Search

In this paper, we introduce a Galerkin method based on Legendre multiwavelet functions to obtain approximate solutions of a fractional model for HIV infection of CD4+T cells corresponding to a class of systems of nonlinear fractional differential equations. The method converts the model problem into a system of nonlinear algebraic equations. A numerical example is included to demonstrate the validity and applicability of the technique and the results are compared with those obtained by existing methods. [ABSTRACT FROM AUTHOR]

Immunotherapy is considered as an effective method for cancer treatment owing to the induction of specific and long-lasting anti-cancer effects. Immunotherapeutic strategies have shown significant success in human malignancies, particularly in prostate cancer (PCa), a major global health issue regarding its high metastatic rates. In fact, the first cancer vaccine approved by FDA was Provenge, which has been successfully used for treatment of PCa. Despite the remarkable success of cancer immunotherapy in PCa, many of the developed immunotherapy methods show poor therapeutic outcomes. Immunosuppression in tumor microenvironment (TME) induced by non-functional T cells (CD4+ and CD8+), tolerogenic dendritic cells (DCs), and regulatory T cells, has been reported to be the main obstacle to the effectiveness of anti-tumor immune responses induced by an immunotherapy method. The present review particularly focuses on the latest findings of the immune checkpoints (ICPs), including CTLA-4, PD-1, PD-L1, LAG-3, OX40, B7-H3, 4-1BB, VISTA, TIM-3, and ICOS; these checkpoints are able to have immune modulatory effects on the TME of PCa. This paper further discusses different approaches in ICPs targeting therapy and summarizes the latest advances in the clinical application of ICP-targeted therapy as monotherapy or in combination with other cancer therapy modalities in PCa. [ABSTRACT FROM AUTHOR]

Despite recent improvements in the treatment of systemic lupus erythematosus (SLE), disease activity, comorbidities and drug toxicity significantly contribute to the risk of progressive irreversible damage accrual and increased mortality in patients with this chronic disease. Moreover, even lupus patients in remission often report residual symptoms, such as fatigue, which have a considerable impact on their health-related quality of life. In recent decades, SLE treatment has moved from the use of hydroxychloroquine, systemic glucocorticosteroids and conventional immunosuppressive drugs to biologic agents, of which belimumab is the first and only biologic agent approved for the treatment for SLE to date. Novel therapies targeting interferons, cytokines and their receptors, intracellular signals, plasma cells, T lymphocytes and co-stimulatory molecules are being evaluated. In the context of a holistic approach, growing evidence is emerging of the importance of correct lifestyle habits in the management of lupus manifestations and comorbidities. The aim of this paper is to provide an overview of current pharmacological and non-pharmacological treatment options and emerging therapies in SLE. [ABSTRACT FROM AUTHOR]

In this paper, a model of HIV infection taking into account cell-free and cell-to-cell transmissions is investigated under latency. The viral production rate of infectious CD4 T cells and the activation rate of latently infected CD4 T cells play a major role in the evolution of the disease. A system of nonlinear differential equations is derived to capture the dynamics and systematically analyzed thanks to the spectral theory of dynamical systems and a Routh-Hurwitz criterion. In particular, numerical simulations will be performed in order to extract the critical epidemiological features of the solution. [ABSTRACT FROM AUTHOR]

This paper seeks to unveil the niche of delay differential equation in harmonizing low HIV viral haul and thereby articulating the adopted model, to delve into structured treatment interruptions. Therefore, an ordinary differential equation is schemed to consist of three components such as untainted CD4+ T-cells, tainted CD4+ T-cells (HIV) and CTL. A discrete time delay is ushered to the formulated model in order to account for vital components, such as intracellular delay and HIV latency which were missing in previous works but have been advocated for future research. It was divested that when the reproductive number was less than unity, the disease free equilibrium of the model was asymptotically stable. Hence the adopted model with or without the delay component articulates less production of virions as per the decline rate. Therefore CD4+ T-cells in the blood remains constant at δ 1 / δ 3 , hence declining the virions level in the blood. As per the adopted model, the best STI practice is intimated for compliance. [ABSTRACT FROM AUTHOR]

HIV infection is one of the most serious causes of death throughout the world. CD4+ T cells which play an important role in immune protection, are the primary targets for HIV infection. The hallmark of HIV infection is the progressive loss in population of CD4+ T cells. However, the pathway causing this slow T cell decline is poorly understood [16]. This paper studies a discontinuous mathematical model for HIV-1 infection, to investigate the effect of pyroptosis on the disease. For this purpose, we use the theory of discontinuous dynamical systems. In this way, we can better analyze the dynamical behavior of the HIV-1 system. Especially, considering the dynamics of the system on its discontinuity boundary enables us to obtain more comprehensive results rather than the previous researches. A stability region for the system, corresponding to its equilibria on the discontinuity boundary, will be determined. In such a parametric region, the trajectories of the system will be trapped on the discontinuity manifold forever. It is also shown that in the obtained stability region, the disease can lead to a steady state in which the population of uninfected T cells and viruses will preserve at a constant level of cytokines. This means that the pyroptosis will be restricted and the disease cannot progress for a long time. Some numerical simulations based on clinical and experimental data are given which are in good agreement with our theoretical results. [ABSTRACT FROM AUTHOR]

Currently, immunomodulation is an alternative in the fight against many diseases, being considered a possibility to fight against many infectious diseases that can affect pig herds. Selenium can be used for this purpose, the effect of its administration on the immune response being the main purpose of the present study. Following the administration of organic selenium, we found that in the case of WBC parameters, granulocytes and agranulocytes percentages and lymphoblastic transformation percentages of B lymphocytes, there are no major differences between the values recorded at the beginning of the experiment and the values recorded in the two experimental moments. Instead, following the administration of organic selenium, we observed significant increases in T lymphocytes percentages (by 9.94%, after 21 days, and respectively by 8.18%, after 30 days), percentages of lymphoblastic transformation of T lymphocytes (by 59.59% after 21 days, and respectively by 64.14% after 30 days), as well as the helper T lymphocytes/supressor T lymphocytes ratio (by 46.15% after 21 days, and respectively by 65.38% after 30 days). Regarding the percentage of B lymphocytes, a decrease of this parameter is observed by 38.34% after 21 days and by 21.84% after 30 days following the administration of the product based on organic selenium. [ABSTRACT FROM AUTHOR]

