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Immune checkpoint blockade (ICB) has had limited utility in several solid tumors such as breast cancer, a major cause of cancer-related mortality in women. Therefore, there is considerable interest in alternate strategies to promote an anti-cancer immune response. A paper co-published in this issue describes how NR0B2, a protein involved in cholesterol homeostasis, functions within myeloid immune cells to modulate the inflammasome and reduce the expansion of immune-suppressive regulatory T cells (T reg). Here, we develop NR0B2 as a potential therapeutic target. NR0B2 in tumors is associated with improved survival for several cancer types including breast. Importantly, NR0B2 expression is also prognostic of ICB success. Within breast tumors, NR0B2 expression is inversely associated with FOXP3, a marker of T regs. While a described agonist (DSHN) had some efficacy, it required high doses and long treatment times. Therefore, we designed and screened several derivatives. A methyl ester derivative (DSHN-OMe) emerged as superior in terms of (1) cellular uptake, (2) ability to regulate expected expression of genes, (3) suppression of T reg expansion using in vitro co-culture systems, and (4) efficacy against the growth of primary and metastatic tumors. This work identifies NR0B2 as a target to re-educate myeloid immune cells and a novel ligand with significant anti-tumor efficacy in preclinical models. • NR0B2 in myeloid immune cells has been shown to attenuate the subsequent expansion of regulatory T cells (Tregs). • NR0B2 is inversely correlated with the T regs , associated with improved survival, and response to immune checkpoint blockade. • Small molecule agonist DSHN has some efficacy, but has poor pharmaceutical properties. • Screening of derivatives identified DSHN-OMe as a superior agonist terms of ability to regulate gene expression and T regs. • DSHN-OMe attenuated growth of primary tumors and metastases in preclinical models, highlighting its therapeutic potential. [ABSTRACT FROM AUTHOR]

Although survival from breast cancer has dramatically increased, many will develop recurrent, metastatic disease. Unfortunately, survival for this stage of disease remains very low. Activating the immune system has incredible promise since it has the potential to be curative. However, immune checkpoint blockade (ICB) which works through T cells has been largely disappointing for metastatic breast cancer. One reason for this is a suppressive myeloid immune compartment that is unaffected by ICB. Cholesterol metabolism and proteins involved in cholesterol homeostasis play important regulatory roles in myeloid cells. Here, we demonstrate that NR0B2, a nuclear receptor involved in negative feedback of cholesterol metabolism, works in several myeloid cell types to impair subsequent expansion of regulatory T cells (T regs); T regs being a subset known to be highly immune suppressive and associated with poor therapeutic response. Within myeloid cells, NR0B2 serves to decrease many aspects of the inflammasome, ultimately resulting in decreased IL1β; IL1β driving T reg expansion. Importantly, mice lacking NR0B2 exhibit accelerated tumor growth. Thus, NR0B2 represents an important node in myeloid cells dictating ensuing T reg expansion and tumor growth, thereby representing a novel therapeutic target to re-educate these cells, having impact across different solid tumor types. Indeed, a paper co-published in this issue demonstrates the therapeutic utility of targeting NR0B2. • Regulatory T cells (Tregs) are associated with poor prognosis in several tumor types including breast cancer. • NR0B2 in myeloid cells suppresses several aspects of the inflammasome, culminating in decreased IL1β. • IL1β works to promote T reg expansion. • Loss of NR0B2 results in increased growth of mammary and melanoma tumors in mice. • NR0B2 represents a way to re-educate myeloid immune cells and relieve the immune-suppressive microenvironment of solid tumors. [ABSTRACT FROM AUTHOR]

