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• Docetaxel boosted anticancer effects of NK cells and CD8 + T lymphocytes. • Docetaxel stimulated the recruitment of tumor-associated macrophages. • Targeting some molecules such as PD-1 enhanced the anticancer activity of docetaxel. There are several interactions within the tumor microenvironment (TME) that affect the response of cancer cells to therapy. There are also a large number of cells and secretions in TME that increase resistance to therapy. Following the release of immunosuppressive, pro-angiogenic, and metastatic molecules by certain cells such as tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and cancer cells, immune evasion, angiogenesis, and metastasis may be induced. However, natural killer (NK) cells and cytotoxic CD8 + T lymphocytes (CTLs) can responsively release anticancer molecules. In addition, anticancer drugs can modulate these cells and their interactions in favor of either cancer resistance or therapy. Docetaxel belongs to taxanes, a class of anti-tumor drugs, which acts through the polymerization of tubulin and the induction of cell cycle arrest. Also, it has been revealed that taxanes including docetaxel affect cancer cells and the other cells within TME through some other mechanisms such as modulation of immune system responses, angiogenesis, and metastasis. In this paper, we explain the basic mechanisms of docetaxel interactions with malignant cells. Besides, we review the diverse effects of docetaxel on TME and cancer cells in consequence. Lastly, the modulatory effects of docetaxel alone or in conjunction with other anticancer agents on anti-tumor immunity, cancer cell resistance, angiogenesis, and metastasis will be discussed. [ABSTRACT FROM AUTHOR]

Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disease that is common in elderly people. Its classification in the spectrum of autoinflammatory and autoimmune diseases is difficult because of its only partially understood immune-mediated mechanisms. The literature concerning the innate and adaptive immune system activation in PMR was systematically reviewed highlighting the relative weight of autoinflammation and autoimmunity in its pathogenesis and disease progression. A literature search on PubMed Central and Embase scientific databases was performed by two independent reviewers. To be eligible, the studies needed to fully satisfy our initial PICO framework: a primary diagnosis of PMR as a population, the search for immune/inflammatory cells, cytokines and autoantibodies as an intervention, a control group consisting in healthy controls, patients with other inflammatory rheumatic diseases or PMR patients in remission after treatment and as outcomes the results of the investigations in the analyzed tissue samples. The most relevant data of the included papers were extracted by using a standardized template. Of the 933 screened abstracts, 52 papers were included in the systematic review and categorized depending on their primary research objectives. The hyper-activity of neutrophils and monocytes, expressing toll-like receptor 7 in active disease, an impaired phagocytosis and endothelial dysfunction, as well as an increased count of innate T cells in patients with remission emerged among the major derangements of the innate immune response in PMR. Among the cytokines profile, interleukin-6 plays a key role but other pro-inflammatory mediators and angiogenesis markers such as chemokines, B-cell activating factor, vascular endothelial growth factor and angiopoietins seem to be involved in refractory or glucocorticoid-resistant PMR. The aberrant adaptive immune response was documented by tissue and serum findings of polarized T cells towards T helper 1 and 17 phenotypes, an increased expression of immunosenescent surface markers and a downregulated immunoregulatory response. The altered distribution of peripheral B cells, detected during active disease, suggested their peripheral migration towards unidentified sites. The interaction between innate and adaptive immune response was documented by a synovial infiltrate of macrophages and T cells. Despite multiple autoantibodies have been detected in PMR patients, none proved to correlate with disease activity seeming to be reactive to the marked inflammation or antigenic determinants provided by environmental triggers or tissue/cell damage. The complex network between innate and adaptive immune system in PMR is supported by findings at molecular and cellular levels. By considering both the ends of the pathophysiological spectrum of immune-mediated rheumatic diseases, PMR may be regarded as an inflammatory immune-mediated disease with mixed mechanisms in a background of genetic and epigenetic factors together with immunological and endocrine senescence. • High concentrations of serum pro-inflammatory cytokines and cell growth factors identify active PMR patients • Innate immune cells might play a role both in PMR disease activity and sub-clinical ongoing inflammation. • T cells are dysregulated in PMR for a hyper-expression of immunosenescent markers and deficient immunoregulatory pathways. • B cells peripheral distribution is altered during active disease suggesting an inflammatory-driven compartmentalization. • Autoantibodies do not seem pathogenetic in PMR but may be reactive to external triggers or damaged tissues self-antigens. [ABSTRACT FROM AUTHOR]