The Th17/ Treg axis is a crucial regulator of anti-inflammatory and proinflammatory pathways that play fundamental roles in cancer and autoimmune diseases. The alteration of the Th17/Tregs axis is highly significant for developing novel therapeutic approaches. Th17 and Treg cells share a large portion of their transcriptome, albeit with distinct functions. The mechanisms governing the bifurcation of Th17 /Treg axis differentiation from naïve T cells are not yet understood. This study aims to identify the differentially expressed genes (DEGs) and gene-enriched pathways that contribute to the distinction between these closely aligned phenotypes. We analyzed RNA sequencing data of CD4+ T cells differentiated in vitro into Th0, Th17, and Tregs phenotypes and built gene enrichment networks. We studied the network rewiring of Th17 and Tregs from Th0 cells. In addition to common pathways and genes that are equally expressed between these two distinct phenotypes, we identified key genes and pathways that contribute to their distinctiveness. For example, the Keap1 gene and several of its interactors such as MCC1 were upregulated in Tregs indicating that Tregs possess mechanisms that prevent the over-activation of antioxidants pathways. Tregs also possess several genes that are involved in the hydrolysis of ATP to ADP as RAB37, ATP1A2, ATP1B, and PDE2A to ensure Treg anti-inflammatory capabilities. Additionally, one of the pathways that ensure Tregs differentiation and function seems to point toward an insulin role mediated by APOL9B and GOLM. Taken together our findings shed light on various essential regulators of the Th17/Treg axis and pave the way for treatment strategies that selectively target one phenotype while sparing the other. [ABSTRACT FROM AUTHOR]

Discrete tissue niches are emerging as essential prerequisites enabling cell communication and function in both homeostasis and disease. In a recent Cell paper, Di Pilato et al. identify a unique dendritic cell-cytotoxic T cell crosstalk within the perivascular space that facilitates T cell survival and proliferation and drives anti-tumor activity. [ABSTRACT FROM AUTHOR]

HIV preferentially infects activated CD4+ T cells. Current antiretroviral therapy cannot eradicate the virus. Viral infection of other cells such as macrophages may contribute to viral persistence during antiretroviral therapy. In addition to cell-free virus infection, macrophages can also get infected when engulfing infected CD4+ T cells as innate immune sentinels. How macrophages affect the dynamics of HIV infection remains unclear. In this paper, we develop an HIV model that includes the infection of CD4+ T cells and macrophages via cell-free virus infection and cell-to-cell viral transmission. We derive the basic reproduction number and obtain the local and global stability of the steady states. Sensitivity and viral dynamics simulations show that even when the infection of CD4+ T cells is completely blocked by therapy, virus can still persist and the steady-state viral load is not sensitive to the change of treatment efficacy. Analysis of the relative contributions to viral replication shows that cell-free virus infection leads to the majority of macrophage infection. Viral transmission from infected CD4+ T cells to macrophages during engulfment accounts for a small fraction of the macrophage infection and has a negligible effect on the total viral production. These results suggest that macrophage infection can be a source contributing to HIV persistence during suppressive therapy. Improving drug efficacies in heterogeneous target cells is crucial for achieving HIV eradication in infected individuals. [ABSTRACT FROM AUTHOR]

Changes in cellular Ca 2 + concentration control a variety of physiological activities including hormone and neurotransmitter release, muscular contraction, synaptic plasticity, ionic channel permeability, apoptosis, enzyme activity, gene transcription and reproduction process. Spatial–temporal Ca 2 + dynamics due to Ca 2 + release, buffering and re-uptaking plays a central role in studying the Ca 2 + regulation in T lymphocytes. In most cases, Ca 2 + has its major signaling function when it is elevated in the cytosolic compartment. In this paper, a two-dimensional mathematical model to study spatiotemporal variations of intracellular Ca 2 + concentration in T lymphocyte cell is proposed and investigated. The cell is assumed to be a circular shaped geometrical domain for the representation of properties of Ca 2 + dynamics within the cell including important parameters. Ca 2 + binding proteins for the dynamics of Ca 2 + are itself buffer and other physiological parameters located in Ca 2 + stores. The model incorporates the important biophysical processes like diffusion, reaction, voltage-gated Ca 2 + channel, leak from endoplasmic reticulum (ER), efflux from cytosol to ER via sarco–ER Ca 2 + adenosine triphosphate (SERCA) pumps, buffers and Na + / Ca 2 + exchanger. The proposed mathematical model is solved using a finite difference method and the finite element method. Appropriate initial and boundary conditions are incorporated in the model based on biophysical conditions of the problem. Computer simulations in MATLAB R2019b are employed to investigate mathematical models of reaction–diffusion equation. The effect of source, buffer, Na + /Ca 2 + exchanger, etc. on spatial and temporal patterns of Ca 2 + in T lymphocyte has been studied with the help of numerical results. From the obtained results, it is observed that, the coordinated combination of the incorporated parameters plays a significant role in Ca 2 + regulation in T lymphocytes. ER leak and voltage-gated Ca 2 + channel provides the necessary Ca 2 + to the cell when required for its proper functioning, while on the other side buffers, SERCA pump and Na + /Ca 2 + exchanger makes balance in the Ca 2 + concentration, so as to prevent the cell from death as higher concentration for longer time is harmful for the cell and can cause cell death. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is a new human infectious disease. The etiology for this outbreak is a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thus far, related research on COVID-19 is still in preliminary stage. This paper summarized the latest outcomes of corresponding study from Chinese centers and clarified the hematopoietic abnormality caused by SARS-CoV-2 and potential mechanism. Lymphopenia was common in the early stage after the onset of COVID-19. A significant decrease was observed in peripheral CD4+ and CD8+ T lymphocytes. As the illness progressed, neutrophilia emerged in several cases, and patients with severe critical pulmonary conditions showed higher neutrophils than common type. Thrombocytopenia was resulting from the consumption and/or the reduced production of platelets in damaged lungs. Anemia was not observed notably, but the decrease in hemoglobin was frequent. The activation of monocyte-macrophage system aggravates the immune damage of lung and other tissues, which leads to the increase of D-dimer, prothrombin time, and platelet consumption. [ABSTRACT FROM AUTHOR]

Aim: The objective of this review is to describe the immunological mechanisms which facilitate maternal tolerance at the maternal‐placental interface, and to discuss how these mechanisms are disrupted in pre‐eclampsia. Methods: A literature review was performed based on the analysis of papers available on PubMed. The most important and relevant studies regarding the immunological mechanisms which facilitate maternal tolerance in healthy pregnancy and pre‐eclampsia are presented in this article. Results: The maternal‐placental interface is the site where the immune tolerance begins and develops. Within the innate immunity, natural killer cells, macrophages and dendritic cells play a pivotal role in tolerance through regulation of inflammation. On the other hand, within the adaptive immunity, the correct increase of regulatory T cells is crucial for ensuring immune tolerance toward placental cells. Disturbances in maternal tolerance can lead to the appearance of pregnancy complications such as pre‐eclampsia, which has a considerable impact on perinatal morbidity and mortality. Conclusion: Our partial knowledge of immunological mechanisms involved in tolerance at the maternal‐placental interface indicates that pre‐eclampsia is characterized by alterations of this maternal immune tolerance, which could represent the origin of the disease. [ABSTRACT FROM AUTHOR]

