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The major histocompatibility complexes of vertebrates play a key role in the immune response. Antigen-presenting cells are loaded on MHC I molecules, which mainly present endogenous antigens; when MHC I presents exogenous antigens, this is called cross-presentation. The discovery of cross-presentation provides an important theoretical basis for the study of exogenous antigens. Cross-presentation is a complex process in which MHC I molecules present antigens to the cell surface to activate CD8+ T lymphocytes. The process of cross-representation includes many components, and this article briefly outlines the origins and development of MHC molecules, gene structures, functions, and their classical presentation pathways. The cross-presentation pathways of MHC I molecules, the cell lines that support cross-presentation, and the mechanisms of MHC I molecular transporting are all reviewed. After more than 40 years of research, the specific mechanism of cross-presentation is still unclear. In this paper, we summarize cross-presentation and anticipate the research and development prospects for cross-presentation. [ABSTRACT FROM AUTHOR]

Differences in genetic origin between nodal and extranodal diffuse large B-cell lymphomas (DLBCL) exist. Using population-based data from the registry of the Danish Lymphoma Group, the present study is the first to analyse clinical implications of nodal versus extranodal presentation of DLBCL. Of 4786 newly diagnosed non-Hodgkin's lymphoma patients in a 16-year period, 1575 (33%) had DLBCL. The annual incidence rate was 2·9 per 100 000; 40% were extranodal. The clinical profile of patients with extranodal DLBCL was different from the nodal DLBCL patients. Extranodal DLBCL was associated with older age and poorer performance score, but also lower tumour burden. In extranodal DLBCL, 51% of the cases were stage I and 36% were stage IV, whereas the patients were relatively equally distributed between the four stages in nodal DLBCL. For stage I patients, extranodal DLBCL was independently associated with poor survival ( P = 0·003). In contrast, among stage IV patients those with extranodal DLBCL survived longer ( P = 0·009). We conclude that there are important clinical differences between nodal and extranodal DLBCL. The addition of these clinical results to the existing aetiological and genetic data suggests that the distinction between nodal and extranodal DLBCL is not only pathogenetically but also clinically important. [ABSTRACT FROM AUTHOR]

Macrophages are the predominant component of innate immunity, which is an important protective barrier of our body. Macrophages are present in all organs and tissues of the body, their main functions include immune surveillance, bacterial killing, tissue remodeling and repair, and clearance of cell debris. In addition, macrophages can present antigens to T cells and facilitate inflammatory response by releasing cytokines. Macrophages are of high concern due to their crucial roles in multiple physiological processes. In recent years, new advances are emerging after great efforts have been made to explore the mechanisms of macrophage activation. Ion channel is a class of multimeric transmembrane protein that allows specific ions to go through cell membrane. The flow of ions through ion channel between inside and outside of cell membrane is required for maintaining cell morphology and intracellular signal transduction. Expressions of various ion channels in macrophages have been detected. The roles of ion channels in macrophage activation are gradually caught attention. K+ channels are the most studied channels in immune system. However, very few of published papers reviewed the studies of K+ channels on macrophages. Here, we will review the four types of K+ channels that are expressed in macrophages: voltage-gated K+ channel, calcium-activated K+ channel, inwardly rectifying K+ channel and two-pore domain K+ channel. [ABSTRACT FROM AUTHOR]

• MR1, a non-polymorphic ubiquitous antigen presenting molecule presents small metabolites to T cells. • MR1T cells recognize small drugs and microbial metabolites presented by MR1. • MR1T cells also recognize self-metabolites accumulating in tumor cells. • MR1T cells are multi-functional and express polyclonal TCR heterodimers. MR1 is an MHC class I-like molecule with unique structural and biological features that make it an important member among the molecules involved in antigen presentation to T cells. Distinctive features include ubiquitous expression of the MR1 gene and its monomorphism. Another relevant property is that the MR1 protein appears at very low levels on the plasma membrane and its surface expression is regulated by antigen binding. Finally, the nature of presented antigens differs from those that bind other presenting molecules and includes small metabolites of microbial and self-origin, small drugs and tumor-associated antigens. This opinion paper describes in detail some of those features and discusses recent literature in the field. [ABSTRACT FROM AUTHOR]

Malignant tumour cells, including malignant keratinocytes of oral squamous cell carcinoma (OSCC), exist in conjunction with other functional cells and it is well recognised that interaction between these groups of cells is important in tumour progression. In addition to cells (tumour cells, immune/inflammatory cells, fibroblasts, vascular and lymphatic endothelial cells, adipocytes) the tumour microenvironment (TME) comprises extracellular matrix and soluble factors, signalling molecules and metabolites such as enzymes, growth factors, cytokines, microRNAs and microvesicles. Our Oral Molecular and Immunopathology Research Group has explored and examined the interactions of the immune network involved in the TME such as tumour infiltrating lymphocytes (TILs), regulatory T cells (Tregs), antigen presenting cells (APCs), associated cytokines such as IL17, IL22, IL23 and other current potential anti-cancer targets such as ER stress and exosomes. This paper will provide an overview of the history of OSCC research at the University of Otago, as well as elaborate current understanding of the TME in OSCC, based on ongoing research undertaken in the Oral Molecular and Immunopathology Research Group of the Sir John Walsh Research Institute at the Faculty of Dentistry, University of Otago. [ABSTRACT FROM AUTHOR]

In this paper, the experimental activity was carried out on five pulverized coals with different particle sizes taken from the industrial demonstration plant of SE-Gasifier Pulverized Coal Gasification in Nanjing, China. Flow properties of pulverized coal including powder cohesion, angle of internal friction and tensile strength were determined by the rotational shear cell accessory of Freeman FT4 Powder Rheometer. These pulverized coal samples were further discharged from a bench-scale discharge system and an industrial device in the SE gasification industrial plant. The effects of mean particle size, fine contents and hopper pressure on the flow properties and the discharge of pulverized coal were discussed. The tensile strength was used to correlate with the feeding characteristics of pulverized coal and proved to be an effective indicator to describe the powder feeding performance. A combination of a continuum approach and a particle–particle approach was therefore built to predict the tensile strength. The model, considered the elastic deformation, was further modified by taking into account the effect of particle size distribution. The predicted tensile strengths were compared with those obtained from the Mohr-Coulomb approach, giving errors mostly below ±25%. It was therefore considered as a valuable way to provide reference for the evaluation of feeding characteristics of pulverized coal for entrained-flow gasification. Unlabelled Image • Pulverized coal was taken from the industrial demonstration plant. • Flow properties and discharge behaviors of pulverized coal were determined. • Tensile strength was correlate with powder feeding performance. • A modified model was built to predict tensile strength. [ABSTRACT FROM AUTHOR]

