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This paper aims to design a nonlinear robust adaptive sliding mode control strategy for a mathematical model describing the innate immune response to influenza virus infection. This model possesses seven state variables (respiratory tract epithelial cells in four possible states, namely: healthy, partially infected, infected, and resistant-to-infection, and interferon (IFN) molecules, natural killers, and viruses). This model is based on resistance-to-infection derived from IFN molecules and the removal of infected cells by natural killers. Two control strategies (vaccination and antiviral treatment) are introduced to eradicate the infection. First, a vaccination strategy is applied to convert healthy cells into resistant-to-infection ones inside the body of the susceptible individual. Second, the infected individual undergoes an antiviral treatment strategy that fights against the spread of the concentration of viruses and converts the healthy cells into resistant-to-infection ones simultaneously. The Lyapunov stability theorem is employed to analyse the stability of the desired strategies. Finally, the simulation results show that the goal is fulfilled satisfactorily. [ABSTRACT FROM AUTHOR]

To explore the impacts of pulse vaccination on the dynamical behaviors of virus, the current paper investigates the persistence and global attractivity of a diffusive viral infection model incorporated with impulsive CTL immune response while the stronger logistic growth mechanism. Based on the comparison principle and the proper upper and lower solutions, we first discuss the existence of the infection-free steady state, and define the crucial CTL-activated viral infection reproduction number $ R_0 $ R 0 . Then, the fundamental extinction and uniform persistence behaviors of virus are distinguished by various cases of the threshold parameter $ R_0 $ R 0 . Finally, the existence and global attractivity of the positive steady state are still established by employing Brouwer's fixed point theorem and auxiliary functional. Our results indicate that high vaccination rates will stimulate the CTL response more effectively, and thus eventually can force the virus to eradicate. [ABSTRACT FROM AUTHOR]

Leishmaniasis, an infectious disease, manifests itself mostly in two forms, cutaneous leishmaniasis (CL) and, a more severe and potentially deadly form, visceral leishmaniasis (VL). The current control strategy for leishmaniasis relies on chemotherapy drugs such as sodium antimony gluconate (SAG) and meglumine antimoniate (MA). However, all these chemotherapy compounds have poor efficacy, and they are associated with toxicity and other adverse effects, as well as drug resistance. While research in vaccine development for leishmaniasis is continuously progressing, no vaccine is currently available. However, some experimental vaccines such as LEISH-F1+MPL-SE (V) have demonstrated some efficacy when used as drugs for CL patients. In this paper we use a mathematical model to address the following question: To what extent vaccine shots can enhance the efficacy of standard chemotherapy treatment of leishmaniasis? Starting with standard MA treatment of leishmaniasis and combining it with three injections of V , we find, by Day 84, that efficacy increased from 29% to 65–91% depending on the amount of the vaccine. With two or just one injection of V , efficacy is still very high, but there is a definite resurgence of the disease by end-time. [ABSTRACT FROM AUTHOR]

Over the past decades, the primary interest in vaccine efficacy or immunogenicity evaluation mostly focuses on the biological effect of immunization in complying with the vaccination schedule in a targeted population. The safety questions, which are essential for vaccines as they are generally given to large healthy populations, need to be clearly defined to reflect the risk assessment of interest. ICH E9 (R1) provides a structured framework to clarify the clinical questions and formulate the treatment effect as an estimand. This paper applies the estimand framework to vaccine clinical trials on common clinical questions regarding efficacy, immunogenicity, and safety. [ABSTRACT FROM AUTHOR]

This paper aims to analyse stability and Hopf bifurcation of the HIV-1 model with immune delay under the functional response of the Holling II type. The global stability analysis has been considered by Lyapunov–LaSalle theorem. And stability and the sufficient condition for the existence of Hopf Bifurcation of the infected equilibrium of the HIV-1 model with immune response are also studied. Some numerical simulations verify the above results. Finally, we propose a novel three dimension system to the future study. [ABSTRACT FROM AUTHOR]

The circadian clock of vertebrates regulates many biological processes, including the immune system. This paper investigated whether responsiveness to poly (I:C), a synthetic analog of double-stranded RNA used as an immunostimulant, exhibits day/night differences in zebrafish. Fish were intraperitoneally (IP) injected with either phosphate-buffered saline (PBS) or poly (I:C) at two different time points: "Zeitgeber Time" (ZT) 4 (day) and ZT16 (night). Then, 6 h later, fish were euthanized, and tissue samples (skin, liver and kidney) were collected. A control group (intact fish) was also sampled at the same time points. The effect of poly (I:C) on the expression of antioxidant and immune genes was time-of-day-dependent, and the response was stronger following poly (I:C) administration in the day than at night. Time-dependent differences were observed for some genes in the PBS and control groups. However, these differences were tissue-specific. In liver, almost all the genes were affected by time of day. In kidney, poly (I:C) affected the expression of all the gene markers regardless of administration time. These findings highlight the importance of considering the time to administer poly (I:C) when evaluating the fish immune response. [ABSTRACT FROM AUTHOR]

Presents the study entitled “Evaluation of the Immune Response and Efficacy in Chickens of Vaccinces Prepared from P. multocida Capsular Type A Grown in Iron-Depleted Conditions,” at the 2004 Spring Meeting of the WPSA UK Branch.