• The importance of drug delivery timing and dosage in chemoimmunotherapy has been studied on a new model proposed in the paper. • The optimal controller is designed to reduce cancer cells for a lower dosage of immunotherapy and a fixed dosage of chemotherapy. • The suggested optimal timing and dosage of immunotherapy is able to reduce cancer cells, with less amount of drug injection compared to a fixed protocol. • The achievement of this paper could be the basis for designing new clinical trials. There are various approaches to control a mathematical dynamic of cancer, each of which is suitable for a special goal. Optimal control is considered as an applicable method to calculate the minimum necessary drug delivery in such systems. In this paper, a mathematical dynamic of cancer is proposed considering tumor cells, natural killer cells, CD8+ T cells, circulating lymphocytes, IL-2 cytokine and Regulatory T cells as the system states, and chemotherapy, IL-2 and activated CD8+ T cells injection rate as the control signals. After verifying the proposed mathematical model, the importance of the drug delivery timing and the effect of cancer cells initial condition are discussed. Afterwards, an optimal control is designed by defining a proper cost function with the goal of minimizing the number of tumor cells, and two immunotherapy drug amounts during treatment Results show that inappropriate injection of immunotherapy time schedule and the number of initial conditions of cancer cells might result in chemoimmunotherapy failure and auxiliary treatment must be prescribed to decrease tumor size before any treatment takes place. The obtained optimal control signals show that with lower amount of drug delivery and a suitable drug injection time schedule, tumor cells can be eliminated while a fixed immunotherapy time schedule protocol fails with larger amount of drug injection. This conclusion can be utilized with the aim of personalizing drug delivery and designing more accurate clinical trials based on the improved model simulations in order to save cost and time. [ABSTRACT FROM AUTHOR]

Food allergy (FA) is a serious food safety and public health issue. Increasing evidence has shed new light on significant interference of gut microbiome with mechanisms involved in the pathophysiology and progression of FA. New insights into the crosstalk between food components and the gut microbiome enable the development of viable strategies for inducing oral tolerance and modulating immune homeostasis. In this review, we first provide a brief outline of the observational evidence that supports associations between microbial exposures and FA, followed by an elaborated description of causation and the mechanisms by which the gut microbiome regulates FA. Subsequently, we highlight in detail how specific food components, pre- and probiotics can modulate the gut microbiome-immune axis and, consequently, modify the development of FA. The gut microbiome is a critical factor affecting FA susceptibility, and its regulatory mechanism is primarily through increasing protective Tregs and enhancing the intestinal mucosal barrier. The intake of high-fiber, tryptophan-rich diet and supplementation of diet with n-3PUFAs, polyphenols, pre- and probiotics, which are known to modulate gut microbiota towards to beneficial outcomes, while avoiding high-fat foods that trigger dysbiosis, can not only provide a potential approach to reduce the risk of FA in a primary prevention setting, but may also be a promising therapeutic strategy. This paper will contribute to dovetail food intervention strategies and bacterial therapeutics to modulate the immune system of allergic individuals in such a way that FA can be prevented and FA symptoms mitigated. • The correlations and causal relationships between the gut microbiome and FA are outlined. • The potential of microbiota-based dietary interventions for the prevention and treatment of FA is discussed. • The fiber/n-3 PUFAs/tryptophan/polyphenol-rich foods have anti-allergic effects. • Pre-/probiotics and FA-associated characteristic bacteria need to be further explored. • The precision microbial therapy of FA requires further research. [ABSTRACT FROM AUTHOR]