Presentation of exogenous antigens loaded on major histocompatibility complex class I molecules by antigen presenting cells, termed cross-presentation, is essential for the induction of CD8+ T cells and is performed mainly by specialized dendritic cell subsets. Research into this field has described two main mechanisms of cross-presentation, the cytosolic pathway and the vacuolar pathway. As the first step in cross-presentation, surface receptors relating to cross-presentation are required in the recognition and uptake of Ags, which include C-type lectin receptors, immunoglobulin γ Fc region receptor, chemokine receptor, scavenger receptor etc. After uptake by the cells, there are also many molecules that enable Ags to participate in cross-presentation pathways. By this approach, exogenous Ags can induce CD8+ T cells into cytotoxic T lymphocytes, which is of great significance to induce antitumor and antiviral immune responses, and the molecular mechanism would facilitate the development of related adjuvants. However, the detailed mechanisms of cross-presentation still remain unknown. In this paper, some latest researches, including two major pathways, DC surface receptors and application prospects are summarized. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA), a chronic inflammatory disease, is characterized by cartilage damage, bone tissue destruction, morphological changes in synovial fluids, and synovial joint inflammation. The inflamed synovial tissue has potential for passive and active targeting because of enhanced permeability and retention effect and the existence of RA synovial macrophages and fibroblasts that selectively express surface receptors such as folate receptor β, CD44 and integrin αVβ. Although there are numerous interventions in RA treatment, they are not safe and effective. Therefore, it is important to develop new drug or drug delivery systems that specifically targets inflamed/swollen joints but attenuates other possible damages to healthy tissues. Recently some receptors such as toll-like receptors (TLRs), the nucleotide-binding oligomerization domain-like receptors, and Fc-γ receptor have been identified in synovial tissue and immune cells that are involved in induction or suppression of arthritis. Analysis of the TLR pathway has moreover suggested new insights into the pathogenesis of RA. In the present paper, we have reviewed drug delivery strategies based on receptor targeting with novel ligand-anchored carriers exploiting CD44, folate and integrin αVβ as well as TLRs expressed on synovial monocytes and macrophages and antigen presenting cells, for possible active targeting in RA. TLRs could not only open a new horizon for developing new drugs but also their antagonists or humanized monoclonal antibodies that block TLRS specially TLR4 and TLR9 signaling could be used as targeting agents to antigen presenting cells and dendritic cells. As a conclusion, common conventional receptors and multifunctional ligands that arte involved in targeting receptors or developing nanocarriers with appropriate ligands for TLRs can provide profoundly targeting drug delivery systems for the effective treatment of RA. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are the most effective professional antigen-presenting cell. They ferry antigen from the extremities to T cells and are essential for the initiation of an adaptive immune response. Despite interest in how DCs respond to chemical stimuli, there have been few attempts to model DC migration. In this paper, we simulate the motility of DCs by modeling the generation of forces by filopodia and a force balance on the cell. The direction of fliopodial extension is coupled to differential occupancy of cognate chemokine receptors across the cell. Our model simulates chemokinesis and chemotaxis in a variety of chemical and mechanical environments. Simulated DCs undergoing chemokinesis were measured to have a speed of 5.1 ± 0.07 μm·min-1 and a persistence time of 3.2 ± 0.46 min, consistent with experiment. Cells undergoing chemotaxis exhibited a stronger chemotactic response when exposed to lower average chemokine concentrations, also consistent with experiment. We predicted that when placed in two opposing gradients, cells will cluster in a line, which we call the “line of equistimulation;” this clustering has also been observed. We calculated the effect of varying gradient steepness on the line of equistimulation, with steeper gradients resulting in tighter clustering. Moreover, gradients are found to be most potent when cells are in a gradient of chemokine whose mean concentration is close to the binding of the Kd to the receptor, and least potent when the mean concentration is 0.1Kd. Comparing our simulations to experiment, we can give a quantitative measure of the strength of certain chemokines relative to others. Assigning the signal of CCL19 binding CCR7 a baseline strength of 1, we found CCL21 binding CCR7 had a strength of 0.28, and CXCL12 binding CXCR4 had a strength of 0.30. These differences emerge despite both chemokines having virtually the same Kd, suggesting a mechanism of signal amplification in DCs requiring further study. [ABSTRACT FROM AUTHOR]

Photoreceptor cells (PRCs) across the animal kingdom are characterized by a stacking of apical membranes to accommodate the high abundance of photopigment. In arthropods and many other invertebrate phyla PRC membrane stacks adopt the shape of densely packed microvilli that form a structure called rhabdomere. PRCs and surrounding accessory cells, including pigment cells and lens-forming cells, are grouped in stereotyped units, the ommatidia. In larvae of holometabolan insects, eyes (called stemmata) are reduced in terms of number and composition of ommatidia. The stemma of Drosophila (Bolwig organ) is reduced to a bilateral cluster of subepidermal PRCs, lacking all other cell types. In the present paper we have analyzed the development and fine structure of the Drosophila larval PRCs. Shortly after their appearance in the embryonic head ectoderm, PRC precursors delaminate and lose expression of apical markers of epithelial cells, including Crumbs and several centrosome-associated proteins. In the early first instar larva, PRCs show an expanded, irregularly shaped apical surface that is folded into multiple horizontal microvillar-like processes (MLPs). Apical PRC membranes and MLPs are covered with a layer of extracellular matrix. MLPs are predominantly aligned along an axis that extends ventro-anteriorly to dorso-posteriorly, but vary in length, diameter, and spacing. Individual MLPs present a "beaded" shape, with thick segments (0.2–0.3 μm diameter) alternating with thin segments (>0.1 μm). We show that loss of the glycoprotein Chaoptin, which is absolutely essential for rhabdomere formation in the adult PRCs, does not lead to severe abnormalities in larval PRCs. • We reconstruct the photoreceptors (PRCs) of the Bolwig Organ (BO) using serial EM. • BO PRCs do not form a rhabdomere but extend long microvillar-like processes (MLPs). • MLPs extend roughly parallel to each other and cover the former apical PRC surface. • MLPs are long and unbranched, with thick segments alternating with thin segments. [ABSTRACT FROM AUTHOR]

