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The signal transduction of human programmed death ligand 1 (PD-L1), as an important checkpoint gene in the immune system, plays a key role in the internal function and survival of cancer cells. In this paper, PD-L1-siRNA and immunostimulatory IL-2 encoding plasmid DNA loaded by polyethylenimine (PEI) lipid nanoparticles (PEI-LNPs) were constructed. Its therapeutic effect on lung cancer was evaluated, and its physical parameters such as particle size and potential were measured. The binding capacity, cytotoxicity, apoptosis, and cell uptake capacity of PD-L1-siRNA/IL-2 DNA-PEI-LNPs were tested by in vitro experiments. The down-regulation effect of PD-L1 in A549 cancer cells and the cytokine level of co-cultured T cells were also examined. The study indicated that the PD-L1-siRNA/IL-2-PEI-LNP complexes can provide effective treatment for lung cancer cells; the significant increase in IFN-γ and TNF-α levels and the decrease in the IL-10 level confirmed the change in secreted cytokines. The lipid NPs combined with the tumor-targeting therapeutic gene siRNA/pDNA constructed in this study had the ability to target cells in vitro and down-regulate the expression of PD-L1, which realized the tumor-specific expression of immunostimulatory cytokines, and were considered to be highly effective and safe nanocarriers for targeted therapy. [ABSTRACT FROM AUTHOR]

Blinatumomab is the first in its class bispecific T-cell engager monoclonal antibody, which binds to CD19 expressed on B-cells and CD3 expressed on T-cells, resulting in lysis of CD19-positive cells common in B-cell malignancies. Blinatumomab is Food and Drug Administration (FDA) approved for the treatment of adults and children with relapsed/refractory or minimal residual disease (MRD) positive precursor B-cell ALL (B-ALL). Despite impressive efficacy for the approved indications and favorable toxicity profile compared to standard-of-care chemotherapy, blinatumomab presents unique health-system challenges related to preparation, administration, toxicity monitoring and medication error prevention. Blinatumomab delivery also offers plethora of opportunities for interdisciplinary planning and collaboration. The purpose of this paper is to discuss practical considerations for safe blinatumomab delivery from the pharmacy and nursing perspectives. [ABSTRACT FROM AUTHOR]

• We first described the S.maltophilia immunosuppressive effect on T cells and it is meaningful for immunosuppressed patients or co-infections. • T cells stimulated by S.maltophilia with CD4 and CD8 degraded via PD-1/PD-L1 pathway, which led to the massive apoptosis of T cells. • T cells were stimulated by S. maltophilia to secrete IFN-γ. Blocking the PD-1/PD-L1 pathway, apoptosis was suppressed. • S.maltophilia down-regulates host immunity by inhibiting immune cells. Smalotrophomonas maltophilia (S. maltophilia) is common in nosocomial infections. However, few studies have revealed the effect of S. maltophilia on cellular immunity in the host's immune system up to now. In clinical work, we accidentally discovered that S. maltophilia directly stimulated T cells to secrete IFN-γ. S. maltophilia was co-cultured with PBMCs to detect secretion of cytokines (IFN-γ, TNF-α and IL-2) and expression of cell surface molecules (CD3, CD4, CD8, CD69, CD147 and CD152) of T cells. We used light microscopy and electron microscopy to observe the cell morphology and subcellular structure of S. maltophilia co-cultured with lymphocytes. Flow cytometry and Western Blot were used to detect the expression of PD-1/PD-L1 and annexin V in cells. T cells stimulated by S. maltophilia secreted a large amount of IL-2, IFN-γ, and TNF-α. The expression of CD4 and CD8 on the cell surface were declined, accompanied by the activation of the PD-1/PD-L1 pathway, which eventually led to the massive apoptosis of T cells. Electron microscopy showed that cells showed significant apoptotic morphology. Blocking the PD-1/PD-L1 pathway can inhibit the apoptosis-inducing effect of S. maltophilia on T cells. These indicates that T cells are inhibited after being stimulated by S. maltophilia , and then accelerated to induce death without the initiation of an immunologic cascade. This paper demonstrates for the first time the inhibitory effect of S. maltophilia on cellular immunity, and the immunosuppressive effect induced by infection of S. maltophilia should be considered. [ABSTRACT FROM AUTHOR]