Abstract: The Negative Selection Algorithm developed by Forrest et al. was inspired by the way in which T-cell lymphocytes mature within the thymus before being released into the blood system. The mature T-cell lymphocytes exhibit an interesting characteristic, in that they are only activated by non-self cells that invade the human body. The Negative Selection Algorithm utilises an affinity matching function to ascertain whether the affinity between a newly generated (NSA) T-cell lymphocyte and a self-cell is less than a particular threshold; that is, whether the T-cell lymphocyte is activated by the self-cell. T-cell lymphocytes not activated by self-sells become mature T-cell lymphocytes. A new affinity matching function termed the feature-detection rule is introduced in this paper. The feature-detection rule utilises the interrelationship between both adjacent and non-adjacent features of a particular problem domain to determine whether an antigen is activated by an artificial lymphocyte. The performance of the feature-detection rule is contrasted with traditional affinity matching functions, currently employed within Negative Selection Algorithms, most notably the r-chunks rule (which subsumes the r-contiguous bits rule) and the hamming distance rule. This paper shows that the feature-detection rule greatly improves the detection rates and false alarm rates exhibited by the NSA (utilising the r-chunks and hamming distance rule) in addition to refuting the way in which permutation masks are currently being applied in artificial immune systems. [Copyright &y& Elsevier]

Zukamu granules (ZKMG), as the preferred drug for the treatment of colds in Uygur medical theory, has been used for 1500 years. It is also widely used in China and included in the National Essential Drugs List (2018 edition). It has unique anti-inflammatory, antitussive and analgesic effects. Aiming at the research of traditional Chinese medicine (TCM) with the characteristics of overall regulation of body diseases and the immune regulation mechanism with the concept of integrity, this paper put forward the integrated application of network composite module analysis and animal experiment verification to study the immune regulation mechanism of TCM. The active components and targets of ZKMG were predicted, and network module analysis was performed to explore their potential immunomodulatory mechanisms. Then acute lung injury (ALI) mice and idiopathic pulmonary fibrosis (IPF) rats were used as pathological models to observe the effects of ZKMG on the pathological conditions of infected ALI and IPF rats, determine the contents of Th1, Th2 characteristic cytokines and immunoglobulins, and study the intervention of GATA3/STAT6 signal pathway. The results of network composite module analysis showed that ZKMG contained 173 pharmacodynamic components and 249 potential targets, and four key modules were obtained. The immunomodulatory effects of ZKMG were related to T cell receptor signaling pathway. The validation results of bioeffects that ZKMG could carry out bidirectional immune regulation on Th1/Th2 cytokines in the stage of ALI and IPF, so as to play the role of regulating immune homeostasis and organ protection. The network composite module analysis and verification method is an exploration to study the immune regulation mechanism of TCM by combining the network module prediction analysis with animal experiments, which provides a reference for subsequent research. [Display omitted] [ABSTRACT FROM AUTHOR]

The immune system is complex, with redundant and overlapping functions. Identifying the correct immune parameters to study the immune status of an animal is challenging. Nutritional immunologists often measure different isotypes of antibodies, hematological parameters, parasite loads, functional assays of macrophages and T cells, pro- and anti-inflammatory cytokines, phosphorylation status of proteins involved in signaling pathways, and several other parameters to identify the immune status of birds. Papers in which authors misinterpret immune parameters are common. This article discusses the drawbacks of some of the common interpretations of several immunological assays available for nutritional immunologists. [ABSTRACT FROM AUTHOR]

Perforin (PFN) is one of the most important protein effectors of the immune system. It is produced by cytotoxic T lymphocytes and natural killer cells and helps with the clearance of virus-infected and tumor cells. PFN is a pore-forming protein that readily binds to the lipid membranes of target cells, oligomerizes at the cell surface and forms transmembrane pores that allow passage of ions and other larger molecules. Its characterization was hindered in the past by a lack of efficient and reliable expression systems that would result in pure and functional product. In this paper we present optimization of PFN expression in a baculovirus expression system. We optimized several parameters of murine PFN (mPFN) expression and purification and showed that the expressed product is pure and hemolytically active and that it forms pores in the plasma membranes of K562 cells. We could also observe circular pores formed on liposome membranes by cryo-electron microscopy (cryo-EM). Our protocol opens the door for further biochemical and biophysical assessment of PFN properties and interactions with small ligands and lipid membranes. [ABSTRACT FROM AUTHOR]