T lymphocytes (T cells) play an important role in orchestrating an adaptive immune response in complex organisms. Recent experiments have shown that when T cells recognize antigen presenting cells, a complex and large-scale reorganization of intercellular membrane proteins and cell shape occurs. The resulting motif is implicated in information transfer between T cells and antigen presenting cells, and has been labeled the immunological synapse. Numerical solutions of a mathematical model that incorporates binding kinetics, protein mobility, and down regulation, and membrane mechanics has proven successful in describing some of these observations. In this paper, we analyze the equations that describe this model, and this sheds light on the origins of pattern formation in the immunological synapse. In particular, the thermodynamic considerations and dynamic instabilities that lead to pattern formation in and out of equilibrium are elucidated. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs), particularly exosomes (30–150 nm), are an emerging delivery system in mediating cellular communications, which have been observed for priming immune responses by presenting parent cell signaling proteins or tumor antigens to immune cells. Therefore, preparation of antigenic exosomes that can play therapeutic roles, particularly in cancer immunotherapy, is emerging. However, standard benchtop methods (e.g., ultracentrifugation and filtration) lack the ability to purify antigenic exosomes specifically among other microvesicle subtypes, due to the non-selective and time-consuming (＞10 h) isolation protocols. Exosome engineering approaches, such as the transfection of parent cells, also suffer from poor yields, low purity, and time-consuming operations. In this paper, we introduce a streamlined microfluidic cell culture platform for integration of harvesting, antigenic modification, and photo-release of surface engineered exosomes in one workflow, which enables the production of intact, MHC peptide surface engineered exosomes for cytolysis activation. A PDMS microfluidic cell culture chip is simply cast from a 3D-printed mold. This proof-of-concept study demonstrated the enhanced ability of harvested exosomes in antigen presentation and T cell activation, by decorating melanoma tumor peptides on the exosome surface (e.g., gp-100, MART-1, and MAGE-A3). Such surface engineered antigenic exosomes were harvested in real-time from the on-chip culture of leukocytes isolated from human blood, leading to much faster cellular uptake. The activation of gp100-specific CD8 T cells which were purified from the spleen of 2 Pmel1 transgenic mice was evaluated using surface engineered exosomes prepared from murine antigen presenting cells. Antigen-specific CD8 T cell proliferation was significantly induced by the engineered exosomes compared to that by native, non-engineered exosomes. This microfluidic platform serves as an automated and highly integrated cell culture device for rapid and real-time production of therapeutic exosomes that could advance cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are highly specialized antigen-presenting cells (APCs) able to induce both specific immunity and immune tolerance. Using information gathered from the tissue where they reside, DCs adjust their functional activity to ensure that protective immunity is favoured while unwanted or exaggerated immune responses are prevented. The remarkable ability of these cells to induce, enhance and orient the immune response, while at the same time maintaining self-tolerance, makes them key players in the immune system. Despite the fact that the role of Ca 2+ has been clearly established in human DC functions, the link between ion homeostasis, mainly Ca 2+ , and DC functions is not fully understood. After all, a growing number of works clearly show the role of SOCE and associated channels in the maturation step, and those of K + channels in migration. This review highlights the key papers published over the past few years and summarizes prospects for the near future. [ABSTRACT FROM AUTHOR]

Oligomannose-coated liposomes (OMLs), containing entrapped antigens, serve as effective antigen delivery vehicles and as a novel adjuvant to induce antigen-specific cellular immune responses. However, in vitro activation of antigen-presenting cells (APCs) by OMLs has not yet been demonstrated. In this paper, we found that OMLs can deliver the antigens and the stimulatory signals into inflammatory monocytes in vitro , leading to differentiation of the cells to mature APCs. When OMLs were co-cultured with peripheral blood mononuclear cells from C57BL/6 mice in the presence of mouse serum, OMLs were preferentially incorporated into both Ly6C high monocytes and Ly6C low monocytes, which are referred to as murine inflammatory and resident monocytes, respectively. The expression of CD11c, CD80, CD86, CCR7, and MHC class II on the Ly6C high monocytes was significantly enhanced during the 24 h after OML uptake, whereas upregulation of these molecules on the Ly6C low monocytes was limited. In addition, the antigenic peptide of OVA encased in OMLs was presented on MHC class I of only Ly6C high monocytes. Furthermore, OVA-encasing OML-ingesting monocytes can activate CD8 + T cells from OT-1 mice, suggesting that antigens encapsulated in OMLs were cross-presented in inflammatory monocytes. Adoptive transfer of the monocytes that engulf OVA-encasing OMLs led to induction of an antigen-specific Th1 immune response in mice. Taken together, mature APCs can be generated from inflammatory monocytes in peripheral blood by ex vivo treatment of the cells with OMLs without any additional stimuli. [ABSTRACT FROM AUTHOR]

Signal peptide peptidase-like 2a (SPPL2a) is an aspartic intramembrane protease which has recently been shown to play an important role in the development and function of antigen presenting cells such as B lymphocytes and dendritic cells. In this paper, we describe the discovery of the first selective and orally active SPPL2a inhibitor (S)-2-cyclopropyl-N1-((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine-2,1'-cyclopropan]-10-yl)-N4-(5-fluoro-2-methylpyridin-3-yl)succinamide 40 (SPL-707). This compound shows adequate selectivity against the closely related enzymes γ-secretase and SPP and a good pharmacokinetic profile in mouse and rat. Compound 40 significantly inhibited processing of the SPPL2a substrate CD74/p8 fragment in rodents at doses ≤10 mg/kg b.i.d. po. Oral dosing of 40 for 11 days at ≥10 mg/kg b.i.d. recapitulated the phenotype seen in Sppl2a knockout (ko) and ENU mutant mice (reduced number of specific B cells and myeloid dendritic cells). Thus, we believe that SPPL2a represents an interesting and druggable pharmacological target, potentially providing a novel approach for the treatment of autoimmune diseases by targeting B cells and dendritic cells. [ABSTRACT FROM AUTHOR]

Immunisation of the newborn represents a key global strategy in overcoming morbidity and mortality due to infection in early life. Potential limitations, however, include poor immunogenicity, safety concerns and the development of tolerogenicity or hypo-responsiveness to either the same antigen and/or concomitant antigens administered at birth or in the subsequent months. Furthermore, the neonatal immunological milieu is polarised towards Th2-type immunity with dampening of Th1-type responses and impaired humoral immunity, resulting in qualitatively and quantitatively poorer antibody responses compared to older infants. Innate immunity also shows functional deficiency in antigen-presenting cells: the expression and signalling of Toll-like receptors undergo maturational changes associated with distinct functional responses. Nevertheless, the effectiveness of BCG, hepatitis B and oral polio vaccines, the only immunisations currently in use in the neonatal period, is proof of concept that vaccines can be successfully administered to the newborn via different routes of delivery to induce a range of protective mechanisms for three different diseases. In this review paper, we discuss the rationale for and challenges to neonatal immunisation, summarising progress made in the field, including lessons learnt from newborn vaccines in the pipeline. Furthermore, we explore important maternal, infant and environmental co-factors that may impede the success of current and future neonatal immunisation strategies. A variety of approaches have been proposed to overcome the inherent regulatory constraints of the newborn innate and adaptive immune system, including alternative routes of delivery, novel vaccine configurations, improved innate receptor agonists and optimised antigen-adjuvant combinations. Crucially, a dual strategy may be employed whereby immunisation at birth is used to prime the immune system in order to improve immunogenicity to subsequent homologous or heterologous boosters in later infancy. Similarly, potent non-specific immunomodulatory effects may be elicited when challenged with unrelated antigens, with the potential to reduce the overall risk of infection and allergic disease in early life. [ABSTRACT FROM AUTHOR]