The paper deals with the finite element modeling and simulation of lab‐on‐a‐chip microfluidic device that is used for counting leukocytes in blood samples. Some aspects regarding the state of the art of lab‐on‐a‐chip devices are presented. These microfluidic devices offer the possibility to perform certain determinations, as it is the case of T lymphocytes, which are impossible by current conventional equipment. Comsol multiphysics and stationary laminar flow module are used for finite element modeling and simulating of device working, and for its geometric optimization. The velocities and the required travel time of the blood sample combined with the lysing and stop lysing substances, within two dedicated circuits are determined. These are formed by multiple coils, two counting channels for two cell types and a cells capture chamber. Then, the execution specifications of the lab‐on‐a‐chip on a millimetric silicon wafer are delivered, by microtechnologies, the modelling results being validated. [ABSTRACT FROM AUTHOR]

[Objectives] The paper was to observe the effects of red ginseng aqueous extract on immune function of mice. [Methods] The aqueous extract of red ginseng was obtained by water extraction and concentration, and 10 mL of aqueous extract was equivalent to 2.86 g of raw materials. Total 240 mice were randomly divided into blank control group, low dose, medium dose and high dose groups of red ginseng aqueous extract, 60 mice each group. Mice in low dose, medium dose and high dose groups were intragastrically administered with 0.24, 0.48, 1.43 g/kg red ginseng aqueous extract once a day respectively, and those in blank control group were intragastrically administered with equal volume of deionized water at the dose of 0.1 ml/10 g once a day for consecutive 30 d. The immunoregulation effects of red ginseng aqueous extract on mice were explored by organ/body weight ratio measurement, delayed type hypersensitivity (DTH) reaction, Con A-induced spleen T lymphocyte transformation test, antibody-producing cells test, half hemolytic value (HC50) test, carbon particle clearance test, phagocytosis test of chicken red blood cells by macrophages and NK cell activity test. [Results] Compared with the blank control group, the degree of toe swelling in low dose group and medium dose group of red ginseng aqueous extract [ (0.62 ± 0.14) mm, (0.53 ± 0.12) mm vs. (0.36 ± 0.10) mm] significantly increased (P<0.05). The ability of T lymphocytes proliferation (0.173 ± 0.054, 0.189 ± 0.063 vs. 0.098 ± 0.012) in low dose group and high dose group significantly increased (P <0.05). The number of haemolytic plaque (137.49 x 10³ ±24.73 x 10³ 148.43 x 10³ ±27.53 x 10³ vs. 112. 96 x 10³ ± 26. 28 x 10³) in medium dose group and high dose group significantly increased (P <0.05). The phagocytosis rate (35.67% ±3.82%, 49.26% ± 6.54%, 57.92% ± 7.36% vs. 24.34% ± 4.22%) and phagocytosis index (0.72 ± 0. 23, 0. 82 ± 0. 15, 0. 91 ± 0. 26 vs. 0. 35 ± 0.11) of low dose, medium dose, high dose groups significantly increased (P <0.05). However, there was no statistical difference in spleen/body weight ratio, thymus/body weight ratio, half hemolytic value, carbon particle clearance and NK cell activity. [Conclusions] Red ginseng aqueous extract could enhance the immunity of mice [ABSTRACT FROM AUTHOR]