The immune system has evolved to make a diverse repertoire of peptides processed from self and foreign proteomes, which are displayed in antigen-binding grooves of major histocompatibility complex (MHC) proteins at cell surface for surveillance by T cells. These antigenic peptides are termed Naturally Processed Peptides or Naturally Presented Peptides (NPPs), which play a major role in cell-mediated immunity and rational vaccine design. Therefore, it is intensely desirable to predict NPPs from a given protein antigen, or to foretell if an MHC-binding peptide can be eluted from a given MHC protein. In this paper, we describe NIEluter, an ensemble predictor based on support vector machine (SVM). It consists of a combination of five SVM models trained with position-specific amino acid composition, position-specific dipeptide composition, Hidden Markov Model, binary encoding, and BLOSUM62 feature. NIEluter can predict NPPs of length 8–11 from six HLA alleles (A0201, B0702, B3501, B4403, B5301, and B5701) at present. Evaluated with five-fold cross-validation and independent datasets if available, NIEluter shows good performance. It outperforms MHC-NP in 7 out of 24 types of situation and precedes NetMHC3.2 in most cases, indicating that it is a helpful complement to available tools. NIEluter has been implemented as a free web service, which can be accessed at http://immunet.cn/nie/cgi-bin/nieluter.pl . [ABSTRACT FROM AUTHOR]

Abstract: In this paper, we study the dynamics of a mathematical model on primary and secondary cytotoxic T-lymphocyte (CTL) response to viral infections by Wodarz et al. This model has three equilibria and their stability criteria are discussed. The system transitions from one equilibrium to the next as the basic reproductive number, , increases. When increases even further, we analytically show that periodic solutions may arise from the third equilibrium via Hopf bifurcation. Numerical simulations of the model agree with the theoretical results and these dynamics occur within biologically realistic parameter range. The normal form theory is also applied to find the amplitude, phase and stability information on the limit cycles. Biological implications of the results are discussed. [Copyright &y& Elsevier]

The major pathway for HIV internalization in CD4+ T cells has been thought to be the direct fusion of virus and cell membranes, because the cell surface is the point of entry of infectious particles. However, the exact contribution of endocytic pathways to the infection of CD4+ T lymphocytes is unknown, and the mechanisms involved in endocytosis of HIV particles are unclear. Recent evidence suggests that endocytosis of cell-free and cell-associated virus particles could lead to effective virus entry and productive infections. Such observations have, in turn, spurred a debate on the relevance of endosomal entry as a mechanism of escape from the immune system and HIV entry inhibitors. In this paper, we review the endocytosis of HIV and discuss its role in HIV infection and pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract: The immune system has evolved to coordinate responses against numerous invading pathogens and simultaneously remain silent facing self-antigens and those derived from commensal organisms. But, if both processes are not maintained in strict balance, a potential threat can emerge due to the risk of chronic inflammation and/or autoimmunity development. Therefore, there is a negative immune regulation where tolerogenic dendritic cells (tDCs) participate actively. Under steady-state conditions, tDC are notably involved in the elimination of autoreactive T cells at the thymus, and in the control of T cells specific to self and harmless antigens in the periphery. But in the presence of foreign antigens in an inflammatory milieu, dendritic cells (DCs) mature and induce T cells activation and their migration to B cell areas to assist in antibody production. Additionally, there are other factors such as infections, anti tumoral immune responses, trauma-mediated disruption, etc. that may induce alterations in the balance between tolerogenic and immunogenic functions of DCs and instigate the development of autoimmune diseases (ADs). Therefore, in recent years, DCs have emerged as therapeutic targets to control of ADs. Diverse strategies in vitro and/or in animal models of ADs have explored the tolerogenic functions of DCs and demonstrated their feasibility to prevent or control an autoimmune process, but still leaving a void in their application in clinical assays. The purpose of this paper is to give a general overview of the current literature on the significance of tDCs in tolerance maintenance to self and innocuous antigens, the most relevant alterations involved in the pathophysiology of ADs, the cellular and molecular mechanisms involved in their tolerogenic function and the current strategies used to exploit their tolerogenic potential. [Copyright &y& Elsevier]