Fasciola hepatica are trematodes that reside in the bile ducts of mammals. Infection causes US$3 billion in losses annually in animal production and is considered a zoonosis of growing importance. An under-represented area in F. hepatica research has been the examination of the different immunomodulatory abilities of various parasite isolates on the host immune system. In this paper, this issue was explored, with the bovine macrophage cell line 'BOMA'. The cells were matured by LPS treatment and stimulated with excretory/secretory antigens (ES) from two Fasciola hepatica isolates: a laboratory isolate 'Weybridge' ( Fh-WeyES) and a wild isolate ( Fh-WildES). As expected, stimulation with antigen mixtures with highly similar compositions resulted in mild transcriptomic differences. However, there were significant differences in cytokine levels. Compared to Fh-WeyES, exposure to Fh-WildES upregulated 27 and downregulated 30 genes. Fh-ES from both isolates diminished the release of TNF-α, whereas only Fh-WildES decreased IL-10 secretion. Neither Fh-WeyES nor Fh-WildES had an impact on IL-12 release. Our results indicate that various isolates can have different immunomodulatory abilities and impacts on the bovine immune system. [ABSTRACT FROM AUTHOR]

Abstract: Multiple sclerosis (MS) is a chronic inflammatory disease characterized by demyelination, remyelination and loss of functions. Even though its etiology is unknown viral, genetic and environmental factors are considered triggers of the disease. MS shows a heterogeneous clinical course, but most patients exhibit exacerbations and remissions from the onset, eventually leading to secondary progressive multiple sclerosis. Systemic inflammatory events are known to signal into the central nervous system (CNS), and can induce a general response known as sickness behavior. Several research papers have demonstrated that a peripheral stimulus can induce the synthesis of cytokines in the brain. In different neurodegenerative diseases peripheral inflammation generates exacerbation to ongoing damage in the brain. In MS, relapsing and remitting episodes are unpredictable; however, peripheral inflammation may exacerbate these events. Clinical studies revealed an association between infections and relapses, which may lead to the worsening of neurological damage. A similar scenario was described in MS animal models demonstrating that peripheral inflammation recrudesced a central ongoing demyelinating lesion. In this paper, we reviewed the existing data on the inflammatory component of MS, with special attention on the effect of peripheral infections in the etiology and progression of MS and its effect on the relapsing and remitting episodes. We also analyzed data concerning the effect of peripheral inflammatory events in MS experimental animal models. This article is part of a Special Issue entitled ''Neuroinflammation in neurodegeneration and neurodysfunction''. [Copyright &y& Elsevier]

Recently, microneedle arrays (MAs) have been developed for painless inoculation of vaccines and possess many prominent advantages, including convenience for inoculation, and exact delivery of vaccine to the exact epidermal and dermal or mucosal compartments which teem with antigen-presenting cells (APCs). Among different types of MAs, while the micro-environmental stimulus-responsive MAs represent one of the developmental trends in the field, the MAs combined with the conventional vaccines that are based on nonvirulent viruses, such as live attenuated or whole inactivated viruses, and antigen-encoding DNA viral vectors, have developed rapidly into the advanced stages, with certain products already on clinical trials. The pre- and clinical research outcomes showed that the painless MA delivery of the conventional vaccines through mammalian skin or mucosa can not only elicit robust systemic and even mucosal immunity to pathogens but also, in certain circumstances, redirect the immune response toward a specific Th1 pathway, resulting in cytotoxic T lymphocytes (CTL) to erase the cell-hidden pathogens, thanks to the robust adjuvant function of MAs exerted through damaging the contacted cells to release dangerous signals. This paper focuses on reviewing the latest research and advancements in MA delivery of the conventional vaccines that are based on nonvirulent viruses, underlining MA enhancement of the overall vaccine performance and the most advanced MA vaccine products that are relatively close to markets. [ABSTRACT FROM PUBLISHER]

Background: The aim of this paper is to study the function of allogeneic and autologous NK cells against Dental Pulp Stem Cells (DPSCs) and Mesenchymal Stem Cells (MSCs) and to determine the function of NK cells in a three way interaction with monocytes and stem cells. Methodology/Principal Findings: We demonstrate here that freshly isolated untreated or IL-2 treated NK cells are potent inducers of cell death in DPSCs and MSCs, and that anti-CD16 antibody which induces functional split anergy and apoptosis in NK cells inhibits NK cell mediated lysis of DPSCs and MSCs. Monocytes co-cultured with either DPSCs or MSCs decrease lysis of stem cells by untreated or IL-2 treated NK cells. Monocytes also prevent NK cell apoptosis thereby raising the overall survival and function of NK cells, DPSCs or MSCs. Both total population of monocytes and those depleted of CD16+ subsets were able to prevent NK cell mediated lysis of MSCs and DPSCs, and to trigger an increased secretion of IFN-γc by IL-2 treated NK cells. Protection of stem cells from NK cell mediated lysis was also seen when monocytes were sorted out from stem cells before they were added to NK cells. However, this effect was not specific to monocytes since the addition of T and B cells to stem cells also protected stem cells from NK cell mediated lysis. NK cells were found to lyse monocytes, as well as T and B cells. Conclusion/Significance: By increasing the release of IFN-γc and decreasing the cytotoxic function of NK cells monocytes are able to shield stem cells from killing by the NK cells, resulting in an increased protection and differentiation of stem cells. More importantly studies reported in this paper indicate that anti-CD16 antibody can be used to prevent NK cell induced rejection of stem cells. [ABSTRACT FROM AUTHOR]

Malignant glioma is the most lethal of a wide array of CNS neoplasms. Its onset and progression are markedly associated with profound immunosupression and paralysis of T-cell survival and proliferation. Myriad immunotherapeutic strategies are presently used to target such T-cell anomalies in glioma. Our recent work has highlighted use of the novel glycopeptide, the CD2 ligand, T11 target structure (T11TS) as an immunotherapeutic agent against experimentally induced glioma in rats. We have shown that T11TS causes multi-target modulation of key components of the T-cell – antigen presenting cell (APC) immunological synapse. This consequently triggers T-cell activation so as to reverse glioma-induced changes to physiological levels. T11TS administration also causes CD2 upregulation. Earlier we also found T11TS to cause enhanced proliferation of both CD4+ and CD8+ T-cells in glioma conditions. These findings led us to believe that downstream CD2-stimulated “alternative pathway” of calcineurin–NFAT could be a possible target for modulation by T11TS. In the present paper we thus show that immunotherapy with T11TS induces a multi-targeted approach towards activation of this “alternative pathway” of T-cell signaling providing an immunotherapeutic advantage against glioma. We show here that T11TS immunotherapy causes positive modulations of the CD2 pathway-associated proteins, viz., p59fyn, protein kinase C-θ (PKC-θ), calcineurin and nuclear factor for activation of T-cells (NFAT) and hint that this may accord greater survival and proliferation advantage to T-cells of the glioma-bearing animals for augmented defence against glioma. These findings help open a molecular immunotherapeutic door – one which is directed towards clinical studies for glioma-immunotherapy using T11TS. [ABSTRACT FROM AUTHOR]