AIDS is a highly harmful malignant infectious disease caused by human immunodeficiency virus infection. The majority of HIV-infected people in the world are caused by HIV-1 infection. The HIV-1 virus mainly invades the most important CD4+ T cells in the human immune system, destroying the cells in large quantities, and ultimately depriving the body of its immune function. At present, there is no vaccine to prevent, and there is no effective drug or method to cure this disease. With the increase of age, the generation of various free radicals in the middle and old people increases, the activity of antioxidant enzymes gradually decreases, and the risk of insufficient intake of various vitamins increases. Due to the importance of micronutrients for human physiological function and the effectiveness of HAART for AIDS treatment, this article attempts to explore the effect of micronutrient supplementation combined with HAART treatment on the nutritional status and immune function of AIDS patients. In this paper, through an experimental simulation of HIV-1 infected patients in a hospital infection department or a specialty clinic, the experimental results show that the virus suppression rate of the micronutrient supplement group and the HAART treatment group is about 35%, and the micronutrient supplement combined with HAART the cure rate of the treatment group was close to 100%. After using mineral interventions, the nutritional status of HIV-infected and AIDS patients has been improved to varying degrees. [ABSTRACT FROM AUTHOR]

Introduction: Interleukin 35 (IL-35) has recently been characterized as a cytokine connected with the IL-12 group. The secretion of IL-35 was described in forkhead box protein 3 (Foxp3) + regulatory T cells (Tregs), peripheral γπ T cells, CD8+ T cells, placental trophoblasts, antigen-presenting cells (APCs) and regulatory B cells (Breg). Aim: The aim of this paper is to systematize current knowledge about IL-35 production and discuss its impact on the pathophysiology and outcome of various diseases. Material and methods: Literature review was conducted. Results and discussion: IL-35 plays a pivotal role in the immune dysregulation in the pathogenesis of cardiovascular diseases including atherosclerosis, psychiatric and neurologic disorders, cancer, allergic and autoimmune diseases and psoriasis, inducing the expression of Treg-related cytokines and inhibiting the expression of Th1- and Th17-related cytokines. Conclusions: Due to the numerous signaling pathways of IL-35, it may be described as an innovative biomarker in the prognosis and treatment of various diseases. [ABSTRACT FROM AUTHOR]

Cutaneous leishmaniasis (CL) is a major public health problem worldwide and spreads to human via the bite of sand flies during blood meal. Following its inoculation, the promastigotes are immediately taken up by phagocytic cells and these leishmania-infected host cells produce proinflammatory cytokines that activate other immune cells and these infected host cells produce more cytokines and reactive nitrogen and oxygen species for efficient control of leishmania infection. Many experimental studies showed that resistance to infection with leishmania paraites is associated with the production of proinflammatory cytokines and activation of CD4+ Th1 response. On the other hand, vulnerability to this parasitic infection is correlated to production of T helper 2 cytokines that facilitate persistence of parasites and disease progression. In addition, some studies have also indicated that CD8+ T cells play a vital role in immune defense through cytokine production and their cytotoxic activity and excessive production of proinflammatory mediators promote amplified recruitment of cells. This could be correlated with excessive inflammatory reaction and ultimately resulted in tissue destruction and development of immunopathogenesis. Thus, there are contradictions regarding the role of immune responses in protection and immunopathogenesis of CL disease. Therefore, the aim of this paper was to review the role of host immune response in protection and its contribution to disease severity for CL infection. In order to obtain more meaningful data regarding the nature of immune response to leishmania, further in-depth studies focused on immune modulation should be conducted to develop better therapeutic strategies. [ABSTRACT FROM AUTHOR]

In this paper, we study the asymptotic and stability dynamics of a chemotaxis model in volume filling constraints on HIV-1-incorporating cytotoxic T lymphocytes (CTLs) cells in defense mechanism against the virus infection. The system of uninfected CD 4 + T -cells, infected and CTL defense cells is globally well-defined in Ω × (0 , ∞) , with uninfected CD 4 + T and CTL cells remaining bounded, while the HIV-1-activated cells decay to the null state at time t = ∞ . Routh–Hurwitz criteria yields asymptotical stability of the system, if the CTL threshold value is sufficiently large with CTL decay small, and instability otherwise. In control theory, it is implied that a bounded control yields the system not completely controllable, but bounded input-bounded output stable (b.i.b.o.-stable) with stabilizability and detectability not guaranteed. If guaranteed, the system is asymptotically stable if and only if it is b.i.b.o.-stable. In addition, numerical simulation results of the model are provided. [ABSTRACT FROM AUTHOR]

Programmed cell death protein 1 (PD-1) has become one of the most investigated targets for cancer immunotherapy. Most research has centered on inhibiting PD-1 on T cells, but there is increased interest in understanding the role of PD-1 on NK cells. While the expression of PD-1 on NK cells has been controversial, with papers publishing contradictory results in multiple models, there is increased clinical interest in NK and PD-1 immunotherapy. In this issue of the JCI, Judge et al. comprehensively explore the lack of PD-1 expression on murine, canine, and human NK cells and the clinical implication of these findings. [ABSTRACT FROM AUTHOR]

Immunoinformatics is a science that helps to create significant immunological information using bioinformatics softwares and applications. One of the most important applications of immunoinformatics is the prediction of a variety of specific epitopes for B cell recognition and T cell through MHC class I and II molecules. This method reduces costs and time compared to laboratory tests. In this state-of-the-art review, we review about 50 papers to find the latest and most used immunoinformatic tools as well as their applications for predicting the viral, bacterial and tumoral structural and linear epitopes of B and T cells. In the clinic, the main application of prediction of epitopes is for designing peptide-based vaccines. Peptide-based vaccines are a considerably potential alternative to low-cost vaccines that may reduce the risks related to the production of common vaccines. [ABSTRACT FROM AUTHOR]

Allergic conjunctivitis (AC) is a common allergic disease that is often associated with the onset of rhinitis or asthma. The incidence of AC has increased significantly in recent years possibly due to air pollution and climate warming. AC seriously affects patients' quality of life and work efficiency. Th (T-helper) 2 immune responses and type I hypersensitivity reactions are generally considered the basis of occurrence of AC. It has been found that new subpopulations of T-helper cells, Th17 cells that produce interleukin-17 (IL-17), play an important role in the Th2-mediated pathogenesis of conjunctivitis. Studies have shown that Th17 cells are involved in a variety of immune inflammation, including psoriasis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, and asthma. However, the role of Th17 and IL-17 in AC is unclear. This paper will focus on how T-helper 17 cells and interleukin-17 are activated in the Th2 immune response of allergic conjunctivitis and how they promote the Th2 immune response of AC. [ABSTRACT FROM AUTHOR]