Newborn screening efforts focusing on the quantification of T cell receptor excision circles (TRECs), as a biomarker for abnormal thymic production of T cells, have allowed for the identification and definitive treatment of severe combined immunodeficiency (SCID) in asymptomatic neonates. With the adoption of TREC quantification in Guthrie cards across the USA and abroad, typical, and atypical SCID constitutes only ~ 10% of cases identified with abnormal TRECs associated with T cell lymphopenia. Several other non-SCID-related conditions may be identified by newborn screening in a term infant. Thus, it is important for physicians to recognize that other factors, such as prematurity, are often associated with low TRECs initially, but often improve with age. This paper focuses on a challenge that immunologists face: the diagnostic evaluation and management of cases in which abnormal TRECs are associated with variants of T cell lymphopenia in the absence of a genetically defined form of typical or atypical SCID. Various syndromes associated with T cell impairment, secondary forms of T cell lymphopenia, and idiopathic T cell lymphopenia are identified using this screening approach. Yet there is no consensus or guidelines to assist in the evaluation and management of these newborns, despite representing 90% of the patients identified, resulting in significant work for the clinical teams until a diagnosis is made. Using a case-based approach, we review pearls relevant to the evaluation of these newborns, as well as the management dilemmas for the families and team related to the resolution of genetic ambiguities. [ABSTRACT FROM AUTHOR]

With the success of immunosuppressive checkpoint in tumor therapy, the corresponding adverse response and drug resistance defects have been exposed. T cells and NK cells are the body's immune system of the two substantial main forces. in recent years, study of T cell checkpoints appeared a certain block, such as PD-1 the effect not benign, on the distribution of NK cell surface excitatory and inhibitory receptors under normal conditions to maintain steady, could be targeted in the tumor treatment blockade have therapeutic effect. This paper reviews the function of NK cells and the effects of corresponding receptors in various types of tumors, providing a direction for the selection of appropriate gate control sites for future treatment. [ABSTRACT FROM AUTHOR]

Early embryonic exogenous feeding of bioactive substances is a topic of interest in poultry production, potentially improving gastrointestinal tract (GIT) development, stimulating immunization, and maximizing the protection capability of newly hatched chicks. However, the biophysiological actions and effects of in ovo administered bioactive substances are inconsistent or not fully understood. Thus, this paper summarizes the functional effects of bioactive substances and their interaction merits to augment GIT development, the immune system, and microbial homeostasis in newly hatched chicks. Prebiotics, probiotics, and synbiotics are potential bioactive substances that have been administered in embryonic eggs. Their biological effects are enhanced by a variety of mechanisms, including the production of antimicrobial peptides and antibiotic responses, regulation of T lymphocyte numbers and immune-related genes in either up- or downregulation fashion, and enhancement of macrophage phagocytic capacity. These actions occur directly through the interaction with immune cell receptors, stimulation of endocytosis, and phagocytosis. The underlying mechanisms of bioactive substance activity are multifaceted, enhancing GIT development, and improving both the innate and adaptive immune systems. Thus summarizing these modes of action of prebiotics, probiotics and synbiotics can result in more informed decisions and also provides baseline for further research. [ABSTRACT FROM AUTHOR]

Background: Understanding the T cell response to SARS-CoV-2 is critical to vaccine development, epidemiological surveillance and disease control strategies. This systematic review critically evaluates and synthesises the relevant peer-reviewed and pre-print literature published from 01/01/2020-26/06/2020. Methods: For this systematic review, keyword-structured literature searches were carried out in MEDLINE, Embase and COVID-19 Primer. Papers were independently screened by two researchers, with arbitration of disagreements by a third researcher. Data were independently extracted into a pre-designed Excel template and studies critically appraised using a modified version of the MetaQAT tool, with resolution of disagreements by consensus. Findings were narratively synthesised. Results: 61 articles were included. 55 (90%) studies used observational designs, 50 (82%) involved hospitalised patients with higher acuity illness, and the majority had important limitations. Symptomatic adult COVID-19 cases consistently show peripheral T cell lymphopenia, which positively correlates with increased disease severity, duration of RNA positivity, and non-survival; while asymptomatic and paediatric cases display preserved counts. People with severe or critical disease generally develop more robust, virus-specific T cell responses. T cell memory and effector function has been demonstrated against multiple viral epitopes, and, cross-reactive T cell responses have been demonstrated in unexposed and uninfected adults, but the significance for protection and susceptibility, respectively, remains unclear. Conclusion: A complex pattern of T cell response to SARS-CoV-2 infection has been demonstrated, but inferences regarding population level immunity are hampered by significant methodological limitations and heterogeneity between studies, as well as a striking lack of research in asymptomatic or pauci-symptomatic individuals. In contrast to antibody responses, population-level surveillance of the T cell response is unlikely to be feasible in the near term. Focused evaluation in specific sub-groups, including vaccine recipients, should be prioritised. [ABSTRACT FROM AUTHOR]