Summary The mononuclear phagocytic system (MPS), comprised of monocytes, macrophages, and dendritic cells, is essential in tissue homeostasis and in determining the balance of the immune response through its role in antigen presentation. It has been identified as a therapeutic target in infectious disease, cancer, autoimmune disease and transplant rejection. Here, we review the current understanding of the immunophenotype and function of the MPS in normal human liver. Using well-defined selection criteria, a search of MEDLINE and EMBASE databases identified 76 appropriate studies. The majority (n = 67) described Kupffer cells (KCs), although the definition of KC differs between sources, and little data were available regarding their function. Only 10 papers looked at liver dendritic cells (DCs), and largely confirmed the presence of the major dendritic cell subsets identified in human blood. Monocytes were thoroughly characterized in four studies that utilized flow cytometry and fluorescent microscopy and highlighted their prominent role in liver homeostasis and displayed subtle differences from circulating monocytes. There was some limited evidence that liver DCs are tolerogenic but neither liver dendritic cell subsets nor macrophages have been thoroughly characterized, using either multi-colour flow cytometry or multi-parameter fluorescence microscopy. The lobular distribution of different subsets of liver MPS cells was also poorly described, and the ability to distinguish between passenger leukocytes and tissue resident cells remains limited. It was apparent that further research, using modern immunological techniques, is now required to accurately characterize the cells of the MPS in human liver. [ABSTRACT FROM AUTHOR]

The Dendritic Cell Algorithm (DCA) is an immune-inspired algorithm based on the behavior of natural dendritic cells. The DCA, as a binary classifier, classifies in a crisp manner each data item as either normal or anomalous. However, it was shown that DCA is sensitive to the input class data order. This problem was solved by the development of the fuzzy dendritic cell algorithm. The performance of the latter algorithm relies on its parameters tuning as this process is based on the use of a fuzzy clustering technique. We, thus, believe that the choice of the right fuzzy clustering technique is crucial for the system. In this paper, we try to review the fuzzy version of DCA and to investigate its performance when hybridized with different fuzzy clustering techniques. The aim of this hybridization is to select the most appropriate fuzzy clustering approach in order to generate an overall automated robust fuzzy DCA classifier. [ABSTRACT FROM AUTHOR]

In today's medical industry, the range of vaccines that exist for administration in humans represents an eclectic variety of forms and immunologic mechanisms. Namely, these are the live attenuated viruses, inactivated viruses, subunit proteins, and virus-like particles for treating virus-caused diseases, as well as the bacterial-based polysaccharide, protein, and conjugated vaccines. Currently, a new approach to vaccination is being investigated with the concept of DNA vaccines. As an alternative delivery route to enhance the vaccination efficacy, microneedles have been devised to target the rich network of immunologic antigen-presenting cells in the dermis and epidermis layers under the skin. Numerous studies have outlined the parameters of microneedle delivery of a wide range of vaccines, revealing comparable or higher immunogenicity to conventional intramuscular routes, overall level of stability, and dose-sparing advantages. Furthermore, recent mechanism studies have begun to successfully elucidate the biological mechanisms behind microneedle vaccination. This paper describes the current status of microneedle vaccine research. [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]

The human gastrointestinal tract is exposed to a huge variety of microorganisms, either commensal or pathogenic; at this site, a balance between immunity and immune tolerance is required. Intestinal dendritic cells (DCs) control the mechanisms of immune response/tolerance in the gut. In this paper we have identified a peptide (STp) secreted by Lactobacillus plantarum, characterized by the abundance of serine and threonine residues within its sequence. STp is encoded in one of the main extracellular proteins produced by such species, which includes some probiotic strains, and lacks cleavage sites for the major intestinal proteases. When studied in vitro, STp expanded the ongoing production of regulatory IL-10 in human intestinal DCs from healthy controls. STp-primed DC induced an immunoregulatory cytokine profile and skin-homing profile on stimulated T-cells. Our data suggest that some of the molecular dialogue between intestinal bacteria and DCs may be mediated by immunomodulatory peptides, encoded in larger extracellular proteins, secreted by commensal bacteria. These peptides may be used for the development of nutraceutical products for patients with IBD. In addition, this kind of peptides seem to be absent in the gut of inflammatory bowel disease patients, suggesting a potential role as biomarker of gut homeostasis. [ABSTRACT FROM AUTHOR]

Multiple layers of suppressive components including regulatory T (TReg) cells, suppressive antigen-presenting cells, and inhibitory cytokines form suppressive networks in the ovarian cancer microenvironment. It has been demonstrated that as a major suppressive element, TReg cells infiltrate tumor, interact with several types of immune cells, and mediate immune suppression through different molecular and cellular mechanisms. In this paper, we focus on human ovarian cancer and will discuss the nature of TReg cells including their subsets, trafficking, expansion, and function. We will briefly review the development of manipulation of TReg cells in preclinical and clinical settings. [ABSTRACT FROM AUTHOR]

Severe malaria infection caused by Plasmodium falciparum is a global life-threatening disease and a leading cause of death worldwide. Intensive investigations have demonstrated that macrophages play crucial roles in control of inflammatory and immune responses and clearance of Plasmodium-falciparum-parasitized erythrocytes (PE). This paper focuses on howmacrophage CD36 recognizes and internalizes PE and participates the inflammatory signaling in response to Plasmodium falciparum. In addition, recent advances in our current understanding of the biological actions of PPARγ on CD36 and malaria clearance from the hosts are highlighted. [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]

Abstract: Allogeneic hematopoietic cell transplantation (HCT) has most commonly been used to treat hematologic malignancies, where it is often the only potentially curative option available. The success of HCT has been limited by transplant-associated toxicities related to the conditioning regimens used and to the common immunologic consequence of donor T cell recognition of recipient alloantigens, graft-vs-host disease (GVHD). The frequency and severity of GVHD observed when extensive HLA barriers are transgressed has essentially precluded the routine use of extensively HLA-mismatched HCT. Allogeneic HCT also has potential as an approach to organ allograft tolerance induction, but this potential has not been previously realized because of the toxicity associated with traditional conditioning. In this paper we review two approaches to HCT involving reduced intensity conditioning regimens that have been associated with improvements in safety in patients with hematologic malignancies, even in the HLA-mismatched transplant setting. These strategies have been applied in the first successful pilot studies for the induction of organ allograft tolerance in humans. Thus, we summarize an example of vertical translational research between animal models and humans and horizontal translation between two separate goals that culminated in the use of HCT to achieve allograft tolerance in humans. [Copyright &y& Elsevier]