Abstract: The capability of the HIV to persist latent inside CD4+ T-cells is currently regarded as a barrier to recovery from infection. On the other hand, immune activation, which is a normal immune reaction to pathogens, is now recognized as a key ingredient to sustaining the HIV caused infection. Further, it has been shown that activation of infected memory T-cells indirectly promotes apoptosis (programmed cell death) of bystander CD4+ and CD8+ T-cells. In this paper we use standard modeling techniques to develop a model compliant with the above mentioned mechanisms. Our farthest goal is to study how the long-term depletion of T-cells that characterizes HIV pathogenesis depends on these mechanisms. Consequently, we conduct parameter estimation, and apply standard results of sensitivity analysis and principal component analysis of the state variables with respect to the parameters. [ABSTRACT FROM AUTHOR]

Abstract: CD40L is a type II membrane protein comprised of 261 amino acids. CD40L plays a crucial role in the immune system where it is primarily expressed on activated T cells and triggers immunoglobulin class switching. The genetic disease X-linked hypergammaglobulinemia (HIGM1, XHIGM or XHIM) is caused by mutations in the CD40L gene. Individuals with HIGM1 are susceptible to recurrent infections to pathogens and a relationship has been shown to exist with malaria [Sabeti, P., Usen, S., Farhadian, S., Jallow, M., Doherty, T., Newport, M., Pinder, M., Ward, R., Kwiatkowski, D., 2002a. CD40L association with protection from severe malaria. Genes Immun. 3, 286–291]. In this paper, we phylogenetically examine the promoter region of CD40L in primates and other mammals via phylogenetic shadowing. This analysis revealed several regions of the CD40L promoter that were highly constrained and thereby inferred to be functional. These constrained regions confirmed many known regulatory sites. In addition, a novel, highly constrained upstream region was also identified which had an NF-AT recognition motif. These analyses also showed that the different mammal groups do not share an exactly similar set of promoter binding sites and taxon-specific promoters have evolved. [Copyright &y& Elsevier]

Abstract: In this paper, an immune-inspired model, named innate and adaptive artificial immune system (IA-AIS) is proposed and applied to the problem of identification of unsolicited bulk e-mail messages (SPAM). It integrates entities analogous to macrophages, B and T lymphocytes, modeling both the innate and the adaptive immune systems. An implementation of the algorithm was capable of identifying more than 99% of legitimate or SPAM messages in particular parameter configurations. It was compared to an optimized version of the naïve Bayes classifier, which has been attained extremely high correct classification rates. It has been concluded that IA-AIS has a greater ability to identify SPAM messages, although the identification of legitimate messages is not as high as that of the implemented naïve Bayes classifier. [Copyright &y& Elsevier]

Abstract: In the past years, research on immune regulation has exploded thanks to the re-emergence of T suppressor cells (Ts), now coined as regulatory T cells (Tregs). It has been established that different populations of Tregs exist in the immune system, and the generation, mechanism of suppression and the cellular and molecular targets of Tregs are being unraveled. This will lead to new opportunities for immune intervention to treat autoimmune disease and to achieve clinical transplantation tolerance. The scientific progress in the field of translational medicine was presented at the 7th International Conference on New Trends in Immunosuppression and Immunotherapy in Berlin in February 2006. In this special issue of International Immunopharmacology, several papers submitted to this congress will highlight some of the advances in this burgeoning field of translational medicine. [Copyright &y& Elsevier]

Abstract: The vasoactive intestinal peptide (VIP)-VPAC1 and VPAC2 G protein-coupled receptor (GPCR) systems are autocrine and paracrine regulators of diverse T cell functions. It has been recognized that VIP evokes two types of T cell responses. The first are rapid in onset and brief in duration, such as altered traffic in blood, lymphoid corridors, and tissues. The second are slow in onset and sustained in duration, such as enhanced helper T cell (Th) differentiation in the thymus and increased survival in lymphoid tissues with biases favoring the Th2-type effector and memory subsets. Investigations of some other sets of GPCRs for peptide and lipid mediators have demonstrated expression both in nuclear membranes and plasma membranes with respective linkages to responses that are slow in onset and sustained, and those that are rapid in onset and brief in duration. The hypothesis presented in this paper suggests that plasma membrane VPAC receptors transduce short-term effects of exogenous VIP on T cell effector functions, whereas nuclear VPAC receptors mediate endogenous VIP alterations in differentiation, proliferation, and survival. The types of substantial additional proof needed to support this hypothesis are described, as are its advantages for more selective VIP-directed therapies. [Copyright &y& Elsevier]