The partial success of tumor immunotherapy induced by checkpoint blockade, which is not antigen-specific, suggests that the immune system of some patients contain antigen receptors able to specifically identify tumor cells. Here we focused on T-cell receptor (TCR) repertoires associated with spontaneous breast cancer. We studied the alpha and beta chain CDR3 domains of TCR repertoires of CD4 T cells using deep sequencing of cell populations in mice and applied the results to published TCR sequence data obtained from human patients. We screened peripheral blood T cells obtained monthly from individual mice spontaneously developing breast tumors by 5 months. We then looked at identical TCR sequences in published human studies; we used TCGA data from tumors and healthy tissues of 1,256 breast cancer resections and from 4 focused studies including sequences from tumors, lymph nodes, blood and healthy tissues, and from single cell dataset of 3 breast cancer subjects. We now report that mice spontaneously developing breast cancer manifest shared, Public CDR3 regions in both their alpha and beta and that a significant number of women with early breast cancer manifest identical CDR3 sequences. These findings suggest that the development of breast cancer is associated, across species, with biomarker, exclusive TCR repertoires. Author summary: More than 1,100 cancer treatments are currently in clinical testing. Of these, 295 are immune-oncology medicines and vaccines. For Checkpoint Immunotherapy alone, 52,539 patients were enrolled in 2017. Of these treatments, 108 are for breast cancer, the leading cancer diagnosed in women. Although checkpoint immunotherapy has yet to be proven beneficial in most types of breast cancer, current observations of which specific T cell go into the tumor, and how these cells are connected to the response to treatment, have lead to a new understating of the role of the immune system. Yet, and in spite of this intense research into the role of T cells in tumors, very little is known about how clones of T cells behave during tumor formation. The paper we present here studies this clonal behavior over time. We study it during mammary tumor development in mice. We see that a set of T cell clones, which comes from a diversity of different nucleotide sequences, stands out in its behavior compared with other T cell clones. Importantly, we show that these mouse T cell clones have a strong connection to human breast cancer. The specific identification of a subset of T cell clones, together with the behavior of these clones over time, is critical to our understanding of the effect of modifications to the immune system, such as the modifications made by immunotherapy treatments, and to our understanding of how to better control the behavior of the immune system. [ABSTRACT FROM AUTHOR]

Immune repertoires provide a unique fingerprint reflecting the immune history of individuals, with potential applications in precision medicine. However, the question of how personal that information is and how it can be used to identify individuals has not been explored. Here, we show that individuals can be uniquely identified from repertoires of just a few thousands lymphocytes. We present "Immprint," a classifier using an information-theoretic measure of repertoire similarity to distinguish pairs of repertoire samples coming from the same versus different individuals. Using published T-cell receptor repertoires and statistical modeling, we tested its ability to identify individuals with great accuracy, including identical twins, by computing false positive and false negative rates < 10−6 from samples composed of 10,000 T-cells. We verified through longitudinal datasets that the method is robust to acute infections and that the immune fingerprint is stable for at least three years. These results emphasize the private and personal nature of repertoire data. Author summary: Immune repertoires are a trove of personal information: unique to each individual, they are also windows into their past and future health. Thanks to their potential for personalized medicine and progress of sequencing technologies, these repertoires are now routinely sequenced. As a consequence they raise the question of identifiability of samples. In this paper, we estimate the quantity of immune cells needed to associate two samples from the same individual: as little as a finger prick worth of blood can serve as an immune fingerprint that can distinguish even identical twins, without giving away genetic information about non-consenting relatives. We show that this fingerprint is stable through time, and is not erased during infections or vaccinations. [ABSTRACT FROM AUTHOR]