As long as breast cancer (BC) stays under immunosurveillance, it can be controlled by treatments eliciting anticancer immune responses. However, once BC escapes immunosurveillance, it becomes therapeutically uncontrollable. A paper in the Journal for ImmunoTherapy of Cancer describes a new hormone receptor-positive BC cell line generating incurable tumors in C57BL/6 mice. [ABSTRACT FROM AUTHOR]

Furazolidone (FZD) is a widely used drug in human and veterinary medicine, and has antibacterial and antiprotozoal action. Although it is widely used as a therapy in various pathological conditions, studies on the efficacy of FZD associated with immune responses are still limited. In this review, we seek to describe which immunopharmacological responses are caused by the administration of FZD. The study followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). A systematic review of clinical trials and in vitro and in vivo experimental studies was carried out, which resulted in 943 papers, of which 35 were considered eligible and, of these 35, 4 were selected for analysis. The studies listed indicated that administration of FZD can modulate pro- or anti-inflammatory pathways, with a probable increase in the expression of reactive oxygen species and a modulation of apoptotic pathways. [ABSTRACT FROM AUTHOR]

In this paper, with eclipse stage in consideration, we propose an HIV-1 infection model with a general incidence rate and CTL immune response. We first study the existence and local stability of equilibria, which is characterized by the basic infection reproduction number R 0 and the basic immunity reproduction number R 1 . The local stability analysis indicates the occurrence of transcritical bifurcations of equilibria. We confirm the bifurcations at the disease-free equilibrium and the infected immune-free equilibrium with transmission rate and the decay rate of CTLs as bifurcation parameters, respectively. Then we apply the approach of Lyapunov functions to establish the global stability of the equilibria, which is determined by the two basic reproduction numbers. These theoretical results are supported with numerical simulations. Moreover, we also identify the high sensitivity parameters by carrying out the sensitivity analysis of the two basic reproduction numbers to the model parameters. [ABSTRACT FROM AUTHOR]

In this paper, a deterministic model characterizing the within-host infection of Hepatitis C virus (HCV) in intrahepatic and extrahepatic tissues is presented. In addition, the model also includes the effect of the cytotoxic T lymphocyte (CTL) immunity described by a linear activation rate by infected cells. Firstly, the non-negativity and boundedness of solutions of the model are established. Secondly, the basic reproduction number R 01 and immune reproduction number R 02 are calculated, respectively. Three equilibria, namely, infection-free, CTL immune response-free and infected equilibrium with CTL immune response are discussed in terms of these two thresholds. Thirdly, the stability of these three equilibria is investigated theoretically as well as numerically. The results show that when R 01 < 1 , the virus will be cleared out eventually and the CTL immune response will also disappear; when R 02 < 1 < R 01 , the virus persists within the host, but the CTL immune response disappears eventually; when R 02 > 1 , both of the virus and the CTL immune response persist within the host. Finally, a brief discussion will be given. [ABSTRACT FROM AUTHOR]

is an obligate, asaccharolytic, gram-negative bacteria commonly associated with increased periodontal and systemic inflammation. P. gingivalis is known to survive and persist within the host tissues as it modulates the entire ecosystem by either engineering its environment or modifying the host's immune response. It interacts with various host receptors and alters signaling pathways of inflammation, complement system, cell cycle, and apoptosis. P. gingivalis is even known to induce suicidal cell death of the host and other microbes in its vicinity with the emergence of pathobiont species. Recently, new molecular and immunological mechanisms and virulence factors of P. gingivalis that increase its chance of survival and immune evasion within the host have been discovered. Thus, the present paper aims to provide a consolidated update on the new intricate and unique molecular mechanisms and virulence factors of P. gingivalis associated with its survival, persistence, and immune evasion within the host. [ABSTRACT FROM AUTHOR]

Herd immunity is a form of indirect protection that is offered to the community when a large proportion of individuals contained in the community are immune to a certain infection. This immunity can be due to vaccination or to the recovery post-disease. Effective herd immunity in SARS-CoV-2 infection has several hurdles upon achievement. Herd immunity cannot be obtained concomitantly in many geographical areas because the areas have different population density and the societal measures to contain the spreading are different. A proportion of 50–66% of the population needs to be immunized naturally or artificially in this SARS-Cov2 pandemic and this percentage is not easily achievable. The duration of herd immunity is another issue while information on the long-term immune response against SARS-CoV2 is yet scarce. Epitope stability, another issue to be solved when achieving herd immunity, is important. Mutation in the viral structure will call upon other sets of neutralizing antibodies and hence for other herd immunity type installment. The societal tactics to achieve the much-needed herd immunity should be developed keeping in mind the welfare of the population. Without being exhaustive, throughout our paper we will elaborate on each of the hurdles encountered in developing herd immunity to SARS-Cov2 infection. [ABSTRACT FROM AUTHOR]

In this paper, we explore the stochastic viral infection model and show that this model has a unique global solution. We use the method of Lyapunov function to study the stochastic asymptotic stability of equilibrium solution for this model. Finally, the sufficient condition for persistence of the disease is established and our mathematical findings are illustrated. [ABSTRACT FROM AUTHOR]

The spleen combines the innate and adaptive immune systems, and the early conceptus must regulate the maternal intrauterine immune and systemic immune response during early pregnancy in sheep. However, it is unclear whether early pregnancy exerts its effects on the characterization of the T helper (Th) cytokines profile in the spleen during early pregnancy in ewes. In this study, spleens were obtained at day 16 of the oestrous cycle and at days 13, 16 and 25 of pregnancy (n = 6 for each group) from ewes, and qRT-PCR, western blot and immunohistochemistry analysis were used to analyze the Th cytokines profile of the spleens. Our results showed that there was down-regulation of IFN-γ at days 13 and 16 of pregnancy, but there was upregulation of IL-2, IL-5 and IL-6 at day 25 of pregnancy, TNF-β at days 16 and 25 of pregnancy, and IL-4 and IL-10 in all pregnant groups. Immunohistochemistry results showed that the IL-6 protein was limited to the capsule, trabeculae and splenic cords. This paper reported, for the first time, that characterization of the Th cytokines profile varied in the maternal spleen during early pregnancy, which may be essential for successful pregnancy in sheep. [ABSTRACT FROM AUTHOR]