Although the roles of each low-frequency immunocompetent cells such as dendritic cells (DCs), γδT cells, and Treg cells in induction of acute or chronic graft versus host disease (GVHD) have been discussed in several reports, there are few papers dealing with an evaluation of these immunocompetent cells together and simultaneously in patients with hematopoietic stem cell transplantation (HSCT) and explored the kinetics of these cells in association with GVHD. In the present study, we assessed the number of plasmacytoid DCs (pDCs), myeloid DCs (mDCs), γδT cells and Treg cells serially in patients who received allogeneic HSCT and analyzed the relationship of these cells with acute or chronic GVHD (cGVHD) by using flow cytometry. The percentages and numbers of pDCs, mDC1s and γδT cells were significantly lowered in the patients with acute GVHD (aGVHD) compared with those with no GVHD. On the contrary, the percentages and numbers of Treg cells were significantly elevated in the patients with aGVHD compared with those with no GVHD. As to the association with cGVHD, Treg cells were elevated in the patients with cGVHD, compared with those with no GVHD. The present study revealed an association of pDCs, mDCs, γδT cells and Treg cells with induction or treatment of GVHD. [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]

T cells orchestrate adaptive immune responses by recognizing short peptides derived from pathogens, and by distinguishing them from self-peptides. To ensure the latter, immature T cells (thymocytes) diffuse within the thymus gland, where they encounter an ensemble of self-peptides presented on (immobile) antigen presenting cells. Potentially autoimmune T cells are eliminated if the thymocyte binds sufficiently strongly with any such antigen presenting cell. We model thymic selection of T cells as a random walker diffusing in a field of immobile traps that intermittently turn 'on' and 'off'. The escape probability of potentially autoimmune T cells is equivalent to the survival probability of such a random walker. In this paper we describe the survival probability of a random walker on a d-dimensional cubic lattice with randomly placed immobile intermittent traps, and relate it to the result of a well-studied problem where traps are always 'on'. Additionally, when switching between the trap states is slow, we find a peculiar caging effect for the survival probability. [ABSTRACT FROM AUTHOR]

Cancer subtype classification and survival prediction both relate directly to patients' specific treatment plans, making them fundamental medical issues. Although the two factors are interrelated learning problems, most studies tackle each separately. In this paper, expression levels of genes are used for both cancer subtype classification and survival prediction. We considered 350 diffuse large B-cell lymphoma (DLBCL) subjects, taken from four groups of patients (activated B-cell-like subtype dead, activated B-cell-like subtype alive, germinal center B-cell-like subtype dead, and germinal center B-cell-like subtype alive). As classification features, we used 11,271 gene expression levels of each subject. The features were first ranked by mRMR (Maximum Relevance Minimum Redundancy) principle and further selected by IFS (Incremental Feature Selection) procedure. Thirty-five gene signatures were selected after the IFS procedure, and the patients were divided into the above mentioned four groups. These four groups were combined in different ways for subtype prediction and survival prediction, specifically, the activated versus the germinal center and the alive versus the dead. Subtype prediction accuracy of the 35-gene signature was 98.6%. We calculated cumulative survival time of high-risk group and low-risk groups by the Kaplan-Meier method. The log-rank test p-value was 5.98e-08. Our methodology provides a way to study subtype classification and survival prediction simultaneously. Our results suggest that for some diseases, especially cancer, subtype classification may be used to predict survival, and, conversely, survival prediction features may shed light on subtype features. [ABSTRACT FROM AUTHOR]

Abstract: Dendritic cells (DCs) are bone marrow-derived professional antigen presenting cells. Due to their role as potent inducers of immune responses, these cells are widely used as adjuvant in experimental clinical settings for cancer immune therapy. We have developed a DC-based vaccine using autologous blood monocytes loaded with allogeneic tumor cell lysate rich in cancer/testis antigens. This vaccine has at present been tested for activity in three phase II clinical trials including two cohorts of patients with advanced colorectal cancer (CRC) and one cohort of patients with advanced non-small-cell-lung-cancer (NSCLC). In the present paper we retrospectively compare the maturation profile based on surface marker expression on DCs generated from the three patient cohorts and between cancer patient cohorts and a cohort of healthy donors. Vaccines were generated under cGMP conditions and phenotypic profiles of DC were analyzed by flow cytometry and the obtained data were used as a basis to set guideline values for our quality control of GMP produced DC vaccines. Each vaccine batch was analyzed for the expression of the surface maturation and differentiation molecules CD14, CD1a, CD83, CD86, MHC class II and CCR7, and the optimal expression pattern is considered as CD14low, CD1a, CD83high, CD86high, MHC class IIhigh and CCR7high. In accordance with data from other studies including other types of cancer patients, especially breast cancer patients, we found that the maturation status of the DC batches depends on cancer type and correlates with clinical status of cancer patients included. [Copyright &y& Elsevier]

This paper describes the design of new controlled delivery systems consisting of a mesoporous support functionalized on the pore outlets with a certain hapten able to interact with an antibody that acts as a nanoscopic cap. The opening protocol and delivery of the entrapped guest is related by a displacement reaction involving the presence in the solution of the antigen to which the antibody is selective. As a proof- of-the-concept, the solid MCM-41 was selected as support and was loaded with the dye [Ru(bipy)3]Cl2. Then a suitable derivative of the hapten 4-(4-aminobenzenesulfonylamino)benzoic acid was anchored on the outer surface of the mesoporous support (solid Si). Finally the pores were capped with a polyclonal antibody for sulfathiazole (solid Si-AB). Delivery of the dye in the presence of a family of sulfonamides was studied in phosphate-buffered saline (PBS; pH 7.5). A selective uncapping of the pores and dye delivery was observed for sulfathiazole. This delivery behavior was compared with that shown by other solids that were prepared as models to assess the effect of the hapten and its interaction with antibody in the dye delivery control in the presence of the antigen. [ABSTRACT FROM AUTHOR]

Abstract: The immune system of vertebrates may attack its own body and cause autoimmunity diseases. To prevent autoimmunity, regulatory T cells suppress the activity of the autoreactive effector T cells, but they also interrupt normal immune reactions against foreign antigens. In this paper, we discuss the advantage of having some regulatory T cells by considering the host''s ability of coping with foreign antigens and the harm of autoimmunity. Assumptions are as follows: the immature T cells reactive to abundant self-antigens are eliminated, those reactive to rare self-antigen will become regulatory T cells, and those that fail to interact with the antigens to which they are reactive will become effector T cells. Some self-reactive immature T cells may fail to interact with their own target antigens during the limited training period, and will later become effector T cells, causing autoimmunity. Analysis suggests that, having some regulatory T cells can never be advantageous to the host, if activated regulatory T cells suppress effector T cells at any location of the body (global suppression). In contrast, producing some regulatory T cells can be beneficial, if the body is composed of many compartments and regulatory T cells suppress the immune reactions only within the same compartment (localized suppression). This requires regulatory T cells to stop circulating once they are activated by their own target self-antigens. [Copyright &y& Elsevier]