The Th17/Treg axis plays a crucial role in immune-mediated inflammatory diseases (IMID) and might represent an interesting drug target of treatment strategy for these diseases. Accumulating evidence suggests a role for traditional Chinese medicine (TCM) in the modulation of Th17/Treg axis, but a comprehensive overview which summarizes this field hitherto is lacked. This paper performs a systematic literature review of the regulatory effects of TCM on the imbalance of Th17/Treg axis and its potential mechanisms. In addition, the frequency analysis and network pharmacology for the collected TCM herbs from clinical trial data were performed. The studies reported the changes in the ratio of Th17 and/or Treg cells as well as their transcription factor and related cytokines were included. Frequency analysis of composition of the 39 assessed TCM prescriptions showed that Astragalus membranaceus var.mongholicus (5.20%), Glycyrrhiza uralensis (3.67%), Paeonia obovate (3.06%), Salvia digitaloides (3.06%), and Angelica sinensis (2.75%) were the top five herbal components, which were closely associated to the treatment of IMID. Network pharmacology showed that six target proteins (transforming growth factor (TGF)-beta receptor type-1, TGF-beta receptor type-2, retineic-acid-receptor-related orphan nuclear receptor gamma (ROR-gamma), TGFB2, IL-17 and IL-2, respectively) might be involved in the regulatory effects of TCM on Th17/Treg axis. Moreover, there were nine active ingredients (including Oxymatrine, Baicalin, Triptolide, Paeoniflorin, Sinomenine, Celastrol, Emodin, Diosgenin and Chlorogenic acid) originating from TCM reported to have an immunological regulation effect on the Th17/Treg axis. The highlight of this systematic review is to reveal the pharmacological basis of TCM treating IMID and is helpful for supporting future pharmacologic-driven studies. Further research elucidates the immune-modulating mechanisms on Th17/Treg axis by TCM might provide a broader insight for the treatment of IMID. [ABSTRACT FROM AUTHOR]

Celiac disease is caused by an abnormal intestinal T cell response to cereal gluten proteins. The disease has a strong human leukocyte antigen (HLA) association, and CD4+ T cells recognizing gluten epitopes presented by disease-associated HLA-DQ allotypes are considered to be drivers of the disease. This paper provides an update of the currently known HLA-DQ restricted gluten T cell epitopes with their names and sequences. [ABSTRACT FROM AUTHOR]

In this paper, a mathematical model is formulated to investigate the dynamics of HIV infection. The model incorporates two routes of infection (namely cell-to-cell transmission and virus-to-cell infection), two types of adaptive immune responses (i.e., cellular and antibody immune response) and two intracellular delays (viz., the eclipse phase and virus production period). By constructing Lyapunov functionals, we show that the global dynamics of the model can be explicitly determined by five reproduction numbers. Using the uncertainty and sensitivity analyses, we obtain the mean values and standard deviation of the five reproduction numbers and find that the reproduction numbers are most sensitive to the death rate of infected cells, viral clearance rate and immune parameters. We further compare four related HIV models and show that cell-to-cell transmission, immune responses and time delays can substantially affect the dynamical behavior of the system. Specifically, cell-to-cell transmission increases the concentration of infected cells. Inclusion of cytotoxic T lymphocyte and virus production delay can significantly reduce the viral load and infected cell concentration, and generate a higher level of uninfected CD4+ T cells. The analytical and numerical results may help to improve the understanding of HIV dynamics. [ABSTRACT FROM AUTHOR]

Background: Cellular therapies using engineered T cells, haploidentical transplants, and autologous gene therapy are increasing. Specified CD3+ or high CD34+ doses are typically required for subsequent manufacturing, manipulation, or CD34+ selection. Simple, practical, and reliable lymphocyte and hematopoietic progenitor cell (HPC) collection algorithms accounting for subsequent CD34+ selection have not been published.Study Design and Methods: In this analysis of 15 haploidentical donors undergoing tandem lymphocyte and HPC collections, we validated one-step, practical prediction algorithms (Appendix S1, available as supporting information in the online version of this paper) that use conservative facility-specific collection efficiencies, CD34+ selection efficiency, and donor-specific peripheral counts to reliably achieve the target CD3+ and CD34+ product doses. These algorithms expand on our previously published work regarding predictive HPC collection algorithms.Results: Ninety-three percent of lymphocyte and 93% of CD34+ collections achieved the final target CD3+ and CD34+ product dose when our algorithm-calculated process volumes were used. Linear regression analysis of our algorithms for CD3+, preselection CD34+, and postselection CD34+ showed statistically significant models with R2 of 0.80 (root mean square error [RMSE], 31.3), 0.72 (RMSE, 385.7), and 0.56 (RMSE, 326.0), respectively, all with p values less than 0.001.Conclusion: Because achievement of CD3+ or CD34+ dose targets may be critical for safety and efficacy of cell therapies, these simple, practical, and reliable prediction algorithms for lymphocyte and HPC collections should be very useful for collection facilities. [ABSTRACT FROM AUTHOR]

Background and objectives: Administration of virus‐specific T cells (VSTs) is a viable antiviral treatment strategy after allogeneic HSCT, even if conventional therapies fail. Third‐party donors are often chosen for the generation of the VST product. The eligibility of the donor has to be tested in a rigorous donor screening procedure, since the isolation technology only targets pre‐existing VSTs. Materials and methods: In a period of 3 years, we performed 32 VST treatments for 28 patients. Targeting four different viruses, 284 healthy individuals underwent 417 donor screening procedures. VSTs were counted by flow cytometry detecting interferon‐gamma (IFN‐γ) producing T cells. Generation of the VSTs was performed from leukapheresis products in a fully automated and closed system using magnetic cell separation. Results: The mean circulating VST frequencies ranged from 0·006% to 0·328%. The average yield of viable VSTs in the product was 1·83·106 cells, while the average VST dose calculated for the patient's body weight was 4·63·104/kg. The mean purity – percentage of VSTs within the T cells – of all T‐cell products was 62·9%. Correlation was identified between the frequency of the VSTs in the peripheral blood of the donor and the VST numbers of the end product; the strongest correlation was seen for CMV. Conclusion: This paper focuses on the T‐cell donors, highlighting some key points on the donor selection process. Based on the findings in connection with the CMV therapies, peripheral VST seems to be the best predictor of the VST content of the final product administered to the patient. [ABSTRACT FROM AUTHOR]

