CNCM I-4034 enhanced innate immune responses, as evidenced by the activation of TLR signalling and the downregulation of a broad array of pro-inflammatory cytokines. The use of supernatants like the one described in this paper could be an effective and safe alternative to using live bacteria in functional foods. [ABSTRACT FROM AUTHOR]

AbstractA major obstacle in the genetic therapy of inherited metabolic disease is host immune responses to the therapeutic protein. This is best exemplified by inhibitor formation in the protein therapy for hemophilia A. An approach to overcoming this is induction of immunological tolerance to the therapeutic protein. Tolerogenic dendritic cells (DCtols) have been reported to induce tolerance. In addition, cytokines such as interleukin (IL)-10 and transforming growth factor (TGF)-β1are known to induce tolerance. To model protein therapy, we used ovalbumin (OVA) as antigen in BALB/c mice and their transgenic derivative, DO11.10 mice. In this study we show that adoptive transfer of antigen-pulsed dendritic cells (DCs) treated with a combination of IL-10 and TGF-β1can suppress the antibody response in mice. Adoptive transfer of cytokine-conditioned DCs in preimmunized mice results in reduction of antibody response in the mice. Furthermore, the effect is antigen specific, as the recipient mice were able to mount a potent antibody response to the control antigen. Last, we show that TGF-β1and IL-10-conditioned DCs are able to inhibit anti-FVIII antibody responses in FVIII knockout (KO) mice. Analysis of the contribution of IL-10 and TGF-β1to the DCtol phenotype shows that IL-10 treatment of DCs is sufficient for inducing OVA-specific tolerance in BALB/c mice, but we observed a requirement for treatment with both human TGF-β1and human IL-10 to significantly inhibit anti-FVIII antibody responses in FVIII KO mice. This paper demonstrates that autologous cell therapy for antigen-targeted immune suppression may be developed to facilitate long-term therapy. [ABSTRACT FROM AUTHOR]

Editor's Highlight: This paper reports an in vitro cell culture system from human donors for the prediction of the allergic potential of drugs. Naive T cells were cultured in the presence of a drug and tested for transformation of the naive phenotype into a memory phenotype. These results demonstrate a system that can predict possible drug allergy resulting in serious adverse effects in a system that does not utilize experimental animals.Adverse drug reactions represent a major stumbling block to drug development and those with an immune etiology are the most difficult to predict. We have developed an in vitro T-cell priming culture method using peripheral blood from healthy volunteers to assess the allergenic potential of drugs. The drug metabolite nitroso sulfamethoxazole (SMX-NO) was used as a model drug allergen to establish optimum assay conditions. Naive T cells were cocultured with monocyte-derived dendritic cells at a ratio of 25:1 in the presence of the drug for a period of 8 days, to expand the number of drug-responsive T cells. The T cells were then incubated with fresh dendritic cells, and drug and their antigen responsiveness analyzed using readouts for proliferation, cytokine secretion, and cell phenotype. All five volunteers showed dose-dependent proliferation as measured by 5-(and 6)-carboxyfluorescein diacetate succinimidyl ester content and by 3H-thymidine uptake. CD4 T cells that had divided in the presence of SMX-NO had changed from a naive phenotype (CD45RA+) to a memory phenotype (CD45RO+). These memory T cells expressed the chemokine receptors CCR2, CCR4, and CXCR3 suggesting a mixture of TH1 and TH2 cells in the responding population, with a propensity for homing to the skin. Drug stimulation was also associated with the secretion of a mixture of TH1 cytokines (interferon γ) and TH2 cytokines (interleukin [IL]-5 and IL-13) as detected by ELISpot. We are currently developing this approach to investigate the allergenic potential of other drugs, including those where an association between specific human leucocyte antigen alleles and susceptibility to an immunological reaction has been established. [ABSTRACT FROM PUBLISHER]