Abstract: Invading pathogens are controlled by the innate and adaptive arms of the immune system. Adaptive immunity, mediated by B and T lymphocytes, recognises pathogens via high affinity receptors. However, the establishment of a primary adaptive immune response is not rapid enough to eradicate invading microorganisms as it involves cell proliferation, gene activation and protein synthesis. More rapid defence mechanisms are provided by innate immunity, which recognises invading pathogens by germ-line-encoded pattern recognition receptors. Recent evidence shows that this recognition can mainly be attributed to the family of TOLL-like receptors (TLR). Binding of pathogen-associated molecular patterns to TLR induces the production of reactive oxygen and nitrogen intermediates, pro-inflammatory cytokines, and up-regulates expression of co-stimulatory molecules, subsequently initiating the adaptive immunity. In this paper, we will discuss the current knowledge with regards to the TLR, and in particular the bovine family of TLR. In addition, we will show the expression of TLR mRNA in bovine antigen-presenting cell subsets, summarise the discovery and the critical roles of TLR2 in host defence against Mycobacteria, and provide evidence for a mycobacteria species-specific response of bovine macrophages. [Copyright &y& Elsevier]

T-cells provide antigen specific focus to the adaptive immune response. However, the receptors that initiate functional responses are not in themselves specific, as they can recognise many different ligands. In this paper, we propose that the immune system deals with TCR degeneracy by an adaptive process that effects both T-cell activation and T-cell function, and exploits TCR degeneracy to limit pathogenic autoimmune disease. [Copyright &y& Elsevier]

γδ T lymphocytes are considered to represent a link between the inflammatory response and adaptive immunity. In the present paper we investigated whether these cells play any role in the remodeling of the immune system described in the elderly. We show that the absolute number of γδ T cells in peripheral blood of old and very old subjects is reduced. Moreover, γδ T cells from old people and centenarians show enhanced levels of the early activation marker CD69 both after culture in medium alone and in LPS-stimulated cells. Furthermore, they show a basal increased production of tumor necrosis factor (TNF)-α as evaluated at the single cell level. Additionally, the response of these cells to IPP in ‘in vitro’ cultures is in part impaired. These results suggest that the high level of basal activation of γδ T cells is due to the ‘inflamed’ environment. However, the changes in number and function of γδ T lymphocytes might influence the resolution of inflammatory immune responses in the elderly. [Copyright &y& Elsevier]

Objective It has been suggested that the development of uterine leiomyomas is positively influenced by an immune system in a chronically inflammatory state and that a lower level of regulating T cell (Treg cells) would play a central role. Since it has been suggested that the W620 variant of protein tyrosine phosphatase non-receptor type 22 (PTPN22) decreases the number of Treg cells, we investigated a possible relationship between PTPN22 polymorphism and uterine leiomyomas. Study design We studied 203 white women from Rome who were hospitalized for symptomatic leiomyomas requiring surgical intervention. These women were considered in a previous paper regarding the relationship between ACP1 and dimension of leiomyomas. As controls we studied 355 healthy women from the same population with comparable age and without clinical evidence of leiomyomas. All women gave written informed consent to participate to the study. Chi square test of independence and T -test for difference between means were performed by SPSS package. Results Considering the whole sample, a borderline association between PTPN22 and leiomyomas was observed: the *C/*T genotype is more frequent in cases than in controls. This association is marked and statistically significant in younger women only. The main diameter of tumor is significantly greater in *C/*T than in *C/*C women. This effect is present in younger women only. The *C/*T genotype also shows a higher tendency to intramural localization, but no effect of age is observed upon this association. Conclusions The data suggest a positive effect of *C/*T genotype on susceptibility to leiomyomas in younger women. In these women a *C/*T genotype favors the growth of leiomyomas. [ABSTRACT FROM AUTHOR]

Abstract: In the past decade it has been established that regulatory T cells (Tregs) control all immune responses. As the induction and effector mechanisms used by Tregs are being unraveled, it is emerging that a reciprocal population of CD4+ T lymphocytes exists in the immune system that produces inflammatory cytokine IL-17, and coined "Th17 cells". Th17 cells have been implicated in the pathogenesis of many forms of human disease. The development, function, mechanism of action, and homeostasis of Tregs and Th17 cells, and the reciprocal control between Tregs and Th17 cells were presented at the Second International Conference on Regulatory T Cells and Th17 Cells and Clinical Application in Human Diseases in Shanghai on 17–20 July 2010 (China Tregs/Th17 2010). In this Special Issue of International Immunopharmacology, several paper submitted to the conference will highlight the biology of Tregs and Th17 cells, and their clinical application in human disease. [Copyright &y& Elsevier]