This paper studies the global stability of discrete-time viral infection models with humoural immunity. We consider both latently and actively infected cells. We study also a model with general production and clearance rates of all compartments as well as general incidence rate of infection. We use nonstandard finite difference method to discretize the continuous-time models. The positivity and boundedness of solutions of the discrete models are established. We establish by using Lyapunov method, the global stability of equilibria in terms of the basic reproduction number R 0 and the humoural immune response activation number R 1 . The results signify that the infection dies out if R 0 ≤ 1. Moreover, the infection persists with inactive immune response if R 1 ≤ 1 < R 0 and with active immune response if R 1 > 1. We illustrate our theoretical results by using numerical simulations. [ABSTRACT FROM AUTHOR]

The innate immunity of a plant represents the first defense line against any invading pathogen. This innate immunity is triggered by the infected plant once it detects a pathogenic infection. Peroxidase, catalase, and total phenols are considered among the main components of the plant's innate immunity. In this regard, copper (CuNPs) and chitosan (CsNPs) nanoparticles showed a potency to modulate that innate immunity. The present work aims to compare between CuNPs and CsNPs in terms of their potencies to modulate the levels of peroxidase, catalase, and total phenols in date palm (Phoenix dactylifera L.) seedlings. Results showed that both CuNPs and CsNPs enhanced the innate immunity of date palm seedlings, wherein treating date palm seedlings with 50 mL of CuNPs (1 g/L) increased peroxidase and catalase levels by 199% and 4.15%, respectively; while total phenols level was decreased by 28.7%. On the other hand, the same treatment regime with CsNPs increased peroxidase, catalase, and total phenols levels by 12.5%, 12.4%, and 7.83%, respectively. These findings provide a possibility to use CuNPs and CsNPs for enhancing the innate immunity of date palm seedlings. In addition, this paper reports for the first time the ability of CuNPs to inhibit the formation of phenolics in date palm seedlings, which may be useful in reducing the oxidative browning caused by these phenolics in date palm explants during In vitro micropropagation. [ABSTRACT FROM AUTHOR]

The immunotoxic potential of drug candidates is assessed through the examination of results from a variety of studies and endpoints. While the functional assessment of CD8+ cytotoxic T-lymphocytes (CTL) is well-characterized in the clinic, the lack of a robust macaque CTL functional assay has been an important hurdle in evaluating and accurately quantifying cell-mediated CD8+ T-cell effector responses in the nonclinical setting. This paper describes the development of an assay to measure CTL activity in peripheral blood mononuclear cells (PBMC) isolated from Cynomolgus macaques. A human EGFR/CD3 Bispecific T-cell Engager (BiTE®) was used to mount a robust CD8+ T-cell response in the presence of target-expressing cells. Upon target engagement, degranulation of CD107a and production of interferon (IFN)-γ both reliably indicated a robust functional response in CD8+ T-cells. The BiTE®-mediated stimulation method proved to be favorable when compared to other methods of stimulation in the absence of target cells. These studies demonstrated acceptable longitudinal variability of the functional assay and sensitivity to dexamethasone-mediated immunosuppression. Taken together, the results indicated an assay leveraging CD3-bispecific antibodies and target-expressing cells can provide a robust approach to the in vitro or ex vivo assessment of CTL function in Cynomolgus macaques. Because the impairment of CTL activity by immunomodulators is recognized to be an important contributor to decreased antiviral defense and increased carcinogenicity risk, we believe that this novel assay to be a valuable addition to the immunotoxicology assessment of therapeutic drug candidates. [ABSTRACT FROM AUTHOR]

This paper addresses the problem of passive fault-tolerant control for linear parameter-varying systems subject to actuator faults. The FTC, based on a linear state feedback, is designed to compensate the impact of actuator faults on system performance by stabilising the closed-loop system using interval observers. The design of interval observers is based on the discrete-time Luenberger observer structure, where uncertainties and faults with known bounds are considered. Sufficient conditions for the existence of the proposed observer are explicitly provided. Simulation results are presented to show the effectiveness of the proposed approach. [ABSTRACT FROM AUTHOR]

The field of immunometabolism is burgeoning, with hundreds of papers published on the topic each year. Our understanding of the contribution of immune cells to metabolic regulation has expanded from a simple idea of innate immune cells, such as macrophages, altering adipose tissue function in obesity, to an awareness of the complex role of adaptive immunity in many different organ systems. Recent findings have clearly demonstrated the presence of adaptive lymphocytes, such as T and B cells, in adipose tissue. Furthermore, these data demonstrated T-cell accumulation and limited T-cell receptor repertoire diversity in obese adipose tissue, indicating that an antigen-specific immune response may occur within this tissue. In a recently published paper, we reported that a mouse model of weight cycling resulted in increased T-cell accumulation in adipose tissue. In the current commentary, we discuss the possibility that this increase in adipose tissue T-cell number could represent a local secondary immune response to self-antigens exposed in adipose tissue during obesity. If further experimentation indicates that this hypothesis is true, these data will fortify the concept that obesity is a complex immune-mediated disease and would emphasize the importance of designing therapies to maintain weight loss. [ABSTRACT FROM AUTHOR]