Purpose: The human peroxiredoxin-5 (hPRDX5) is a member of the family of antioxidant enzymes, which could resist immunosuppression by promoting immune organs development, lymphocyte proliferation and up-regulation of the levels of serum cytokines. However, being a recombinant protein, the hPRDX5 exhibits some problems including the high production cost and bad tissue penetration. Compared to macromolecular therapeutic agents, synthetic peptides have several advantages as drug candidates, such as lower manufacturing costs, reduced immunogenicity, and better organ or tumor penetration. The purpose of this research was to design the novel peptides come from hPRDX5 that can block the interaction of PD-1 and PD-L1.Methods: Herein in this work, we firstly confirmed the inhibitory activity of hPRDX5 on the binding of PD-L1 to PD-1 based on the previous observation, subsequently, in silico proteolysis and rational design (such as alanine scanning mutagenesis and truncation) were used to automate the design of new peptides derived from hPRDX5 with anti-tumour activity.Results: We found that the most potent peptide could block the PD-1/PD-L1 interaction effectively with an IC50 of 0.646 μM, and could restore the function of Jurkat T cells which had been suppressed by stimulated HCT116 cells. Moreover, experiments with tumor-bearing mice models showed that the peptide IMB-P6-10 could effectively inhibit tumor growth and showed extraordinary low acute toxicity in vivo.Conclusions: The peptides described in this paper may provide novel low-molecular-weight drug candidates for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Recently approved by the FDA and European Medicines Agency, CAR-T cell therapy is a new treatment option for B-cell malignancies. Currently, CAR-T cells are manufactured in centralized facilities and face bottlenecks like complex scaling up, high costs, and logistic operations. These difficulties are mainly related to the use of viral vectors and the requirement to expand CAR-T cells to reach the therapeutic dose. In this paper, by using Sleeping Beauty-mediated genetic modification delivered by electroporation, we show that CAR-T cells can be generated and used without the need for ex vivo activation and expansion, consistent with a point-of-care (POC) approach. Our results show that minimally manipulated CAR-T cells are effective in vivo against RS4;11 leukemia cells engrafted in NSG mice even when inoculated after only 4 h of gene transfer. In an effort to better characterize the infused CAR-T cells, we show that 19BBz T lymphocytes infused after 24 h of electroporation (where CAR expression is already detectable) can improve the overall survival and reduce tumor burden in organs of mice engrafted with RS4;11 or Nalm-6 B cell leukemia. A side-by-side comparison of POC approach with a conventional 8-day expansion protocol using Transact beads demonstrated that both approaches have equivalent antitumor activity in vivo. Our data suggest that POC approach is a viable alternative for the generation and use of CAR-T cells, overcoming the limitations of current manufacturing protocols. Its use has the potential to expand CAR immunotherapy to a higher number of patients, especially in the context of low-income countries. [ABSTRACT FROM AUTHOR]

*: BackgroundGenetic instability is known to relate with carcinogenesis by providing tumors with a mechanism for fast adaptation. However, mounting evidence also indicates causal relation between genetic instability and improved cancer prognosis resulting from efficient immune response. Highly unstable tumors seem to accumulate mutational burdens that result in dynamical landscapes of neoantigen production, eventually inducing acute immune recognition. How are tumor instability and enhanced immune response related? An important step towards future developments involving combined therapies would benefit from unraveling this connection. *: MethodsIn this paper we present a minimal mathematical model to describe the ecological interactions that couple tumor adaptation and immune recognition while making use of available experimental estimates of relevant parameters. The possible evolutionary trade-offs associated to both cancer replication and T cell response are analysed, and the roles of mutational load and immune activation in governing prognosis are studied. *: ResultsModeling and available data indicate that cancer-clearance states become attainable when both mutational load and immune migration are enhanced. Furthermore, the model predicts the presence of well-defined transitions towards tumor control and eradication after increases in genetic instability numerically consistent with recent experiments of tumor control after Mismatch Repair knockout in mice. *: ConclusionsThese two main results indicate a potential role of genetic instability as a driver of transitions towards immune control of tumors, as well as the effectiveness of increasing mutational loads prior to adoptive cell therapies. This mathematical framework is therefore a quantitative step towards predicting the outcomes of combined therapies where genetic instability might play a key role. [ABSTRACT FROM AUTHOR]

Tumor immunotherapy using gene-modified T cells has already met with considerable success in the treatment of metastatic melanoma and B cell lymphoma. With improving patient prognoses, new questions arise. In particular, the long-term consequences of treatment among individuals of childbearing age could now be considered. Former patients can carry a cohort of transgenic memory T cells long after treatment has ceased and the effector T cell population has contracted. When patients become parents well after treatment is completed, expectant mothers may still pass transgenic T cells to their unborn children. Consequences should be more measurable if the mother also breastfeeds the baby. Maternal T cells may shape immune responses in the child, can tolerize the child to maternal antigens, and might cause either beneficial or adverse effects in the offspring. The hypothesis put forth is that transgenic T cells transferred from mother to child during and after pregnancy might have consequences that have not been adequately considered to date. Depending on the targeted antigen and the MHC eventually required to present it, such transfer may be beneficial, uneventful or even damaging. Such potential consequences are addressed in this paper. The transgenic T cells might form a pocket of memory T cells in secondary lymphoid organs of the child, expand upon antigen stimulation, and react. However, simple measures might be devised to avoid any reason for concern. These considerations provide ample incentive to probe transgenerational transfer of transgenic T cells. [ABSTRACT FROM AUTHOR]

Influenza A virus (IAV) is the major cause of seasonal epidemics and flu outbreaks worldwide. Given that interleukin 16 (IL16) can regulate T cell function and is one of the signature markers for virus infection including IAV infection, the impact of IL16 on IAVinduced T cell immune response hasn't been elucidated yet. In this paper, we infected wild type and IL16 knockout (KO) mice with IAV and analyzed the immunity of mice by flow cytometry. We observed an increase in the percentage of T helper (Th) 1 cells in the spleens of IL16 KO mice and elevation of IFN-α and TNF-α secretion from CD8+ T cells in the lungs and spleens of IL16 KO mice in response to IAV infection. Moreover, the expression of major histocompatibility complex II which represents the maturation of dendritic cells (DCs) was upregulated in the lungs of IL16 KO mice. Taken together, our study suggests that IL16 deficiency enhanced Th1 and cytotoxic T lymphocyte response as well as DC maturation upon IAV infection, which provides new insight into the host regulation of T cell immune responses during IAV infection. [ABSTRACT FROM AUTHOR]