Previously, we prepared a chondroitin sulfate-soluble undenatured type II collagen complex (CS-SC II) with low salt content. This paper further explored the differences between CS-SC II and SC II in terms of gastrointestinal digestive characteristics and osteoarthritis (OA) improvement. In vitro and in vivo experiments showed that the gastric digestive stability of CS-SC II was high under both pH 2.0 and pH 3.0, the α1 chain and triple helix structure of type II collagen retained >60 %. However, SC II had high gastric digestive stability only under pH 3.0. Furthermore, intestinal digestion had little effect on α1 chains of CS-SC II and SC II, and distribution experiments showed that they might exert their biological activities in the intestine. CS-SC II had obvious improvement in OA rats at 1.0 mg/kg/d, that is, the joint swelling was significantly reduced and the weight-bearing ratio of the right hind limb was increased to 49 %, which was close to that of 4.0 mg/kg/d SC II. The wear of articular cartilage, Mankin and OARSI scores of rats in CS-SC II group were significantly reduced. The effects of low-dose CS-SC II on the proportion of regulatory T cells (Treg), mRNA expression of OA key biomarkers (Il6, Ccl7, MMP-3 and MMP13) and signaling pathway genes (NF-κB, AKT or AMPKα) were comparable to those of high-dose SC II. These results showed that CS-SC II might have greater potential to improve OA at a lower dose than SC II due to its high gastrointestinal digestive stability at a wide range of pH conditions. [Display omitted] • Study on chondroitin sulfate-soluble undenatured type II collagen complex (CS-SC II) • The gastric digestive stability of CS-SC II was high under both pH 2.0 and pH 3.0. • SC II had high gastric digestive stability only under pH 3.0. • The improvement of 1.0 mg/kg/d CS-SC II in OA rats was close to 4.0 mg/kg/d SC II. • CS-SC II regulated the expression of key OA biomarkers and signaling pathway genes. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Treg cells), defined as CD4 + CD25 + FoxP3 + T cells by expression of CD4, high-affinity IL-2 receptor and the transcription factor, forkhead box P3 (FoxP3). They play a pivotal role in protecting individuals from autoimmunity and a growing body of evidence suggests their role in the prevention of multiple sclerosis development. However, there are discrepancies about the type of defect in the Treg cells of multiple sclerosis patients and especially whether the Treg number alteration could be contributed to multiple sclerosis pathogenesis. Indeed, whether low number of Treg cells can be a risk factor contributing to multiple sclerosis pathogenesis is the matter of debate and there is not any comprehensive agreement on it. Thus, the objective of this systematic review and meta-analysis was to precisely quantify the nature and magnitude of the association between Treg cell number and the risk ratio/odds ratio (OR) of multiple sclerosis in the case-control studies. Hence, medical databases of Embase, PubMed/Medline, PubMed, PubMed Central and SCOPUS were searched for empirical papers using “Regulatory T cell frequency”, “Treg frequency” in combination with “multiple sclerosis”. In the case-control studies, papers were reviewed for inclusion/exclusion criteria and 8 publications were included. Under random-effect model meta-analysis the data showed that the frequency of Treg cells was not a risk factor in multiple sclerosis using current laboratory methods. [ABSTRACT FROM AUTHOR]

Sepsis is characterized by the extensive release of cytokines and other mediators. It results in a dysregulated immune response and can lead to organ damage and death. Curcumin has anti-inflammatory properties and immunoregulation functions in various disorders such as sepsis, cancer, rheumatoid arthritis, cardiovascular diseases, lung fibrosis, gallstone formation, and diabetes. This paper investigates the effects of curcumin on immune status and inflammatory response in mice subjected to cecal ligation and puncture (CLP). Inflammatory tissue injury was evaluated by histological observation. Magnetic microbeads were used to isolate splenic CD4 + CD25 + regulatory T cells (Tregs), and phenotypes were then analyzed by flow cytometry. The levels of Foxp3 were detected by Western blot and real-time PCR and cytokine levels were determined by enzyme-linked immunosorbent assay. We found that the administration of curcumin significantly alleviated inflammatory injury of the lung and kidney in septic mice. The suppressive function of Treg cells was enhanced and the plasma levels of IL-10 increased after treatment with curcumin. Furthermore, the secretion of plasma TNF-α and IL-6 was notably inhibited in septic mice treated with curcumin and administration with curcumin could improve survival after CLP. These data suggest that curcumin could be used as a potential therapeutic agent for sepsis. [ABSTRACT FROM AUTHOR]