The glucocorticoid receptor (GR) is a transcription factor able to support either target gene activation via direct binding to DNA or gene repression via interfering with the activity of various proinflammatory transcription factors. An improved therapeutic profile for combating chronic inflammatory diseases has been reported through selectively modulating the GR by only triggering its transrepression function. We have studied in this paper the activity of Compound A (CpdA), a dissociated GR modulator favoring GR monomer formation, in a predominantly Th2-driven asthma model. CpdA acted similarly to the glucocorticoid dexamethasone (DEX) in counteracting OVA-induced airway hyperresponsiveness, recruitment of eosinophils, dendritic cells, neutrophils, B and T cells, and macrophages in bronchoalveolar lavage fluid, lung Th2, Tc2, Thl7, Tc17, and mast cell infiltration, collagen deposition, and goblet cell metaplasia. Both CpdA and DEX inhibited Th2 cytokine production in bronchoalveolar lavage as well as nuclear translocation of NF-&kgr;B and its subsequent recruitment onto the I&kgr;B&agr; promoter in the lung. By contrast, DEX but not CpdA induces expression of the GR-dependent model gene MAPK phosphatase 1 in the lung, confirming the dissociative action of CpdA. Mechanistically, we demonstrate that CpdA inhibited IL-4-induced STAT6 translocation and that GR is essential for CpdA to mediate chemokine repression. In conclusion, we clearly show in this study the anti-inflammatory effect of CpdA in a Th2-driven asthma model in the absence of transactivation, suggesting a potential therapeutic benefit of this strategy. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (Mtb) infection is a major international public health problem. One-third of the world's population is thought to have latent tuberculosis, a condition where individuals are infected by the intracellular bacteria without active disease but are at risk for reactivation, if their immune system fails. Here, we discuss the role of nonspecific inflammatory responses mediated by cytokines and chemokines induced by interaction of innate receptors expressed in macrophages and dendritic cells (DCs). We also review current information regarding the importance of several cytokines including IL-17/IL-23 in the development of protective cellular and antibody-mediated protective responses against Mtb and their influence in containment of the infection. Finally, in this paper, emphasis is placed on the mechanisms of failure of Mtb control, including the immune dysregulation induced by the treatment with biological drugs in different autoimmune diseases. Further functional studies, focused on the mechanisms involved in the early host-Mtb interactions and the interplay between host innate and acquired immunity against Mtb, may be helpful to improve the understanding of protective responses in the lung and in the development of novel therapeutic and prophylactic tools in TB. [ABSTRACT FROM AUTHOR]

Despite advances in prevention and treatment, atherosclerotic vascular disease continues to account for significant morbidity, mortality, and economic burden in the western world. Our current understanding of this disease presents atherosclerosis as a chronic inflammatory process involving multiple cell types in various stages of activation, apoptosis, and necrosis. These cells include monocyte/macrophage, dendritic cells, lymphocytes, endothelial cells, and vascular smooth muscle cells. Activation of these cells and their processes is initiated and sustained by a complex network of soluble factors termed cytokines. Cytokines are produced and recognized by both inflammatory and resident vascular cells, allowing crosstalk between these two systems. Cytokines also regulate the phenotype of many of these cell types. Recognizing functions of these cytokines and their effects on cells which populate atherosclerotic plaque is key to uncovering targets of therapeutic intervention. This paper will present recent studies which describe the cellular protagonists of atherosclerosis and the role they play in formation of atherosclerotic plaque. It will also describe the cytokines which have been identified as produced by and directly affecting dysfunction of these cells. Because atherosclerosis is considered an inflammatory condition, emphasis will be placed on inflammatory cytokines and their effects on atherogenesis. We will conclude with new directions in therapeutic strategies and points of emphasis for future research. [ABSTRACT FROM AUTHOR]