Impaired regulation of immune function characterised by chronic inflammation together with a declining protective immune response is a major challenge to healthy ageing. It is therefore important to understand the mechanisms that regulate immune function and the impact of ageing upon such processes. Appropriate induction and resolution of the immune response require adequate availability of polyunsaturated fatty acids (PUFAs) for incorporation into cell membranes. However, humans are unable to synthesise PUFAs de novo and are dependent upon dietary intake for pre‐formed PUFAs or synthesis by the liver from the essential fatty acids, linoleic acid (LA, 18:2n‐6) and alpha‐linolenic acid (aLNA, 18:3n‐3). We have shown that activation of peripheral blood mononuclear cells increases PUFA biosynthesis from essential fatty acids via a mechanism that involves altered epigenetic regulation of a key gene in the pathway. Moreover, induction of PUFA synthesis is directly involved in the regulation of lymphocyte activation and proliferation. The aim of the Biotechnology and Biological Sciences Research Council responsive mode award described in this paper, 'How does polyunsaturated fatty acid biosynthesis regulate T‐lymphocyte function?', is to determine how PUFA biosynthesis regulates T‐cell function and the effect of ageing on this process. The project will identify points of regulation in the biosynthetic pathway and how these might influence the capacity for up‐regulation of PUFA synthesis in older individuals. We will use stable isotope tracers of LA and aLNA to determine whether newly synthesised PUFAs are preferential substrates for synthesis of lipid mediators and whether they are involved in formation of membrane microdomains that mediate cell signalling. [ABSTRACT FROM AUTHOR]

The role of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) in neurosurgical practice is a secondary one, however they are still constantly involved in perioperative management of pain or in nonoperative management of acute radiculopathy. Beside the well-known adverse reactions (ADRs), the neurosurgeon practitioner should also take in account the drug hypersensitivity reactions (DHRs) of NSAIDs and be able to deal with it. The aim of this paper was to review the diagnostic and management steps for NSAIDs-induced Hypersensitivity Reactions. The actual stratification of NSAIDs-induced Hypersensitivity Reactions is based on understanding of the heterogeneity of immunological/non-immunological mechanisms of reactions and complexity of clinical manifestations. Practically, this stratification allows the physician to assess suspicion of DHR, based on anamnesis and clinical analysis, and to consider further practical steps to manage and eventually confirm the diagnosis. Drug allergies are considered only the DHRs for which a definite immunological mechanism (either drug-specific antibody or T cell) is demonstrated. In conclusion, clinical analysis and anamnesis of patient with NSAIDs-induced Hypersensitivity Reactions can be realized by any physician and could be enough to diagnose, but it is not sufficient to confirm the diagnosis. In vitro tests and oral provocation challenges may be necessary to be undertaken by an allergy specialist. [ABSTRACT FROM AUTHOR]

Nocardia affects immunocompromised human host exhibiting an altered cell-mediated immunity. Infectious risk after allogeneic hematopoietic cell transplantation (AHCT) is significantly correlated to the recovery status of donor-derived immune system, especially CD4+ T-cells reconstitution and thymopoiesis. The purpose of this paper is to highlight a lack of cell-mediated immunity recovery for patients presenting a nocardiosis compared to a control cohort. This is a case control retrospective monocentric study. We retrospectively analyzed a monocentric cohort of 15 cases of nocardiosis after AHCT and we explored the degree of patients' immunosuppression by phenotyping circulating lymphoid subpopulations, including NK cells, CD8+ T-cells, CD4+ T-cells and CD19+ B-cells. We focused on CD4+ T-cell subsets to appreciate thymic output, especially on naive CD4+ T-cells (NTE, CD45RA+/RO− CD4+ T-cells) and recent thymic emigrants (RTE, CD4+CD45RA+/RO−/CD31+). Infected patients were paired with a control cohort of patients with identical transplantation characteristics screened on hematological disease, AHCT conditioning, primary graft- versus -host disease (GHVD) prophylaxis, graft type, sex, age, and season at the AHCT and data concerning immunological reconstitution were compared. At onset of nocardiosis, circulating lymphocytes and CD4+ T-cells means count were respectively 730/μL and 162/μL. CD8+ T-cells, CD56+ NK cells and CD19+ B-cells means count were respectively 362/μL, 160/μL, 112/μL. CD4+ T-cells subpopulations, naïve CD4+ T-cells production was impaired with NTE and RTE means count at 26/μL and 11/μL respectively. Comparison between nocardiosis cohort and control cohort over time highlight significant lower cellular count for lymphocytes, CD4+ T-cells, NTE and RTE with p = 0.001, p < 0.001, p < 0.001, p < 0.001 respectively. Immune recovery monitoring follow-up after AHCT is of particular importance to identify patients susceptible to develop Nocardiosis. Efficient microbiological investigations toward Nocardia such PCR should be used in case of compatible clinical presentation. [ABSTRACT FROM AUTHOR]

It has become anticipated that regenerative medicine will extend into the field of veterinary medicine as new treatments for various disorders. Although the use of allogeneic stem cells for tissue regeneration is more attractive than that of autologous cells in emergencies, the therapeutic potential of allogeneic transplantation is often limited by allo-immune responses inducing graft rejection. Therefore, a methodology for quantifying and monitoring alloreactive T cells is necessary for evaluating allo-immune responses. The mixed lymphocyte reaction (MLR) is widely used to evaluate T cell alloreactivity. In human, flow cytometric MLR with carboxyfluorescein diacetate succinimidyl ester has been established and used as a more useful assay than conventional MLR with radioisotope labeling. However, the available information about alloreactivity based on the differences of dog major histocompatibility complex (MHC) (dog leukocyte antigen, DLA) is quite limited in dog. In this paper, we describe our established flow cytometric MLR method that can quantify the T cell alloreactivity while distinguishing cell phenotypes in dog, and T cell alloreactivity among DLA-type matched pairs was significantly lower than DLA-mismatched pairs, suggesting that our developed flow cytometric MLR method is useful for quantifying T cell alloreactivity. In addition, we demonstrated the advantage of DLA homozygous cells as a donor (stimulator) for allogeneic transplantation. We also elucidated that the frequency of alloreactive T cell precursors was almost the same as that of mouse and human (1–10%). To our knowledge, this is the first report to focus on the degree of allo-immune responses in dog based on the differences of DLA polymorphisms. [ABSTRACT FROM AUTHOR]