[Display omitted] • IDO1 induces immune tolerance within TME. • Serum profiling of IDO1 metabolites is of prognostic value. • IDO1 upregulation occurs after ICI therapy. • IDO1 inhibitors can be used safely with ICI therapy. • Epacadostat plus ICI renders promising clinical responses. • Clinical efficacy of anti-PD-L1/IDO inhibitor vaccination is promising. Metabolic alterations occur commonly in tumor cells as a way to adapt available energetic sources for their proliferation, survival and resistance. Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular enzyme catalyzing tryptophan degradation into kynurenine. IDO1 expression shows a rise in the stroma of many types of human cancers, and it provides a negative feedback mechanism for cancer evasion from immunosurveillance. Upregulation of IDO1 correlates with cancer aggression, poor prognosis and shortened patient survival. The increased activity of this endogenous checkpoint impairs effector T cell function, increases regulatory T cell (Treg) population and induces immune tolerance, so its inhibition potentiates anti-tumor immune responses and reshapes immunogenic state of tumor microenvironment (TME) presumably through normalizing effector T cell activity. A point is that the expression of this immunoregulatory marker is upregulated after immune checkpoint inhibitor (ICI) therapy, and that it has inducible effect on expression of other checkpoints. These are indicative of the importance of IDO1 as an attractive immunotherapeutic target and rationalizing combination of IDO1 inhibitors with ICI drugs in patients with advanced solid cancers. In this review, we aimed to discuss about the impact of IDO1 on tumor immune ecosystem, and the IDO1-mediated bypass of ICI therapy. The efficacy of IDO1 inhibitor therapy in combination with ICIs in advanced/metastatic solid tumors is also a focus of this paper. [ABSTRACT FROM AUTHOR]

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]

A recent paper by Shi et al. defines the role of regulatory T cells (Tregs) in white matter recovery after ischemic stroke. This study elucidates the mechanisms by which Tregs direct microglia to alter their phenotype to support oligodendrogenesis, thereby improving white matter integrity and functional recovery after stroke in mice. [ABSTRACT FROM AUTHOR]

Establishment and maintenance of pregnancy represents a challenge for the maternal immune system since it has to defend against pathogens and tolerate paternal alloantigens expressed in fetal tissues. Regulatory T (Treg) cells, a subset of suppressor CD4 + T cells, play a dominant role in the maintenance of immunological self-tolerance by preventing immune and autoimmune responses against self-antigens. Although localized mechanisms contribute to fetal evasion from immune attack, in the last few years it has been observed that Treg cells are essential in promoting fetal survival avoiding the recognition of paternal semi-allogeneic tissues by maternal immune system. Several functional studies have shown that unexplained infertility, miscarriage and pre-clampsia are often associated with deficit in Treg cell number and function while normal pregnancy selectively stimulates the accumulation of maternal forkhead-box-P3 + (FoxP3 + ) CD4 + Treg cells with fetal specificity. Some papers have been reported that the number of Treg cells persists at elevated levels long after delivery developing an immune regulatory memory against father's antigens, moreover these memory Treg cells rapidly proliferate during subsequent pregnancies, however, on the other hand, there are several evidence suggesting a clear decline of Treg cells number after delivery. Different factors such as cytokines, adipokines, pregnancy hormones and seminal fluid have immunoregulatory activity and influence the success of pregnancy by increasing Treg cell number and activity. The development of strategies capable of modulating immune responses toward fetal antigens through Treg cell manipulation, could have an impact on the induction of tolerance against fetal antigens during immune-mediated recurrent abortion. [ABSTRACT FROM AUTHOR]

A failure of central immune tolerance driven by autoantigen specific T regulatory (Treg) cells is a major cause of many autoimmune diseases. Restoration of proper autoantigen Treg specific response holds promise as a highly effective, long-term therapy for a wide variety of autoimmune diseases. Generating autoantigen specific Tregs remains a challenge due to the non-specific nature of most tolerizing agents and the complexities of generating Tregs in vivo. Here we show a new push/pull method for inducing antigen-specific Treg tolerance via induction of tolerogenic dendritic cells (tolDCs). We identified a combination of three tolerogenic drugs, dexamethasone, simvastatin and SC-514, which when used in combination with toll-like-receptor (TLR) agonists induces an active tolDC phenotype. When the tolerogenic combination was packaged into a liposome with a model antigen such as ovalbumin (OVA), these tolDCs induce differentiation of OVA specific Tregs both ex vivo and in vivo. We examined the tolerizing potential of the combination in an experimental autoimmune encephalomyelitis (EAE) disease model. Given the antigen specificity of this technique, this paper presents an attractive preclinical autoimmune therapy. [ABSTRACT FROM AUTHOR]