In this paper, we designed and analysed a discrete model to solve a delayed within-host viral infection model by using non-standard finite difference scheme. The original model that we considered was a delayed viral infection model with cell-to-cell transmission, cell-mediated immune response and general nonlinear incidence. We show that the discrete model has equilibria which are exactly the same as those of the original continuous model and the conditions for those equilibria to be globally asymptotically stable are consistent with the original continuous model with no restriction on the time step size. The results imply that the discretization scheme can efficiently preserves the qualitative properties of solutions for corresponding continuous model. [ABSTRACT FROM PUBLISHER]

In this paper, we use a two-host one pathogen immuno-epidemiological model to argue that the principle for host evolution, when the host is subjected to a fatal disease, is minimization of the case fatality proportion. This principle is valid whether the disease is chronic or leads to recovery. In the case of continuum of hosts, stratified by their immune response stimulation ratea, we suggest thathas a minimum because a trade-off exists between virulence to the host induced by the pathogen and virulence induced by the immune response. We find that the minimization of the case fatality proportion is an evolutionary stable strategy for the host. [ABSTRACT FROM AUTHOR]

Time delays can affect the dynamics of HIV infection predicted by mathematical models. In this paper, we studied two mathematical models each with two time delays. In the first model with HIV latency, one delay is the time between viral entry into a cell and the establishment of HIV latency, and the other delay is the time between cell infection and viral production. We defined the basic reproductive number and showed the local and global stability of the steady states. Numerical simulations were performed to evaluate the influence of time delays on the dynamics. In the second model with HIV immune response, one delay is the time between cell infection and viral production, and the other delay is the time needed for the adaptive immune response to emerge to control viral replication. With two positive delays, we obtained the stability crossing curves for the model, which were shown to be a series of open-ended curves. [ABSTRACT FROM AUTHOR]

Time delays can affect the dynamics of HIV infection predicted by mathematical models. In this paper, we studied two mathematical models each with two time delays. In the first model with HIV latency, one delay is the time between viral entry into a cell and the establishment of HIV latency, and the other delay is the time between cell infection and viral production. We defined the basic reproductive number and showed the local and global stability of the steady states. Numerical simulations were performed to evaluate the influence of time delays on the dynamics. In the second model with HIV immune response, one delay is the time between cell infection and viral production, and the other delay is the time needed for the adaptive immune response to emerge to control viral replication. With two positive delays, we obtained the stability crossing curves for the model, which were shown to be a series of open-ended curves. [ABSTRACT FROM PUBLISHER]

Toll-like receptors (TLRs) are essential components of the innate immune system. They play an important role in the pathogenesis of allergic diseases, especially asthma. Since TLRs significantly orchestrate innate and adaptive immune response, their manipulation has widely been considered as a potential approach to control asthma symptoms. It is well established that helminths have immunoregulatory effects on host immune responses, especially innate immunity. They release bioactive molecules such as excretory-secretory (ES) products manipulating TLRs expression and signaling. Thus, given the promising results derived from preclinical studies, harnessing helminth-derived molecules affecting TLRs can be considered as a potential biological therapy for allergic diseases. Prospectively, the data that are available at present suggest that, in the near future, it is possible that helminth antigens will offer new therapeutic strategies and druggable targets for fighting allergic diseases. This review describes the interactions between helminths and TLRs and discusses the potential possibilities for asthma therapy. In this opinion paper, the authors aimed to review the updated literatures on the interplay between helminths, TLRs, and asthma with a view to proposing helminth-based asthma therapy. [ABSTRACT FROM AUTHOR]

HIV-infected patients who receive treatment survive for some years after they have acquired the disease. The received treatment causes sustained reduction of viral reproduction by improving the immune function, leading to prolonged progression period to AIDS development. This prolonged progression period has created variability in survival times that affects estimates produced using mathematical models that do not include delay in disease related mortality. This paper investigates the effect of including delay in AIDS death occurrence in HIV/AIDS transmission models. A simple mathematical model with two stages of HIV progression is developed and extended to include time delay in the occurrence of AIDS deaths. Numerical simulations indicate that time delay changes the mortality curves considerably but has less effect on the proportion of infectives. The study highlights the importance of incorporating delay in models of HIV/AIDS for the production of accurate HIV/AIDS estimates. [ABSTRACT FROM AUTHOR]

This paper introduces a novel immuno-eco-epidemiological model of competition in which one of the species is affected by a pathogen. The infected individuals from species one are structured by time since- infection and the within-host dynamics of the pathogen and the immune response is also modelled. A novel feature of the model is the impact of the species two numbers on the ability of species one to mount an immune response. The within-host model has three equilibria: an extinction equilibrium, pathogen-only equilibrium and pathogen and immune response equilibrium which exists if the immune response reproduction number R0 > 1. The extinction equilibrium is always unstable, the pathogen-only equilibrium is stable if R0 < 1, and the coexistence equilibrium is stable whenever it exists. The between-host competition model has six equilibria: an extinction equilibrium, three disease-free equilibria: species one-only equilibrium, species two-only equilibrium and a disease-free species coexistence equilibrium. There are also two disease-present equilibria: species one-only disease equilibrium and disease coexistence equilibrium. The existence and stability of these equilibria are governed by six reproduction numbers. Results show that for a nonfatal disease, the disease coexistence equilibrium is stable whenever it exists. [ABSTRACT FROM AUTHOR]