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

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

Purpose: Major area of a die is consumed in memory components. Almost 60-70% of chip area is being consumed by "Memory Circuits". The dominant memory in this market is SRAM, even though the SRAM size is larger than embedded DRAM, as SRAM does not have yield issues and the cost is not high as compared to DRAM. At the same time, the other attractive feature for the SRAM is speed, and it can be used for low power applications. CMOS SRAM is the crucial component in microprocessor chips and applications, and as the said major portion of the area is dedicated to SRAM arrays, CMOS SRAM is considered to be the stack holders in the memory market. Because of the scaling feature of CMOS, SRAM had its hold in the market over the past few decades. In recent years, the limitations of the CMOS scaling have raised so many issues like short channel effects, threshold voltage variations. The increased thrust for alternative devices leads to FinFET. FinFET is emerging as one of the suitable alternatives for CMOS and in the region of memory circuits. Design/methodology/approach: In this paper, a new 11 T SRAM cell using FinFET technology has been proposed, the basic component of the cell is the 6 T SRAM cell with 4 NMOS access transistors to improve the stability and also makes it a dual port memory cell. The proposed cell uses a header scheme in which one extra PMOS transistor is used which is biased at different voltages to improve the read and write stability thus, helps in reducing the leakage power and active power. Findings: The cell shows improvement in RSNM (read static noise margin) with LP8T by 2.39× at sub-threshold voltage 2.68× with D6T SRAM cell, 5.5× with TG8T. The WSNM (write static noise margin) and HM (hold margin) of the SRAM cell at 0.9 V is 306 mV and 384 mV. It shows improvement at sub-threshold operation also. The leakage power is reduced by 0.125× with LP8T, 0.022× with D6T SRAM cell, TG8T and SE8T. The impact of process variation on cell stability is also discussed. Research limitations/implications: The FinFet has been used in place of CMOS even though the FinFet has been not been a matured technology; therefore, pdk files have been used. Practical implications: SRAM cell has been designed which has good stability and reduced leakage by which we can make an array and which can be used as SRAM array. Social implications: The cell can be used for SRAM memory for low power consumptions. Originality/value: The work has been done by implementing various leakage techniques to design a stable and improved SRAM cell. The advantage of this work is that the cell has been working for low voltage without degrading the stability factor. [ABSTRACT FROM AUTHOR]

In this paper, we construct a mathematical model to investigate the interaction between the tumor cells, the immune cells and the helper T cells (HTCs). We perform mathematical analysis to reveal the stability of the equilibria of the model. In our model, the HTCs are stimulated by the identification of the presence of tumor antigens. Our investigation implies that the presence of tumor antigens may inhibit the existence of high steady state of tumor cells, which leads to the elimination of the bistable behavior of the tumor-immune system, i.e. the equilibrium corresponding to the high steady state of tumor cells is destabilized. Choosing immune intensity c as bifurcation parameter, there exists saddle-node bifurcation. Besides, there exists a critical value c ∗ , at which a Hopf bifurcation occurs. The stability and direction of Hopf bifurcation are discussed. [ABSTRACT FROM AUTHOR]

Aim and Objective: HIV (Human Immunodeficiency Virus) has been reported to weaken the immune system by binding to CD4+ receptor of T lymphocytes, thereby making the affected individual to become more susceptible to several microbial infections leading to life threatening problems. Recent literature indicate there is promsing advancement in identifying drug targets through CD4+ receptor binding capabilities with its ligand. The main purpose of this paper was to study the various molecular interactions of HIV to other molecules like receptors CD4+ and also co-receptors like CCR5 and CXCR4. Materials and Required: The molecules are going to be modeled by using software known as Swiss PDB viewer. The first objective is to get the FASTA sequence from the NCBI website. Then we need to paste the sequence onto the Swiss PDB viewer. Conclusion: The requierd protein/molecule is modeled. We are going to follow this method to obtain templates and modles for the following molecukles: HIV, GP120, CCR5 and CXCR4. [ABSTRACT FROM AUTHOR]

In this paper, we proposed a multidelayed in‐host HIV model to represent the interaction between human immunodeficiency virus and immune response. One delay was considered to incorporate the time required by the virus for various intracellular events to make a host cell productively infective, and the second delay was introduced to take into account the time required for adaptive immune system to respond against infection. We extensively analyzed this multidelayed model analytically and numerically. We show that delay may have both destabilizing and stabilizing effects even when the system contains a single immune response delay. It happens when there exists two sequences of critical values of this delay. If the system starts with stable state in absence of delay, then the smallest value of these critical delays causes instability and the next higher value causes stability. The system may also show stability switching for different values of the virus replication factor. These results demonstrate the possible reasons of intrapatients and interpatients variability of CD4+ T cells and virus counts in HIV‐infected patients. [ABSTRACT FROM AUTHOR]

Objective: Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment for relapsed/refractory acute lymphoblastic leukemia (ALL) in pediatric oncology. However, little is known about the cognitive functioning of these patients. This study examines the neuropsychological functioning of pediatric patients referred for CAR T-cell therapy. Method: Data was obtained from a longitudinal observational study of CAR T-cell therapy patients (ages 1–30 years) at the Children's Hospital of Philadelphia. Neuropsychological data and neurotoxicity ratings were collected before and after CAR T-cell infusion, with brief cognitive testing at 28 days and 180 days post-infusion to assess acute changes. Cognitive testing included pencil-and-paper measures of intellectual functioning, attention, processing speed, and psychological functioning, as well as NIH Toolbox subtests. Results: Of 13 patients completing pre-infusion cognitive testing, 44% of patients scored below average (1 SD below the mean) on a timed visual-motor processing speed test. 20–25% of the sample scored below average on measures of executive functioning, attention/working memory, and expre0111111ssive vocabulary, exceeding what would be expected in a normal distribution. Fewer patients completed post-infusion assessments (n = 8, 28 days; n = 5, 6 months; n = 3, 1 year), with up to 50% scoring below average on the timed visual-motor processing speed test and 33% scoring below average on a measure of inhibitory control and selective attention after 1 year. Conclusions: Pediatric CAR T-cell therapy patients have high rates of cognitive dysfunction prior to receiving infusions, with evidence for increasing problems with timed visual-motor and executive functioning. Findings highlight the need to monitor pediatric CAR T-cell therapy patients throughout treatment. [ABSTRACT FROM AUTHOR]

Background: Synovitis is an inflammation-related disease linked to rheumatoid arthritis, osteoarthritis, infections and trauma. This inflammation is accompanied by immune cells infiltration which initiates an inflammatory response causing pain, discomfort and affecting the normal joint function. The treatment of synovitis is based on the administration of anti-inflammatory drugs or biological agents such as platelet rich plasma and mesenchymal stem cells. However, the evaluation and validation of more effective therapies of synovitis requires the establishment of clinically relevant animal models. Results: In this study, Large White pigs were pre-immunized to evaluate an antigen-induced synovitis. The immune monitoring of synovial fluids in this model allowed us the identification of IL-12p40 and T cell subsets as immune biomarkers. Moreover, the evolution of synovitis was performed by arthroscopic procedures and kinetic analysis. In summary, this paper describes an animal model of antigen-induced synovitis to be used in the evaluation of anti-inflammatory therapies. Conclusions: The novelty of this paper lies in the development of a clinically relevant model of synovitis which permits the simultaneous evaluation of synovitis from an immunological, surgical and kinetic point of view. [ABSTRACT FROM AUTHOR]