Abstract: Myasthenia gravis (MG) is an antibody mediated, T cell dependent autoimmune disease characterized by muscle fatigability in which autoantibodies directed to the acetylcholine receptor (AChR) impair neuromuscular transmission. The identification of CD4+CD25+Foxp3+ Treg cells as important regulators of tolerance opened a major area of investigation raising the possibility that a dysfunction in the Treg compartment is involved in the etiology and pathogenesis of autoimmune diseases, including MG. In this paper we summarize shortly Treg abnormalities that were reported in MG patients and report on our studies of Treg in experimental autoimmune MG (EAMG). Hopefully these studies would pave the way towards the development of novel Treg-based treatment modalities that will restore self-tolerance in MG and other autoimmune diseases. In our previous studies in EAMG we have shown that Treg cells transferred from healthy rat donors to myasthenic rats suppress EAMG. However, Treg cells from sick animals do not have the same in vivo suppressive activity as those from healthy donors. The objective of the present study was to further characterize quantitative and qualitative alterations in Treg cells of rats with EAMG. We found that the frequency of CD4+CD25+Foxp3+ Treg cells within the spleen and PBL was decreased in EAMG rats as compared to naïve and CFA-immunized healthy controls. Treg cells from myasthenic rats were less effective than Treg cells from controls in suppressing the proliferation of CD4+ T effector cells in response to ConA and of B cells in response to LPS. Moreover, CD4+CD25+ cells from EAMG rats exhibited an elevated extent of apoptosis and expressed upregulated levels of FAS and of Th17-associated cytokines. Since EAMG is an induced disease, these quantitative and qualitative alterations in Treg cells do not reflect predisposing impairments and seem to be associated with the specific autoimmune response resulting from AChR immunization. [Copyright &y& Elsevier]

Abstract: The development of the anti-CTLA-4 antibody (ipilimumab; marketed as Yervoy 1 [1] Yervoy is an FDA approved human anti-CTLA-4 monoclonal antibody developed by Bristol-Myers Squibb. ) immune regulatory therapy was based on the premise that “Abrogation of the function of CTLA-4 would permit CD28 to function unopposed and might swing the balance in favor of immune stimulation, tolerance breakdown and tumor eradication…” (). By now, the vast majority of data collected from more than 4000 patients proves that this prediction was entirely correct. Paradoxically, the successful blockade of immune checkpoints raises the question whether an anti-CTLA-4 antibody could ever become an important therapy against cancer. T cells lost their ability to discriminate between self and non-self. Thus, tolerance to self tissues was broken in ∼70% of the patients. In the recent industry-sponsored phase III clinical trial of ipilimumab, 147 (38.7%) of the patients experienced severe adverse events and 6.8% suffered dose-limiting events (8.4%, in the ipilimumab-alone group). There were 14 deaths related to the study drugs and 7 of these were associated with immune-related adverse events. In contrast, the complete response rate was only 0.2%, in one patient out of 403 who received ipilimumab plus a peptide vaccine. Promoters of ipilimumab appear to be unmindful of the clinical trial catastrophe in London. Then, a humanized “superagonist” anti-CD28 monoclonal antibody, TGN1412, which “preferentially” activated regulatory T cells, at a higher dose, also activated all CD28 positive T cells. This precipitated a “cytokine storm” leading to life-threatening multiple organ failure in the six healthy human volunteers. Neither anti-CD28 nor anti-CTLA-4 therapies rely on antigen-specificity. Both release free antibody into the body against common molecular targets that are expressed on the targeted as well as on the non-targeted T cells. At lower antibody doses specific T cells are preferentially activated. With increasing antibody dose, however, the kinetics of the interaction is pushed in favor of widespread non-specific T cell expansion. Using the law of mass action we calculated that the vast majority of the CTLA-4 receptors on all activated T cells (including melanoma specific T cells) in the phase III clinical trial of ipilimumab will have been saturated. This would explain the runaway immune response observed. The conclusions drawn by the authors of the ipilimumab trial paper could bear an independent inspection and reassessment concerning the validation of the blockade of immune checkpoints as an important therapeutic strategy against cancer. [Copyright &y& Elsevier]