Objective and design: This systematic review aims to establish the role of CD8 + T lymphocytes in COPD. Methods: Forty-eight papers published in the last 15 years were identified for inclusion. Results: CD8 + T-cells are increased in the lungs of patients with COPD (17 studies, 16 positive) whereas in the circulation, findings were inconclusive. Activation of CD8 + T-cells was enhanced in lungs (four studies, three positive) but cell phenotype was unclear. There was substantial evidence of a higher proportion of type 1 CD8 + (Tc1) cells in COPD (11 studies, 9 positive), though the population of type 2 (Tc2) cells was also increased (5 studies, 4 positive). CD8 + T-cells in COPD exhibited greater expression of cytotoxic proteins (five studies, five positive). Studies assessed a variety of questions so evidence was insufficient to draw firm conclusions. The role of CD8 + T-cells at acute exacerbation of COPD and also their contribution to alveolar destruction can only be hypothesised at this stage. Conclusions: Not only is the number of CD8 + T-cells increased in COPD, these cells have increased capacity to exert effector functions and are likely to contribute to disease pathogenesis. Several mechanisms highlighted show promise for future investigation to consolidate current knowledge. [ABSTRACT FROM AUTHOR]

Background In October 2015, 65 people came into direct contact with a healthcare worker presenting with a late reactivation of Ebola virus disease (EVD) in the United Kingdom. Vaccination was offered to 45 individuals with an initial assessment of high exposure risk. Methods Approval for rapid expanded access to the recombinant vesicular stomatitis virus–Zaire Ebola virus (rVSV-ZEBOV) vaccine as an unlicensed emergency medicine was obtained from the relevant authorities. An observational follow-up study was carried out for 1 year following vaccination. Results Twenty-six of 45 individuals elected to receive vaccination between 10 and 11 October 2015 following written informed consent. By day 14, 39% had seroconverted, increasing to 87% by day 28 and 100% by 3 months, although these responses were not always sustained. Neutralizing antibody responses were detectable in 36% by day 14 and 73% at 12 months. Common side effects included fatigue, myalgia, headache, arthralgia, and fever. These were positively associated with glycoprotein-specific T-cell but not immunoglobulin (Ig) M or IgG antibody responses. No severe vaccine-related adverse events were reported. No one exposed to the virus became infected. Conclusions This paper reports the use of the rVSV-ZEBOV vaccine given as an emergency intervention to individuals exposed to a patient presenting with a late reactivation of EVD. The vaccine was relatively well tolerated, but a high percentage developed a fever ≥37.5°C, necessitating urgent screening for Ebola virus, and a small number developed persistent arthralgia. [ABSTRACT FROM AUTHOR]

Evaluation of the frequency of chromosome translocations in peripheral blood T-lymphocytes is a generally accepted method of retrospective biodosimetry. Accidental contamination of the Techa River (Chelyabinsk Oblast) in 1950s with bone-seeking long-lived strontium-90 gave an opportunity to evaluate the effect of local red bone marrow (RBM) exposure on translocation formation in the peripheral T-lymphocytes of local inhabitants. The studies of the inhabitants using fluorescent in situ hybridization (FISH) showed that RBM doses calculated based on FISH results were lower than those estimated based on 90Sr body burden measurements. The current study presents analytical review of the published data dealing with the most important processes of the T-lymphocyte development and formation of chromosome aberrations: characteristics of the main compartments where the exposure of T-cell occurs; assessment of the time spent by T-lymphocytes and their progenitors in these compartments; analysis of the dynamics of T-cell populations (proliferation and death); age-related aspects. The paper presents a concept of T-cell Genus (TG) united all the progeny of T progenitor with inheritable specific aberrations that could have developed in bone marrow. [ABSTRACT FROM AUTHOR]