Necrotising retinopathies can be visually devastating. Most often associated with the viral family Herpesviridae and seen in both immune-competent and immunocompromised hosts, possible complications of necrotising retinopathies include progressive retinal necrosis with or without macular involvement, optic neuropathy and ultimately, secondary retinal detachment. Examples include progressive outer retinal necrosis, acute retinal necrosis and cytomegaloviral retinitis. If diagnosed early and treated aggressively, visual complications can be prevented; however, there is no current consensus on the most appropriate antiviral regimen for each of the different varieties of necrotising herpetic retinopathy. This paper reviews aspects of varieties of necrotising herpetic retinopathy, including pathophysiology, treatment and diagnostic testing. [ABSTRACT FROM AUTHOR]

In this paper, we develop and validate with bootstrapping techniques a mechanistic mathematical model of immune response to both BK virus infection and a donor kidney based on known and hypothesized mechanisms in the literature. The model presented does not capture all the details of the immune response but possesses key features that describe a very complex immunological process. We then estimate model parameters using a least squares approach with a typical set of available clinical data. Sensitivity analysis combined with asymptotic theory is used to determine the number of parameters that can be reliably estimated given the limited number of observations. [ABSTRACT FROM PUBLISHER]

In this paper, we propose and analyse a virus dynamics model with humoral immune response including latently infected cells. The incidence rate is given by Beddington–DeAngelis functional response. We have derived two threshold parameters, the basic infection reproduction numberand the humoral immune response activation numberwhich completely determined the basic and global properties of the virus dynamics model. By constructing suitable Lyapunov functions and applying LaSalle's invariance principle we have proven that if, then the infection-free equilibrium is globally asymptotically stable (GAS), if, then the chronic-infection equilibrium without humoral immune response is GAS, and if, then the chronic-infection equilibrium with humoral immune response is globally asymptotically stable. These results are further illustrated by numerical simulations. [ABSTRACT FROM PUBLISHER]

Background and objective. We have previously reported that N-acetylcysteine (NAC), ambroxol and azithromycin (AZM) (partially) correct the chloride efflux dysfunction in cystic fibrosis bronchial epithelial (CFBE) cells with the ΔF508 homozygous mutation in vitro. Methods. In the present paper, we further investigated possible immunomodulatory effects of these drugs on the regulation of the innate immune system by studying the expression of the cytosolic NOD-like receptors NLRC1 and NLRC2, and interleukin (IL)-6 production in CFBE cells. Results. Under basal conditions, PCR and Western Blot data indicate that the NLRC2 receptor has a reduced expression in CF cells as compared to non-CF (16HBE) cells, but that the NLRC1 expression is the same in both cell lines. AZM significantly upregulated NLRC1 and NLRC2 while NAC upregulated only NLRC2 receptor expression in CF cells. Reduced basal IL-6 production was found in CF cells as compared to non-CF cells. MDP (an NLRC2 agonist), NAC and AZM, but not Tri-DAP (an NLRC1 agonist), increased IL-6 production in CF cells, indicating that in CF cells IL-6 upregulation is independent of NLRC1, but involves the activation of NLRC2. Conclusion. Overall, the results indicate that NAC and AZM not only can correct the chloride efflux dysfunction but also have a weakly strengthening effect on the innate immune system. [ABSTRACT FROM AUTHOR]

Adjuvants have been incorporated into vaccines for decades to improve the immune response to vaccine antigens. In developing new vaccines or simply improving existing vaccines, interest in adjuvants has been growing rapidly, with various types of adjuvant (some novel; some already incorporated into specific vaccines) used in clinical research or under development. The development of adjuvants is generally closely linked to the development of a specific vaccine. With the adjuvant being an integral constituent of the final medicinal product, current legislation does not foresee authorization being granted for an adjuvant as a stand-alone product. A dedicated EU guideline addresses the quality non-clinical and clinical development of vaccine adjuvants, and this guidance needs to be considered alongside the specific guidelines for medicinal products in general. This paper provides an overview of the requirements for developing or modifying an adjuvanted vaccine. The authors also address the experience gained for the adjuvanted 2009 H1N1 pandemic influenza vaccine and its implications. [ABSTRACT FROM AUTHOR]

Human enteroviruses (HEV), very common and important human pathogens, cause infections in diverse ways. Recently, the large epidemic of HFMD caused by HEV infection became a growing threat to public health in China. As the first line of immune response, the type I interferon (IFN-α/β) pathway plays an essential role in antiviral infection, particularly in limiting both the early and late stages of infection. Because of co-evolution with the host, the viruses have evolved multiple strategies to evade or subvert the host immunity to ensure their survival. In this paper, we systematically reviewed and summarized the interaction between HEV infections and host type I IFN responses. We firstly described the recent findings of HEV recognition and IFN induction, specifically on host pattern-recognition receptors (PRRs) in HEV infection. Then we discussed the antiviral effect of IFN in HEV infection. Finally, we timely summarized the mechanisms of HEV to circumvent the IFN responses. Clarification of the complexity in this battle may provide us new strategies for prevention and antiviral treatment. [ABSTRACT FROM AUTHOR]