Two recent papers published in Immunity and Cell Host & Microbe underline the great importance of B cells and of antibodies (Abs) in orchestrating crucial T helper cell type 2 (Th2) protective immune responses to gastrointestinal nematodes. The findings in animal models now raise major questions as to how B cells and Abs carry out these functions in humans. Here we discuss recent technological advances in humanizing animal models at the level of both Abs and their Fc-receptors, that might provide some answers. [Copyright &y& Elsevier]

Abstract: In this paper we develop a new mathematical model of immunotherapy and cancer vaccination, focusing on the role of antigen presentation and co-stimulatory signaling pathways in cancer immunology. We investigate the effect of different cancer vaccination protocols on the well-documented phenomena of cancer dormancy and recurrence, and we provide a possible explanation of why adoptive (i.e. passive) immunotherapy protocols can sometimes actually promote tumour growth instead of inhibiting it (a phenomenon called immunostimulation), as opposed to active vaccination protocols based on tumour-antigen pulsed dendritic cells. Significantly, the results of our computational simulations suggest that elevated numbers of professional antigen presenting cells correlate well with prolonged time periods of cancer dormancy. [Copyright &y& Elsevier]

This paper reports the application of molecular dynamics methods to understand the interactions between dendritic molecules with spermine surface groups and double-helical DNA. Importantly, we are able to reproduce the binding effects observed experimentally, indicating that this type of modeling is robust and reliable. The energetic effects were deconvoluted in order to quantify the binding of each spermine unit to the DNA double helix. Importantly, for the first-generation dendron G1, DNA binding was adversely affected by increasing levels of NaCl (>10% of the interaction energy is lost). For second-generation G2 however, we observed a compensation effect, in which some ligands "sacrifice" themselves, losing large amounts of binding energy with DNA. However, these ligands screen the complex, which enables the other spermine residues to bind more effectively to DNA. In this way, the multivalent array is able to maintain its high affinity binding, even as the salt concentration increases (only ca. 1% of the interaction energy is lost). These modeling studies are in agreement with, and provide a unique insight into; the experimental results. Clearly, ligand flexibility and ability to reorganize the interactions with DNA are important, demonstrating that high levels of preorganization and ligand framework rigidity are not always beneficial for multivalent recognition. The concept suggested by this modeling study, in which ligand "sacrifice" and binding site screening combine to enable high-affinity binding, is a new paradigm in multivalency. [ABSTRACT FROM AUTHOR]

Abstract: Antigen presenting molecules play an important role in both innate and adoptive immune responses by priming and activating T cells. Among them, CD1 molecules have been identified to present both exogenous and endogenous lipid antigens to CD1-restricted T cells. The involvement of CD1-restricted T cells in autoimmune diseases and in defense against infectious diseases, however, remains largely unknown. Identifying novel antigenic lipids that bind to CD1 molecules and understanding the role of CD1-restricted T cells should lead to the successful development of vaccines, because the lipids can be used as antigens and also as adjuvants. In this paper, we have constructed functional recombinant human CD1 dimeric proteins and established a competitive ELISA assay to measure the lipid binding to CD1 molecules using the CD1 dimers. By using the competitive ELISA assay, we were able to show that the lipid extracts from murine malaria parasites can actually be loaded onto CD1 molecules. In addition, we have demonstrated that artificial antigen-presenting cells, which consist of magnetic beads coated with CD1d dimer and anti-CD28 antibody, stimulated and expanded human invariant NKT cells as efficiently as autologous immature DCs. A set of the tools presented in the current study should be valuable for screening various CD1 molecule-binding lipid antigens and for isolating CD1-restricted T cells. [Copyright &y& Elsevier]

Abstract: Cytotoxic T lymphocytes (CTLs) play a dominant role in the pathogenesis of autoimmune diabetes, commonly denoted Type 1 Diabetes (T1D). These CTLs (notably T cells) recognize and kill insulin-secreting pancreatic cells, reducing their number by . The resulting reduction of insulin secretion causes the defective regulation of glucose metabolism, leading to the characteristic symptoms of diabetes. Recognition of cells as targets by CTLs depends on the interactions between MHC-peptide complexes on the surface of cells and receptors (TCRs) on T cells. Those CTLs with high affinity TCRs (also called high avidity T cells) cause most of the harm, while those with low affinity TCRs (also called low avidity T cells) play a more mysterious role. Recent experimental evidence suggests that low avidity T cells accumulate as memory T cells during the disease and may be protective in NOD mice (a strain prone to developing T1D), delaying disease progression. It has been hypothesized that such low avidity T cells afford disease protection either by crowding the islets of Langerhans, where cells reside, or by killing antigen presenting cells (APCs). In this paper, we explore the hypothesized mechanisms for this protective effect in the context of a series of models for (1) the interactions of low and high avidity T cells, (2) the effect of APCs and (3) the feedback from cell killing to autoantigen-induced T cell proliferation. We analyze properties of these models, noting consistency of predictions with observed behaviour. We then use the models to examine the influence of various treatment strategies on the progression of the disease. The model reveals that progressive accumulation of memory low avidity autoreactive T cells during disease progression makes treatments aimed at expanding these protective T cell types more effective close to, or at the onset of clinical disease. It also provides evidence for the hypothesis that low avidity T cells kill APCs (rather than the alternate hypothesis that they crowd the islets). [Copyright &y& Elsevier]

[Display omitted] • Liposomes self-assembled from lipids are excellent targeted transport carrier materials. • Lipids have the role of immune stimulation, which can stimulate the effect of innate immunity. • Liposomes combined with targeted transport and immunostimulatory effects have great advantages in cancer vaccines. Cancer is still a major threat for human life, and the cancer immunotherapy can be more optimized to prolong life. However, the effect of immunotherapy is not encouraging. In order to achieve outstanding immune effect, it is necessary to strengthen antigens uptake of antigen presenting cells. Adjuvants were added to vaccines to achieve this purpose, which could be divided into two types: as an immunostimulatory molecule, the innate immunities of the body were triggered; or as a delivery carrier, and antigens were cross-delivery through the "cytoplasmic pathway" and released at a specific location. This paper reviewed the relevant research status of tumor vaccine immune adjuvants in recent years. Among the review, the function, combination strategies and derivatives of lipid A were discussed in detail. In addition, some suggestions on the existing problems and research direction of lipids as tumor vaccine adjuvants were put forward. [ABSTRACT FROM AUTHOR]