Background: The immunosuppressive properties of regulatory T cells have emerged as an attractive tool for the development of immunotherapies in various disease contexts, e.g. to treat transplantation induced immune reactions. This paper focuses on the process of obtaining and functionally characterizing CD4+CD25+FoxP3+ regulatory T cells and Tr1 cells from uremic patients awaiting kidney transplantation. Methods: From October 2010 to March 2011 uremic patients awaiting living donor kidney transplantation, and their corresponding kidney donors, were enrolled in the study. A total of seven pairs were included. Isolation of CD4+CD25+FoxP3+ regulatory T cells was performed by magnetic activated cell sorting of peripheral blood mononuclear cells obtained from the uremic patients. Donor specific Trl cells were differentiated by repetitive stimulation of immature CD4+ T cells with immature dendritic cells, with the T cells coming from the future kidney recipients and the dendritic cells from the corresponding kidney donors. Cells were then expanded and functionally characterized by the one-way mixed leukocyte reaction and assessment of IL-10 production. Phenotypic analysis was performed by flow cytometry. Results: The fraction of CD4+CD25+FoxP3+ regulatory T cells after expansion varied from 39.1 to 50.4% and the cells retained their ability to substantially suppress the mixed leukocyte reaction in all but one patient (3.8-19.2% of the baseline stimulated leukocyte activity, p<0.05). Trl cells were successfully differentiated from all but one patient and produced high levels of IL-10 when stimulated with immature dendritic cells (1,275-11,038% of the baseline IL-10 secretion, p<0.05). Conclusion: It is practically feasible to obtain and subsequently expand CD4+CD25+FoxP3+ regulatory T cells and Tr1 cells from uremic patients without loss of function as assessed by in vitro analyses. This forms a base for adoptive regulatory T cell therapy in the setting of living donor kidney transplantation. [ABSTRACT FROM AUTHOR]

Abstract: For decades Experimental Autoimmune Encephalitis (EAE) has remained as an unsurpassed multiple sclerosis (MS) animal model. C-Phycocyanin (C-Pc) has been reported to exhibit pharmacological properties that may be expected to symptomatically improve EAE and MS. However, in this paper we reveal a basic underlying mechanism that may provide a new approach to the rationale of the overall beneficial effect of this natural antioxidant. We demonstrate that C-Pc is able to trigger mechanisms preventing or downgrading EAE expression and induces a regulatory T cell (Treg) response, in peripheral blood mononuclear cells (PBMC) from MS patients. These results agree with reports suggesting that Treg limit acute MS attacks and that C-Pc may act as a neuroprotector and thereby reverts the organic and functional damage in neurodegenerative disorders of the central nervous system (CNS). Moreover, evidence is provided on the antioxidant activity of C-Pc within the CNS, intended to improve the myelin and axonal damage of EAE induced Lewis rats. Our results indicate that specific Treg activation may represent a central and essential mechanism in supporting the therapeutic potential of C-Pc for MS and may lead to new and more effective therapies; this property would then complement and enhance other proven active principles such as interferons (IFN), giving rise to combined therapies. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are the dominant class of antigen-presenting cells in humans; therefore, a range of DC-based approaches have been established to promote an immune response against cancer cells. The efficacy of DC-based immunotherapeutic approaches is markedly affected by the immunosuppressive factors related to the tumor microenvironment, such as adenosine. In this paper, based on immunological theories and experimental data, a hybrid model is designed that offers some insights into the effects of DC-based immunotherapy combined with adenosine inhibition. The model combines an individual-based model for describing tumor-immune system interactions with a set of ordinary differential equations for adenosine modeling. Computational simulations of the proposed model clarify the conditions for the onset of a successful immune response against cancer cells. Global and local sensitivity analysis of the model highlights the importance of adenosine blockage for strengthening effector cells. The model is used to determine the most effective suppressive mechanism caused by adenosine, proper vaccination time, and the appropriate time interval between injections. [Display omitted] • We propose a hybrid model to describe the immunosuppressive function of adenosine in tumor micro environment. • Our model provides immunologists with a new level of insight into the role of immunosuppressive factors of the immune system. • Our model highlights the importance of adenosine blockage for strengthening effector cells and suppressing Treg cells. • Model simulations are compatible with in vivo experimental data. • The results reveals that the appropriate time interval for administration of adenosine inhibitor is between 2 and 4 days. [ABSTRACT FROM AUTHOR]