Context: We had available records on over 300 workers evaluated with the beryllium bronchoalveolar lavage lymphocyte proliferation test (BeBALLPT) at three expert chronic beryllium disease (CBD) diagnostic centers. Objective: The objective was to describe the contribution of the BeBALLPT to classification of workers with respect to beryllium sensitization (BeS) and beryllium-induced lung inflammation. Methods: Company records were used to identify beryllium workers who had undergone diagnostic bronchoscopy with BeBALLPT. Clinical, work and smoking information was abstracted from electronic and paper databases. We analyzed factors influencing BeBALLPT outcome, and its relation to blood-determined BeS and granulomatous inflammation. Results: Positive BeBALLPTs contributed evidence of BeS in subjects without prior positive beryllium blood lymphocyte proliferation tests (BeBLPTs) and of pulmonary inflammation in persons without granulomata evident on lung biopsy. Positive BeBALLPTs were associated with positive BeBLPTs and more strongly with granulomata. The rate of both positive BeBALLPT and granulomata increased with time worked through 4 years and were lower in smoking subjects. The false negative rate of the BeBALLPT was 20%. Conclusion: A positive BeBALLPT is closely linked to the presence of granulomata on lung biopsy and can be considered as an indicator of lung inflammation in addition to BeS. The ability to use BeBALLPT as a substitute for the more risky lung biopsy is limited by the BeBALLPT false negative rate and lack of information on the false positive rate. It is not recommended that a positive BeBALLPT be considered sufficient evidence for both lung inflammation and BeS. [ABSTRACT FROM AUTHOR]

In this paper, on the basis of the simplified two-dimensional virus infection dynamics model, we propose two extended models that aim at incorporating the influence of activation-induced apoptosis which directly affects the population of uninfected cells. The theoretical analysis shows that increasing apoptosis plays a positive role in control of virus infection. However, after being included the third population of cytotoxic T lymphocytes immune response in HIV-infected patients, it shows that depending on intensity of the apoptosis of healthy cells, the apoptosis can either promote or comfort the long-term evolution of HIV infection. Further, the discrete-time delay of apoptosis is incorporated into the pervious model. Stability switching occurs as the time delay in apoptosis increases. Numerical simulations are performed to illustrate the theoretical results and display the different impacts of a delay in apoptosis. [ABSTRACT FROM AUTHOR]

Deleterious health effects induced by inorganic vanadium compounds are linked with carcinogenic, immunotoxic and neurotoxic insults. The goal of this review is to provide a summary of mammalian cell culture studies (from the 1990s to most recent) looking into the mode of the above-mentioned adverse actions of vanadium. Regarding the carcinogenicity potential, the key cell-based studies have evidenced the ability of vanadium to induce genotoxic lesions, cell morphological transformation and anti-apoptotic effects in a certain type of cells. Two contradictory effects of vanadium on the immune functions of cells have been observed in cell culture studies. The first effect involves reduction of cell immune responses such as vanadium-dependent inhibition of cytokine-inducible functions, which may underlie the mechanism of vanadium-induced immunosuppression. The second one involves stimulation of immune activity, for example, a vanadium-mediated increase in cytokine production, which may contribute to vanadium-related inflammation. So far, an in vitro evaluation of vanadium neurotoxicity has only been reported in few articles. These papers indicate probable cytotoxic mechanisms resulting from exposure of neurons and glial cells to vanadium. In summary, this literature review collects in vitro reports on adverse vanadium effects and thus provides vanadium researchers with a single, concise source of data. [ABSTRACT FROM AUTHOR]

Since the first clinical heart transplant in 1967, there has been a heightened need to understand immune and inflammatory responses to 'foreign' tissues. Research efforts in those early days were based on species that would now be considered 'large' and were typically out-bred individuals. While this closely mirrors the clinical scenario, where genetic mismatches of donors and recipients can only be minimized in the selection process, these were not ideal models for studying the complexities and nuances of the immune system. Even when the rat was considered the standard model those early endeavors were limited by a small number of rat strains. The mouse model has provided us with an overwhelming array of strains, knockouts, knockins and transgenics that allow us to investigate the many layers of the innate and adaptive immune systems leading to a much greater understanding of immune responses. Fully vascularized heterotopic cardiac transplantation in the mouse has now been with us for four decades; the original papers describing this technique being published by Corry in 1973. In the subsequent 40 years, this technique has been used by many laboratories, including our own, and has become a powerful tool for the investigation of transplant immunity and ischemia reperfusion injury. Given the modern availability of mouse strains and mouse-related reagents, our current understanding of transplant immunity undoubtedly would not exist without such a technique. [ABSTRACT FROM AUTHOR]

Purpose: Heat shock protein 70 (HSPA family) is a multi-functional protein which protects individual cells from proteotoxic shock and the whole organism from microbial, viral and oncogenic pathogens. These diverse functions may depend upon 'chaperone' activity that allows Hsp70 to regulate the mechanism of damaged protein recovery or utilisation inside a cell and to be a potent adjuvant, stimulating immune activity against a variety of viral or tumour antigens. The aim of this review is to present recent data on specific roles of intracellular and extracellular Hsp70 in cancerous tissue. Conclusion: The data presented in this paper show that endogenous Hsp70 protects cancer cells of different origins from a variety of cytotoxic threats including cancer cell therapeutics. In contrast, however, Hsp70 released from stressed cancer cells can serve as a danger signal or may recruit cells responsible for the generation of innate and adaptive immune responses against tumour cells. [ABSTRACT FROM AUTHOR]

The article discusses several papers published within the issue including one about the immune suppressing role of major histocompatibility complex (MHC), another regarding polyclonal immunoglobulin therapy and a paper on immune danger sensing through the unfolded protein response (UPR)