Success of pregnancy depends on many factors. Three phenomena inducing immune tolerance against semi-allogeneic conceptus may play a crucial role in the pre-implantation period of pregnancy: influence of sex hormones in sex cycle, presence of oocyte or embryo and the presence of semen in the female reproductive tract. On the other hand dendritic cells are the most effective antigen- -presenting cells in regulation of immune phenomena and also are considered as potent participants in inducing immune tolerance in the pregnancy. They communicate with T cells in cell contact- dependent manner or via cytokines. During cell-cell contacts, costimulatory molecules play a key role and their expression is often dependent on cytokines milieu. Both costimulatory molecules and cytokines influence generation of T regulatory cells. Interactions of these molecules are closely related. In this paper we would like to pay attention to the importance of antigen presenting cells costimulatory potency in immune regulation during a pre-implantation period of pregnancy. [ABSTRACT FROM AUTHOR]

Summary Atopic dermatitis (AD), a skin disease characterized by pruritus and chronic inflammation, results from a complex interplay between environmental and genetic factors. Thymic stromal lymphopoietin (TSLP), an IL-7-like cytokine, is believed to propagate AD lesions through T helper 2 (Th2) polarization. This paper describes the immunologic mechanisms involving TSLP in the generation of allergic disease. Specifically in AD, TSLP has been shown to be an inducer of myeloid dendritic cells, Th2 responses, mast cells, and natural killer T cells, thereby leading to cytokine secretion and the development of AD. We hope that further understanding of the TSLP pathway and its role in the pathogenesis of AD will lead to improved clinical management of AD in the future. Cite this as: S. P. Jariwala, E. Abrams, A. Benson, J. Fodeman and T. Zheng, Clinical & Experimental Allergy, 2011 (41) 1515-1520. [ABSTRACT FROM AUTHOR]

The innate immune system is equipped with many molecular sensors for microbial DNA/RNA to quickly mount antimicrobial host immune responses. In this paper, we identified DHX9, a DExDc helicase family member, as an important viral dsRNA sensor in myeloid dendritic cells (mDCs). Knockdown of DHX9 expression by small heteroduplex RNA dramatically blocked the ability of mDCs to produce IFN-α/β and proinflammatory cytokines in response to polyinosine-polycytidylic acid, influenza A, and reovirus. DHX9 could specifically bind polyinosine-polycytidylic acid via its double-strand RNA binding motifs. DHX9 interacted with IPS-1 via the HelicC-HA2-DUF and CARD domains of DHX9 and IPS-1, respectively. Knockdown of DHX9 expression in mDCs blocked the activation of NF-κB and IFN regulatory factor 3 by dsRNA. Collectively, these results suggest that DHX9 is an important RNA sensor that is dependent on IPS-1 to sense pathogenic RNA. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) competent to express the regulatory enzyme IDO in mice are a small but distinctive subset of DCs. Previously, we reported that a high-dose systemic CpG treatment to ligate TLR9 in vivo induced functional IDO exclusively in splenic CD19+ DCs, which stimulated resting Foxp3-lineage regulatory T cells (Tregs) to rapidly acquire potent suppressor activity. In this paper, we show that IDO was induced in spleen and peripheral lymph nodes after CpG treatment in a dose-dependent manner. Induced IDO suppressed local T cell responses to exogenous Ags and inhibited proinflammatory cytokine expression in response to TLR9 ligation. IDO induction did not occur in T cell-deficient mice or in mice with defective B7 or programmed death (PD)-1 costimulatory pathways. Consistent with these findings, CTLA4 or PD-1/PD-ligand costimulatory blockade abrogated IDO induction and prevented Treg activation via IDO following high-dose CpG treatment. Consequently, CD4+CD25+ T cells uniformly expressed IL-17 shortly after TLR9 ligation. These data support the hypothesis that constitutive interactions from activated T cells or Tregs and IDO-competent DCs via concomitant CTLA4→B7 and PD-1→PD-ligand signals maintain the default potential to regulate T cell responsiveness via IDO. Acute disruption of these nonredundant interactions abrogated regulation via IDO, providing novel perspectives on the proinflammatory effects of costimulatory blockade therapies. Moreover, interactions between IDO-competent DCs and activated T cells in lymphoid tissues may attenuate proinflammatory responses to adjuvants such as TLR ligands. [ABSTRACT FROM AUTHOR]