The field of regenerative medicine (RM) is championed as a potential source of curative treatments and economic wealth, and initiatives have been launched in several countries to facilitate innovation within the field. As a way of examining the social dimensions of innovation within regenerative medicine, this paper explores the sociotechnical representations of RM technologies in the UK, and the tensions, affordances and complexities these representations present for actors within the field. Specifically, the paper uses the Science and Technology Studies-inspired notions of ‘technology identity’ and ‘development space’ to examine how particular technologies are framed and positioned by actors, and how these positionings subsequently shape innovation pathways. Four developing RM technologies are used as case studies: bioengineered tracheas; autologous chondrocyte implantation; T-cell therapies; and a ‘point-of-care’ cell preparation device. Using these case studies we argue that there are particular identity aspects that have powerful performative effects and provide momentum to innovation projects, and we argue that there are particular stakeholders in the UK RM landscape who appear to have considerable power in shaping these technology identities and thus innovation pathways. [ABSTRACT FROM AUTHOR]

In the first of two papers we described the development in the field of allergy mechanisms as described by Clinical and Experimental Allergy in 2015. Experimental models of allergic disease, basic mechanisms, clinical mechanisms and allergens are all covered. A second paper will cover clinical aspects. [ABSTRACT FROM AUTHOR]

Neurodegeneration is a pathological condition that predominantly affects neurons. It represents a large spectrum of disorders with heterogeneous symptoms and distinct clinical features. In addition to the devastating effects it can have on the affected individual, it constitutes a heavy burden to the society in terms of health care costs. Although the exact cause of neurodegeneration is not known, there are plenty of evidences supporting the notion that the immune system is strongly associated with various forms of neurodegenerative diseases. Given the numerous functions of immune cells, a change in their expression can either be beneficial or deleterious to the host. A better understanding of the molecular and cellular processes in neurodegeneration is therefore needed. This could facilitate the development of new therapeutic targets and provide effective means to dampen the progression of neurodegenerative disorders. The overarching aim of this paper is to provide an overview of the roles that the innate and adaptive immune systems play in the central nervous system, and to discuss their beneficial or detrimental effects during neurodegeneration. This paper also critically examines the contribution of immune and inflammatory-mediated responses in the development of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyloid lateral sclerosis by illustrating key findings from animal and human studies. [ABSTRACT FROM AUTHOR]

The human adaptive immune response is known to weaken in advanced age, resulting in increased severity of pathogen-born illness, poor vaccine efficacy, and a higher prevalence of cancer in the elderly. Age-related erosion of the T cell compartment has been implicated as a likely cause, but the underlying mechanisms driving this immunosenescence have not been quantitatively modeled and systematically analyzed. T cell receptor diversity, or the extent of pathogen-derived antigen responsiveness of the T cell pool, is known to diminish with age, but inherent experimental difficulties preclude accurate analysis on the full organismal level. In this paper, we formulate a mechanistic mathematical model of T cell population dynamics on the immunoclonal subpopulation level, which provides quantitative estimates of diversity. We define different estimates for diversity that depend on the individual number of cells in a specific immunoclone. We show that diversity decreases with age primarily due to diminished thymic output of new T cells and the resulting overall loss of small immunoclones. [ABSTRACT FROM AUTHOR]

Many mRNA-based vaccines have been investigated for their specific potential to activate dendritic cells (DCs), the highly-specialized antigen-presenting cells of the immune system that play a key role in inducing effective CD4+ and CD8+ T-cell responses. In this paper we report a new vaccine/gene delivery platform that demonstrates the benefits of using a self-amplifying (“replicon”) mRNA that is protected in a viral-protein capsid. Purified capsid protein from the plant virus Cowpea Chlorotic Mottle Virus (CCMV) is used to in vitro assemble monodisperse virus-like particles (VLPs) containing reporter proteins (e.g., Luciferase or eYFP) or the tandem-repeat model antigen SIINFEKL in RNA gene form, coupled to the RNA-dependent RNA polymerase from the Nodamura insect virus. Incubation of immature DCs with these VLPs results in increased activation of maturation markers – CD80, CD86 and MHC-II – and enhanced RNA replication levels, relative to incubation with unpackaged replicon mRNA. Higher RNA uptake/replication and enhanced DC activation were detected in a dose-dependent manner when the CCMV-VLPs were pre-incubated with anti-CCMV antibodies. In all experiments the expression of maturation markers correlates with the RNA levels of the DCs. Overall, these studies demonstrate that: VLP protection enhances mRNA uptake by DCs; coupling replicons to the gene of interest increases RNA and protein levels in the cell; and the presence of anti-VLP antibodies enhances mRNA levels and activation of DCs in vitro. Finally, preliminary in vivo experiments involving mouse vaccinations with SIINFEKL-replicon VLPs indicate a small but significant increase in antigen-specific T cells that are doubly positive for IFN and TFN induction. [ABSTRACT FROM AUTHOR]

Experimentally accessible tools to replicate the complex biological events of in vivo organs offer the potential to reveal mechanisms of disease and potential routes to therapy. In particular, models of inter-organ communication are emerging as the next essential step towards creating a body-on-a-chip, and may be particularly useful for poorly understood processes such as tumor immunity. In this paper, we report the first multi-compartment microfluidic chip that continuously recirculates a small volume of media through two ex vivo tissue samples to support inter-organ cross-talk via secreted factors. To test on-chip communication, protein release and capture were quantified using well-defined artificial tissue samples and model proteins. Proteins released by one sample were transferred to the downstream reservoir and detectable in the downstream sample. Next, the chip was applied to model the communication between a tumor and a lymph node, to test whether on-chip dual-organ culture could recreate key features of tumor-induced immune suppression. Slices of murine lymph node were co-cultured with tumor or healthy tissue on-chip with recirculating media, then tested for their ability to respond to T cell stimulation. Interestingly, lymph node slices co-cultured with tumor slices appeared more immunosuppressed than those co-cultured with healthy tissue, suggesting that the chip may successfully model some features of tumor-immune interaction. In conclusion, this new microfluidic system provides on-chip co-culture of pairs of tissue slices under continuous recirculating flow, and has the potential to model complex inter-organ communication ex vivo with full experimental accessibility of the tissues and their media. [ABSTRACT FROM AUTHOR]