Estrogen deficiency following menopause results in atrophic skin changes and acceleration of skin aging. estrogens significantly modulate skin physiology, targeting keratinocytes, fibroblasts, melanocytes, hair follicles and sebaceous glands, and improve angiogenesis, wound healing and immune responses. estrogen insufficiency decreases defense against oxidative stress; skin becomes thinner with less collagen, decreased elasticity, increased wrinkling, increased dryness and reduced vascularity. its protective function becomes compromised and aging is associated with impaired wound healing, hair loss, pigmentary changes and skin cancer. Skin aging can be significantly delayed by the administration of estrogen. This paper reviews estrogen effects on human skin and the mechanisms by which estrogens can alleviate the changes due to aging. The relevance of estrogen replacement, selective estrogen receptor modulators (SerMs) and phytoestrogens as therapies for diminishing skin aging is highlighted. Understanding estrogen signaling in skin will provide a basis for interventions in aging pathologies. [ABSTRACT FROM AUTHOR]

In this paper, we introduce ordinary and delay differential equations to describe the interactions between a malignant tumour and the immune systemin vivoin the presence of human immunodeficiency virus (HIV) infection of CD4+T-cells. In the delay model, we take into account the time lags required by the healthy effector cell components to recognize the pathogens and tumour cells. The models consist of four populations: tumour cells, healthy effector cells (CD4+T-cells), effector cells infected by HIVs and free viral particles. The presence of delay term in the model leads to a notable increase in the complexity of the observed behaviour. We investigate the qualitative behaviour of the models and find the conditions that guarantee the asymptotic stability of the steady states. Numerical simulations are provided to illustrate and extend the theoretical results. The obtained results are consistent with the real phenomena and give a better understanding of cancer immunity and viral oncogenesis. [ABSTRACT FROM PUBLISHER]

Thermal ablation is increasingly being used for treatment of liver tumours. Among the techniques of thermal ablation, radiofrequency ablation (RF) is undoubtedly being used most frequently because of its advantages, such as morbidity and mortality rates, effective tumour ablation, as well as being less time-consuming. This paper presents the state of the art of RF ablation technique. This includes the theoretical development, experimental study and clinical application of the radiofrequency ablation technique. First, it introduces the principle of this technique. Second, it shows the development of this technique and valuable achievements. These achievements include the device, strategy of operation and extension to other diseases. Third, it concludes future issues to be addressed in order to further advance this technique. [ABSTRACT FROM AUTHOR]

Vanadium (V) is a transition metal found in air adsorbed onto suspended particles. As a result, urban populations are often exposed to this element as a constituent of particulate matter (PM). One aspect of the myriad toxicities that might arise from these exposures is altered immune responses. Previous reports from the laboratory reported modifications in splenic architecture - with germinal center hyperplasia and a suppressed humoral immune response - in mice that had been exposed to vanadium agents via inhalation. This paper reports a decrease in the presence of the CD11c surface marker on mouse thymic dendritic cells (DC) as a result of host exposure to vanadium (here, in the form of vanadium pentoxide; V2O5) over a period of 4 weeks. All results were obtained using immunohistochemistry and flow cytometry. It is surmised that this decrease might induce a dysfunction, including possible negative selection of T-cells, which could increase the presence of autoreactive clones in the exposed host. Such an outcome could, in turn, increase the risk for development of autoimmune reactions in different organs specifically, and of autoimmune diseases in general in these V-exposed hosts. [ABSTRACT FROM AUTHOR]

IgM is the first antibody produced during the immune response to infection or immunization, and it can be secreted as pentamer (containing a small polypeptide, termed as J chain) or hexamer (lacking J chain). In this paper we have analyzed structural characteristics (by electrophoresis and immunoblot) and anti-bacterial specificity (by enzyme-linked immunosorbent assay) of IgM antibodies purified from female patients suffering from recurrent bacterial infections of lower urinary tract and therapeutically immunized with the mixture of heat-inactivated uropathogenic bacteria. We report on changes in the composition of IgM polymers in tested patients. The immunization induced the raise of the levels of hexamers in patients that did not respond to immunization (non-responders), while the IgM polymers remained on the pentameric level in immunization dependent responders. We propose that the composition of IgM polymers could influence the immunization outcome and should be taken in count regarding the treatment of recurrent bacterial infections. [ABSTRACT FROM AUTHOR]

Plasmacytoid dendritic cell (PDC) is a Th2-type dendritic cell precursor. It is an important professional effector cell characterized by its capacities to produce large amount of alpha interferon and to differentiate into dendritic cell. PDCs are scarce in normal condition. They circulate in the blood as veiled cells and enter the lymph node and mucosal site in response to immune stimulation. Besides the recent and wide-open field of the implication of PDCs in inflammatory diseases and in the microenvironment of solid or lymphoid tumours it has also been observed that PDCs can also be tumoral cells. In this paper, the authors present the different tumours thought to be originating from tumoral PDCs. To date, two kinds of tumoral conditions are recognized: the so-called PDCs proliferations in patients with myeloid disorders and the blastic plasmacytoid dendritic cell neoplasm. These two entities are exposed and discussed. [ABSTRACT FROM AUTHOR]

The intestinal environment is considered to play an important role both in colorectal tumor development and in the evolution and modulation of mucosal immunity. Studies in animals reared in germ-free (GF, without any intestinal microflora) versus conventional (CV, with regular microflora in bowel) conditions can aid in clarifying the influence of bacteria on carcinogenesis and anti-cancer immune responses in situ. The lower incidence of colon cancers and better immunological parameters in GF animals versus CV ones after chemically-induced carcinogenesis raises questions about specific characteristics of the immunological networks in each respective condition. Different levels of tolerance/regulatory mechanisms in the GF versus CV animals may influence the development of immune responses not only at the level of mucosal, but also at the systemic, immunity. We hypothesize that GF animals can better recognize and respond to evolving neoplasias in the bowel as a consequence of their less-tolerogenic immunity (i.e., due to their more limited exposure to antigens to become tolerated against at the intestinal level). In this paper, we review the role of bacteria in modulating gut environment and mucosal immunity, their importance in cancer development, and aspects of immune regulation (both at local and systemic level) that can be modified by bacterial microflora. Lastly, the use of GF animals in comparison with conventionally-raised animals is proposed as a suitable and potent model for understanding the inflammatory network and its effect on cancer immunity especially during colorectal cancer development. [ABSTRACT FROM AUTHOR]