An ability to sense pathogens by a number of specialized cell types including the dendritic cells plays a central role in host's defenses. Activation of these cells through the stimulation of the pathogen-recognition receptors induces the production of a number of cytokines including Type I interferons (IFNs) that mediate the diverse mechanisms of innate immunity. Type I IFNs interact with the Type I IFN receptor, composed of IFNAR1 and IFNAR2 chains, to mount the host defense responses. However, at the same time, Type I IFNs elicit potent anti-proliferative and pro-apoptotic effects that could be detrimental for IFN-producing cells. Here, we report that the activation of p38 kinase in response to pathogen-recognition receptors stimulation results in a series of phosphorylation events within the IFNAR1 chain of the Type I IFN receptor. This phosphorylation promotes IFNAR1 ubiquitination and accelerates the proteolytic turnover of this receptor leading to an attenuation of Type I IFN signaling and the protection of activated dendritic cells from the cytotoxic effects of autocrine or paracrine Type I IFN. In this paper we discuss a potential role of this mechanism in regulating the processes of innate immunity. [ABSTRACT FROM AUTHOR]

Abstract: Establishment of a leukemia plasmacytoid dendritic cell line (PMDC05) and intra-lineage transformation from pDCs to mDCs in PMDC05 has been reported. In this paper, we show the applicability of PMDC05 for cellular immunotherapy. By stimulation with LPS, PMDC05 showed enhancement in expression of antigen presentation-associated surface molecules and production of cytokines (IL-12p70 and TNF-α). The antigen presenting ability was markedly increased in PMDC05 stimulated with LPS. By co-culturing of CD8+ T cells with LPS-stimulated and WT1/CMVpp65 peptide-pulsed PMDC05, WT1/CMVpp65 tetramer+ cytotoxic T lymphocytes were efficiently generated. These findings reveal the applicability of PMDC05 in cellular immunotherapy for tumor and severe viral infections. [Copyright &y& Elsevier]

Interaction between the nervous and immune systems greatly contributes to inflammatory disease. In organs at the interface between our body and the environment, the sensory neuropeptide substance P (SP) is one key mediator of an acute local stress response through neurogenic inflammation but may also alter cytokine balance and dendritic cell (DC) function. Using a combined murine allergic inflammation/noise stress model with C57BL/6 mice, we show in this paper that SP-released during repeated stress exposure-has the capacity to markedly attenuate inflammation. In particular, repeated stress exposure prior to allergen sensitization increases DC-nerve fiber contacts, enhances DC migration and maturation, alters cytokine balance, and increases levels of IL-2 and T regulatory cell numbers in local lymph nodes and inflamed tissue in a neurokinin 1-SP-receptor (neurokinin-1 receptor)-dependent manner. Concordantly, allergic inflammation is significantly reduced after repeated stress exposure. We conclude that SP/repeated stress prior to immune activation acts protolerogenically and thereby beneficially in inflammation. [ABSTRACT FROM AUTHOR]

Abstract: Dendritic cells (DCs) are widely distributed throughout the lymphoid and nonlymphoid tissues, and are important initiators of acquired immunity and also serve as regulators by inducing self-tolerance. However, it has not been thoroughly clarified whether DCs are involved in the termination of immune responses. In this paper, we have examined the kinetical movement of dendritic cells (DCs) in the lamina propria using the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced ileitis model (an animal model for Crohn''s disease). Increased numbers of DCs were recruited to the inflammatory sites from day 1 to day 3 at which time the inflammatory responses was clearly observed, then gradually decreased to a steady-state level on day 7 along with the cessation of responses. Three subsets of DCs, PIR-A/Bhigh, PIR-A/Bmed, and PIR-A/B− DCs in the CD11c+/B220− conventional DCs (cDCs) were noted on day 3; the number of PIR-A/Bmed cDCs increased when the inflammatory responses ceased on day 7. The expression of costimulatory molecules such as CD86 and CD54 was lower in the PIR-A/Bmed DCs compared with the other two cDC subsets or splenic DCs. Furthermore, the stimulatory activity of PIR-A/Bmed cDCs was lower than those of PIR-A/Bhigh or PIR-A/B− cDCs, and far lower than that of splenic DCs. In addition, an increase in the message level of IL-10 was clearly observed in the PIR-A/Bmed cDCs on day 7 while that of proinflammatory cytokines such as IL-6 and IL-12 was low. These data demonstrate that PIR-A/Bmed cDCs which increase at the final stage of inflammation may be involved in the termination of the TNBS-induced ileitis by the delivery of anergic signals to effector T cells due to the lower expressions of costimulatory molecules and the production of immunoregulatory cytokine. [Copyright &y& Elsevier]