Background: Regulatory T cells are central actors in the maintenance of tolerance of self-antigens or allergens and in the regulation of the intensity of the immune response during infections by pathogens. An understanding of the network of the interaction between regulatory T cells, antigen presenting cells and effector T cells is starting to emerge. Dynamical systems analysis can help to understand the dynamical properties of an interaction network and can shed light on the different tasks that can be accomplished by a network. Methodology and Principal Findings: We used a mathematical model to describe a interaction network of adaptive regulatory T cells, in which mature precursor T cells may differentiate into either adaptive regulatory T cells or effector T cells, depending on the activation state of the cell by which the antigen was presented. Using an equilibrium analysis of the mathematical model we show that, for some parameters, the network has two stable equilibrium states: one in which effector T cells are strongly regulated by regulatory T cells and another in which effector T cells are not regulated because the regulatory T cell population is vanishingly small. We then simulate different types of perturbations, such as the introduction of an antigen into a virgin system, and look at the state into which the system falls. We find that whether or not the interaction network switches from the regulated (tolerant) state to the unregulated state depends on the strength of the antigenic stimulus and the state from which the network has been perturbed. Conclusion/Significance: Our findings suggest that the interaction network studied in this paper plays an essential part in generating and maintaining tolerance against allergens and self-antigens. [ABSTRACT FROM AUTHOR]

Mercury accumulation in aquatic foodwebs and its effects on aquatic biota are of growing concern both for the health of the fish and the piscivores that prey upon them. This is of particular concern for western U.S. National Parks because it is known that mountainous and Arctic areas are sinks for some contaminants. The Western Airborne Contaminants Assessment Project seeks, in part, to ascertain mercury concentrations and evaluate effects of contaminants on biota in 14 lakes from 8 National Parks or Preserves. In this paper we report that mercury has accumulated to concentrations in trout that may negatively impact some piscivorous wildlife, indicating potential terrestrial ecosystem effects. Additionally, we show that mercury concentrations increase with age in 4 species of trout, providing evidence of bioaccumulation. Finally, we demonstrate that mercury is associated with tissue damage in the kidney and spleen, as indicated by increases in macrophage aggregates. This finding suggests that mercury, and possibly other contaminants, are negatively affecting the trout that inhabit these remote and protected ecosystems. Our results indicate that mercury is indeed a concern for the U.S. National Parks, from an organismic and potentially an ecosystem perspective. [ABSTRACT FROM AUTHOR]

Background. The complex interplay between B-cell lymphoma 2 (Bcl-2) family proteins constitutes a crucial checkpoint in apoptosis. Its detailed molecular mechanism remains controversial. Our former modeling studies have selected the 'Direct Activation Model' as a better explanation for experimental observations. In this paper, we continue to extend this model by adding interactions according to updating experimental findings. Methodology/Principal Findings. Through mathematical simulation we found bistability, a kind of switch, can arise from a positive (double negative) feedback in the Bcl-2 interaction network established by anti-apoptotic group of Bcl-2 family proteins. Moreover, Bax/Bak auto-activation as an independent positive feedback can enforce the bistability, and make it more robust to parameter variations. By ensemble stochastic modeling, we also elucidated how intrinsic noise can change ultrasensitive switches into gradual responses. Our modeling result agrees well with recent experimental data where bimodal Bax activation distributions in cell population were found. Conclusions/Significance. Along with the growing experimental evidences, our studies successfully elucidate the switch mechanism embedded in the Bcl-2 interaction network and provide insights into pharmacological manipulation of Bcl-2 apoptotic switch as further cancer therapies. [ABSTRACT FROM AUTHOR]

Abstract: RANDAM-2, a type-I transmembrane antigen constitutively expressed on the neuronal cell lineage during mouse neurogenesis, shows the highest expression level between embryonic day 8.5 (E8.5) and E10.5. As the period well overlaps with the proliferating stages of neural stem cells (NSCs), it is conceivable that NSCs are efficiently separable based on the expression level of RANDAM-2. In this paper, we show that NSCs can be efficiently enriched as RANDAM-2high+ cells by fluorescence-activated cell sorting. Many cells in the RANDAM-2high+ cells had the characteristics of the self-renewal capability and potential for multilineage differentiation into neural cells. In contrast, almost all of the RANDAM-2low+/− cells exhibited not only the extremely low self-renewability but the differentiation capability restricted to neurons. These two subpopulations also differed from each other in terms of the expression level of molecules associated with neural differentiation. These findings demonstrate that RANDAM-2 can be regarded as a useful marker for enrichment of NSCs. [Copyright &y& Elsevier]

Obesity is becoming one of the most serious public health problems in industrialized societies, due to the profound changes in lifestyle, and notably in nutrition. Beside diabetes, cardiovascular diseases or hypertension, increased susceptibility to infection is one of the pathological consequences of being overweight. In this paper, we have assessed the influence of a high-fat diet (HFD) rich in saturated fatty acids on the immune system of DO11.10 mice, which are transgenic for a T-cell receptor specifically recognizing a peptide of ovalbumin. We showed that the specific T-cell immune response was impaired by high-fat feeding, and that the expression of this defect is different depending on whether T cells are naive or Ag experienced. Indeed, on in vitro ovalbumin stimulation, spleen T cells from naive HFD-fed transgenic mice showed proliferation similar to that of cells from standard diet (SD)-fed mice, but exhibited a strong inflammatory profile as shown by the markedly increased IFN- γ/IL-4 ratio. Inversely, spleen T cells from ovalbumin-immunized HFD mice were impaired in their Ag-dependent proliferation compared to cells from SD mice. By co-culture experiments, we showed that both T cells and antigen-presenting cells were involved in this impairment. Moreover, in ovalbumin-immunized HFD animals, a trend towards Th2 response was noted, compared to immunized SD mice. This data implies that naive T cells could participate actively in the low-grade systemic inflammation observed in overweight patients. Moreover, the impaired activity of Ag-experienced T cells could have major consequences both in defence against infection and/or in vaccination protocols. [ABSTRACT FROM AUTHOR]

Lymph nodes are traditionally regarded as having three compartments, the cortex, paracortex and medulla. B and T cells home to separate areas within these compartments, interact with antigen presenting cells, and undergo clonal expansion. This paper provides structural and functional details about how the lymph node brings lymphocytes and antigen presenting cells together. The concept of the lymphoid lobule as the basic functional and anatomic unit of the lymph node is developed and utilized to provide a framework for understanding lymph node pathobiology. Understanding the histomorphologic features of the lymphoid lobule and the role of the reticular meshwork scaffolding of the lymph node and how these related to the cortex, paracortex and medulla provides a unique approach to understanding lymph node structure and function. [ABSTRACT FROM AUTHOR]