In this paper, we addressed the immune adjuvant effects of interleukin(IL)-21 on DNA vaccine constructs expressing mycobacterium tuberculosis (TB) Ag85A and compared immune responses induced in mice inoculated DNA vaccine constructs expressing Ag85A and IL-21 with mice inoculated DNA vaccine constructs expressing Ag85A alone or Bacillus Galmette-Guérin(BCG.). In this experiment, the gene of IL-21 was firstly amplified from plasmid pcDNA3.1-mIL21 by PCR and cloned into the plasmid pRSC, forming recombinant plasmid pRSC-IL21. Then, the gene of Ag85A was amplified from the plasmid pIRES-Ag85A by PCR and cloned into the recombinant pRSC-IL21 again, finally forming co-expression DNA vaccine constructs pRSC-IL21-Ag85A. It was identified by the analysis of endonuclease digestion, DNA sequencing, the IL-21 and Ag85A expression in SP2/0 cells. Mice were i.m. immunized with BCG, DNA vaccine constructs pRSC-Ag85A or pRSC-IL21-Ag85A respectively, and the immune responses induced in mice was compared with other vaccines. The results showed that the DNA vaccine constructs pRSC-IL21-Ag85A was successfully constructed since the Ag85A and IL-21 was correctly expressed in SP2/0 cells respectively, and it elicited stronger immune responses in Balb/c mice than that of mice immunized with pRSC-Ag85A and the efficiency was as BCG did. We concluded that the IL-21 was a promising immune adjunctive modality to enhance immunigenicity of DNA vaccine containing Ag85A and the study provided the possibility of further development of immune accessory effect of IL-21 on DNA vaccine against TB. [ABSTRACT FROM AUTHOR]

Nasal vaccination is a promising alternative to classical parental vaccination, as it is non-invasive and, in principle, capable of eliciting strong systemic and local immune responses. However, the protective efficacy of nasally administered antigens is often impaired because of delivery problems: free antigens are readily cleared from the nasal cavity, poorly absorbed by nasal epithelial cells and generally have low intrinsic immunogenicity. In this review paper, we describe the main physiological hurdles to nasal vaccine delivery, survey the progress made in technological approaches to overcome these hurdles and discuss emerging opportunities for improving nasal vaccines. According to current insights, encapsulation of the antigen into bioadhesive (nano)particles is a promising approach towards successful nasal vaccine delivery. These antigen-loaded particles can be tailor made by supplying them with targeting ligands, adjuvants or endosomal escape mediators to form the desired vaccine that provides long-lasting protective immunity. [ABSTRACT FROM AUTHOR]

The identification of antigen-recognizing receptors in the innate immune system significantly helped us to understand the initiation and regulation of the innate immune response. Dectin-1 was recently identified as the most important receptor for β-glucan. Recognition of β-glucan by dectin-1 triggers effective immune response, including phagocytosis and proinflammatory factor production, to eliminate infecting fungi, which especially benefits immunocompromised patients against opportunistic fungal infection. In addition, dectin-1 is involved in the adaptive immune response as well as autoimmune diseases and immune tolerance. In this paper, we will mainly focus on the characteristics of dectin-1 and its biological role in immune response. [ABSTRACT FROM AUTHOR]

Increased expectations from a number of regulatory agencies, e.g., Environmental Protection Agency (EPA), Food and Drug Administration (FDA), European Medicines Agency (EMEA), and the Ministry of Health, Labour and Welfare (MHLW) of Japan, call for the evaluation of potential adverse effects on the immune system. As recently summarized in the ICH S8 guideline, the T-cell-dependent antibody response (TDAR) has been identified in a regulatory context as a main functional test of immunotoxicity. While the characterization of immunotoxic potential is pertinent to both the chemical and pharmaceutical industries, the use of immunotoxicology data for hazard identification and/or risk assessment in each case is different. Therefore, multiple approaches to immunotoxicity testing have evolved. The assays that evaluate TDAR function include both well-established tests, e.g., anti-sheep red blood cell plaque-forming cell (PFC) assay, and newer models, e.g., anti-keyhole limpet hemocyanin (KLH) antibody ELISA. These tests vary in the study design, antigen application and analytical methods. However, they all evaluate the same endpoint - a competent immune (e.g., antibody) response to an antigen. Numerous issues have been identified in the application of TDAR tests, including high animal to animal variability; differences in antigen source and potency; a lack of established "normal range" of the immune response and uncertainty about the degree of inhibition of the TDAR to be considered toxicologically important. As such, the need for a forum to discuss these issues was recognized by the immunotoxicology community, and was addressed at the 2006 Society of Toxicology (SOT) Workshop. A series of papers will summarize that forum with the ultimate objectives being to build a consensus among immunotoxicologists on the implications of these factors on using TDAR results in hazard identification and/or risk assessment, and to establish a criteria to classify compounds as immunotoxicants. [ABSTRACT FROM AUTHOR]