In the present paper, we have investigated early pathophysiological events in graft-versus-host disease (GVHD), a major complication to hematopoietic stem cell transplantation (HSCT). BLLB/c female mice conditioned with busulfan/cyclophosphamide (Bu- Cy) were transplanted with allogeneicmale C57BL/6. Control group consisted of syngeneic transplanted Balb/cmice. In allogeneic settings, significant expansion and maturation of donor dendritic cells (DCs) were observed at day +3, while donor T-cells CD8+ were increased at day +5 (230%) compared to syngeneic HSCT. Highest levels of inflammatory cytokines IL-2, IFN-gamma, and TNF-alfa at day +5 matched T-cell activation. Concomitantly naïve T-cells gain effecr-memory phenotype and migrated from spleen to peripheral lymphoid organs. Thus, in the very early phase of GHVD following Bu-Cy conditioning donor, DCs play an important role in the activation of donor T cells. Subsequently, donor naïve T-cells gain effector-memory phenotype and initiate GVHD. [ABSTRACT FROM AUTHOR]

The ultimate outcome of T cell receptor recognition is determined by the context in which the antigen is encountered. In this fashion both antigen-presenting cells and T cells must integrate multiple environmental cues in the form of pathogen-associated molecular patterns, cytokines and accessory molecule signals. The mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that plays a central role in integrating environmental signals critical to regulating metabolism and cell survival. In this paper we review the data demonstrating that mTOR integrates signals from the immune microenvironment and therefore facilitates the generation of the adaptive immune response. Specifically, we review the role of mTOR in promoting dendritic cell activation and maturation, in regulating full T cell activation versus anergy, and influencing the induction of regulatory T cells. [ABSTRACT FROM AUTHOR]

Ablation of liver tissue produces in situ tumoural antigens and elicits specific immune responses. The aim of this review is to examine the available data about the local and systemic responses produced and to compare differences between the methods available. A literature search was undertaken for all papers focusing on immune responses following ablative therapy of the liver, including experimental and clinical studies. Following ablative procedures, the cellular response is elicited by the presentation of antigens by dendritic cells to specific CD4+ T cells, which in turn stimulate natural killer or CD8+ cytotoxic cells. The local release of intracellular debris activates Kupffer cells to produce cytokines, which, in the immediate vicinity, activate monocytes/macrophages or specific T cells that respond and produce systemic reactions such as fever, thrombocytopaenia or shock. The immune responses elicited by cryotherapy, both cellular and cytokine, seem far greater than those produced by radiofrequency or microwave ablation, probably as a consequence of the peculiar mechanism of cell death of the former (disruptive necrosis). This mechanism is considered central to the pathogenesis of cryoshock. Ablative techniques stimulate the immune system and provide an easy way to achieve in vivo vaccination against tumoural antigens. Immunomodulatory approaches have the potential to augment the initial immune stimulation and this combined approach could pave the way to a more selective and specific method of treating liver tumours. [ABSTRACT FROM AUTHOR]

Inappropriate T cell responses cause the four classical types of hypersensitivity immune reactions. All of these can target the kidney and cause distinct forms of glomerulonephritis. CD4+ T cells can mediate glomerular immunopathology by cytokine secretion, by activating effector cells such as macrophages or by inducing auto-antibodies or immune-complexes. Cytotoxic CD8+ T cell responses and failure of regulatory T cells may represent two additional types of anti-renal hypersensitivity. T cell activation is critically dependent on dendritic cells (DC), whose role in renal disease appears to be protective, but underlying mechanisms are largely unknown. In this paper, we summarized mechanistic information from rodent models on the roles of DC and T cells in glomerular immunopathology. [ABSTRACT FROM AUTHOR]