Abstract : Type I Interferon (IFN-α/β) therapy has altered the natural course of multiple sclerosis. In this paper we evaluate the possible molecular mechanisms involved in the in vitro effects of IFN-α/β on peripheral blood mononuclear cells from patients with clinically definite Relapsing-Remitting Multiple Sclerosis. The total RNA from IFN-α, IFN-β treated cells and untreated cells was extracted and amplified for CD86, CD28, CTLA-4, TNF-α, IFN-γ, CCL2, CCR5, IL-13, MMP-9, TIMP-1, CD25, TGF-β, IL-10 and the transcriptional factor Foxp3 by Reverse Transcription–Polymerase Chain Reaction and the CD4+CD25high subset was evaluated using flow cytometry. In general, there were no significant differences concerning the modulation of the genes studied in the response to IFN-α and IFN-β treatments, which suggest a similar mechanism of action for both interferons. However, we found a significant increment in IFN-γ expression after IFN-α but not after IFN-β treatments. The in vitro treatment of mononuclear cells from multiple sclerosis patients with both interferons significantly increased the CD25 mRNA. Furthermore, we observed a CD25/Foxp3 correlation and an increment of the CD4+CD25high subset, indicating that the induction of regulatory T cells could be a crucial mechanism involved in the type I interferon effects. [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]

The status of ‘partial’ tolerance to organ allografts versus the status of complete tolerance is the main topic of this paper. Progress made in immunosuppression, particularly by use of various lymphocyte depleting agents for ‘induction therapy’, seems to favor the subsequent development of T cells with suppressor/regulatory properties. The effective deletion of alloreactive T helper and cytotoxic cells in conjunction with the expansion of antigen-specific suppressor (CD8 + CD28 - F0XP3+) and regulatory (CD4 + CD25+ F0XP3+) T cells creates a milieu in which the graft is well tolerated under an ‘umbrella’ of low dosage immunosuppression. The most elective induction treatment is Campath-1H, although ATGAM at high dosage is also widely used. Total lymphoid irradiation (TL1) is another very effective pretreatment strategy in spite of the risks which are associated with it. The induction of ‘partial’ tolerance is a step in the right direction for exploring strategies that may lead to the induction of complete tolerance. It is safe for the patients and can prolong significantly the function of the graft, preventing the onset of chronic rejection. [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]

Abstract: Regulatory T cells (Tregs) are subsets of T cells that are specifically dedicated to controlling immune responses. It has been established that Tregs play a key role in regulating autoimmune disease, allergy, cancer, infectious disease, and in the induction of transplantation tolerance. The latest progress in the development, function, mechanism of action, and homeostasis of regulatory T cells, and their translation to the clinic were presented at the International Conference on Regulatory T Cells and Clinical Application in Human Diseases in Beijing on 25–27 October 2008 (China Tregs 2008). In this Special Issue of International Immunopharmacology, several papers submitted to the China Tregs 2008 will highlight some of the recent advances in the biology of regulatory T cells and current strategies to translate regulatory T cells into the clinic. [Copyright &y& Elsevier]