Background: The purpose of the present paper was to investigate dendritic cell (DC) and T-cell functions in patients with chronic hepatitis B (CHB) and determine whether therapeutic DC vaccines could restore T-cell function in those patients in vitro. Methods: Twelve patients with CHB and 10 normal control subjects with positivity for antibodies to hepatitis B surface and core antigens (anti-HBs and anti-HBc positivity) were enrolled in the present study. Phenotype analysis and allogeneic mixed lymphocyte reaction assay of DC from CHB patients and normal controls were made in the absence or presence of a cocktail of cytokines: interleukin-1β (IL-1β), prostaglandin E2 (PGE2), IL-6 and tumor necrosis factor-α (TNF-α). Autologous T-cell proliferation assays and the enzyme-linked immunospot (ELISPOT) method for detecting interferon-γ (IFN-γ)-producing CD8+ T cells were used to evaluate the efficacy of DC loaded in vitro with HBsAg or HBcAg. Results: The DC from CHB patients had a lower expression of costimulatory molecules CD80, CD86 and impaired allogeneic mixed lymphocyte reaction capacity compared to those from normal controls. However, the impaired DC function could be restored partially by cytokine cocktail supplemented in vitro. Mature DC loaded with HBsAg or HBcAg showed a greater capacity for autologous T-cell proliferation and antigen-specific IFN-γ production than immature DC. Moreover, as a DC -loading antigen, HBcAg was more immunogenic than HBsAg. Conclusions: The impaired function of DC in patients with CHB may be restored by supplementation in vitro with a cocktail of cytokines, and therapeutic DC vaccines might be effective to treat CHB infection in humans. [ABSTRACT FROM AUTHOR]

Considerable evidence supports the role of dendritic cells (DC) in the pathogenesis of allergic diseases. Dendritic cells, as the most potent antigen-presenting cells (APC) for the induction of primary immune response to antigen, are deeply involved in the differentiation of naïve T cells into Th2 cells, thereby developing the development of allergic sensitization. After sensitization, DC may also function as a major APC to control the activation and clonal expansion of memory Th2 cells. In addition, DC are able to produce chemokines to recruit Th2 cells into inflammatory sites, indicating DC are important agents in various phases of allergic inflammation. Recently, we have demonstrated that monocyte chemotactic protein-1 not only regulates the homing of DC, but also modulates DC function. The present paper reviews the role of DC in the regulation of the Th2 response in allergic diseases and discusses the possibility of a new therapeutic strategy targeting chemokine-mediated regulation of DC function. [ABSTRACT FROM AUTHOR]

Immature dendritic cells (iDCs) can ingest apoptotic cells, which do not lead to maturation of the iDCs. In this paper we examine the phagocytosis of apoptotic cells by iDCs in the absence of stimuli for the maturation of iDCs and the subsequent cytokine production. Phagocytosis was observed by confocal microscopy, and it increased as apoptosis proceeded. The coculturing of iDCs with apoptotic cells did not induce the maturation of iDCs even after the subsequent LPS treatment, as assessed as to the expression of MHC class II, CD80, CD86, and CD40. Moreover, IL-6 and IL-12p40 among the cytokines examined were specifically up-regulated by the coculturing at the mRNA and protein levels. The coculturing decreased the expression of MHC class II on iDCs and allogenic T cell proliferation induced by iDCs. Although anti-IL-6 antibodies only partially reversed the effect of coculturing with apoptotic cells, exogenous IL-6 decreased significantly the expression of MHC class II on iDCs and allogenic T cell proliferation induced by iDCs, raising the possibility that IL-6 may be partly involved in maintaining the immature status of iDCs in an autocrine manner. [Copyright &y& Elsevier]

and The crosstalk between innate adaptive immunity is regulated by cytokines and complex interactions between cells of the immune system. A variety of endogenous agents are involved in the regulation of the cytokine network. Especially, eicosanoids and ROIs have a great impact on the regulation of cytokine production. Eicosanoids (prostanoids, leukotrienes and lipoxins) are produced mainly by inflammatory cells while their receptors are distributed on the cells of both arms of the immune system. Depending on the predominant prostanoid produced and the profile of prostanoid receptors expression on immune cells, eicosanoids can selectively regulate the production of Th1 and Th2 driven cytokines. Inflammatory cells (neutrophils, macrophages), are also a rich source of large amounts of ROIs. In this paper we have focused on the role of taurine chloramine (TauCl), the physiological product of neutrophil MPO-halide system, in the regulation of immune system. It is well documented that TauCl has pleiotropic effects on the inductive phase of the immune response. TauCl''s immunoregulatory properties result from its ability to modulate the production of cytokines and eicosanoids. Finally, we conclude that eicosanoids and ROIs provide an important link between the afferent branches and the innate and adaptive immune response. [Copyright &y& Elsevier]

Simple Summary: Osteosarcoma is the most common primary bone tumor and has a poor prognosis. Therefore, it is important to understand the mechanism of the development of osteosarcoma to overcome therapy resistance. Several mathematical models have been developed to study the initiation and progression of many cancer types. However, there are currently no mathematical models for the progression of osteosarcoma, to the best of our knowledge. In this work, we develop a data-driven mathematical model to analyze the impact of the immune cell interactions on the growth of osteosarcoma tumors that have distinct immune patterns. Our model provides a foundation for investigating the effect of various treatments on the dynamics of key players in the primary tumor, including immune cells and cytokines, and ultimately the whole tumor. As the immune system has a significant role in tumor progression, in this paper, we develop a data-driven mathematical model to study the interactions between immune cells and the osteosarcoma microenvironment. Osteosarcoma tumors are divided into three clusters based on their relative abundance of immune cells as estimated from their gene expression profiles. We then analyze the tumor progression and effects of the immune system on cancer growth in each cluster. Cluster 3, which had approximately the same number of naive and M2 macrophages, had the slowest tumor growth, and cluster 2, with the highest population of naive macrophages, had the highest cancer population at the steady states. We also found that the fastest growth of cancer occurred when the anti-tumor immune cells and cytokines, including dendritic cells, helper T cells, cytotoxic cells, and IFN- γ , switched from increasing to decreasing, while the dynamics of regulatory T cells switched from decreasing to increasing. Importantly, the most impactful immune parameters on the number of cancer and total cells were the activation and decay rates of the macrophages and regulatory T cells for all clusters. This work presents the first osteosarcoma progression model, which can be later extended to investigate the effectiveness of various osteosarcoma treatments. [ABSTRACT FROM AUTHOR]

Psoriasis is a common non-communicable chronic immune-mediated skin disease, affecting approximately 125 million people in the world. Its pathogenesis results from a combination of genetic and environmental factors. The pathogenesis of psoriasis seems to be driven by the interaction between innate immune cells, adaptive immune cells and keratinocytes, in a process mediated by cytokines (including interleukins (IL)-6, IL-17 and IL-22, interferon and tumor necrosis factor) and other signaling molecules. This leads to an inflammatory process with increased proliferation of epidermal cells, neo-angiogenesis and infiltration of dendritic cells in the skin. Dysfunctional de novo glucocorticoid synthesis in psoriatic keratinocytes and the skin microbiome have also been suggested as mediators in the pathogenesis of this disease. To understand psoriasis, it is essential to comprehend the processes underlying the skin immunity and neuroendocrinology. This review paper focuses on the skin as a neuroendocrine organ and summarizes what is known about the skin immune system, the brain–skin connection and the role played by the serotonergic system in skin. Subsequently, the alterations of neuroimmune processes and of the serotonergic system in psoriatic skin are discussed, as well as, briefly, the genetic basis of psoriasis. [ABSTRACT FROM AUTHOR]