Summary: Prolonged cytopenia after CAR‐T cell therapy is an acknowledged problem. At present, the causes and implications of prolonged cytopenia are unclear. The paper by Kitamura et al identified that prolonged cytopenia is associated with alterations in the bone marrow niche identified before CAR‐T therapy, indicating a potential predictor of this serious side‐effect of treatment. Commentary on: Kitamura et al. Bone marrow microenvironment disruption and sustained inflammation with prolonged haematologic toxicity after CAR T‐cell therapy? Br J Haematol 2023;202:294‐307. [ABSTRACT FROM AUTHOR]

Kaempferol (kae) and its glycosides are widely distributed in nature and show multiple bioactivities, yet few reports have compared them. In this paper, we report the antitumor, antioxidant and anti-inflammatory activity differences of kae, kae-7-O-glucoside (kae-7-O-glu), kae-3-O-rhamnoside (kae-3-O-rha) and kae-3-O-rutinoside (kae-3-O-rut). Kae showed the highest antiproliferation effect on the human hepatoma cell line HepG2, mouse colon cancer cell line CT26 and mouse melanoma cell line B16F1. Kae also significantly inhibited AKT phosphorylation and cleaved caspase-9, caspase-7, caspase-3 and PARP in HepG2 cells. A kae-induced increase in DPPH and ABTS radical scavenging activity, inhibition of concanavalin A (Con A)-induced activation of T cell proliferation and NO or ROS production in LPS-induced RAW 264.7 macrophage cells were also seen. Kae glycosides were used to produce kae via environment-friendly enzymatic hydrolysis. Kae-7-O-glu and kae-3-O-rut were hydrolyzed to kae by β-glucosidase and/or α-L-rhamnosidase. This paper demonstrates the application of enzymatic catalysis to obtain highly biologically active kae. This work provides a novel and efficient preparation of high-value flavone-related products. [ABSTRACT FROM AUTHOR]

In this paper, the Pseudospectral Legendre (PL) method is presented to approximate the solution of the HIV infection model of CD4+T cells. The method is based on the Lagrangian interpo- lation and the zeros of Legendre polynomial. Using the proposed method, the given system of three differential equations is converted into a system of algebraic equations. By solving the system of the algebraic equations, the unknown coefficients are computed and then the approximate solutions are obtained. The main aim of this paper is to demonstrate the PL method, and a comparison is made with the existing methods in the literature. [ABSTRACT FROM AUTHOR]

This paper presents a comprehensive methodology to characterize the mission profile of photovoltaic systems, through which a powerful set of relevant information may be obtained and used in order to improve the design of power converters. Characterizing a photovoltaic system accurately is not trivial and this paper aims to present a detailed methodology on how to obtain a PV real field mission profile. Three cities with different climate were considered and a large dataset of four variables was used: global horizontal, direct, and diffuse irradiances and ambient temperature. Data were measured at one-minute intervals over multiple years. For each location, four scenarios of panel orientation were analyzed: horizontal position, fixed tilt, 1-axis and 2-axis mechanical tracker. A mathematical model to estimate instantaneous in-plane irradiance based on measured data and mounting type was used. An average profile of solar energy and ambient temperature for each city were built; these profiles were used as input for estimation of annual energy yield of a commercial photovoltaic panel, which was mathematically modeled and validated. Current and power processing throughout a year in a one-minute resolution were investigated, along with the most frequent and most significant operating points in each scenario. Panel operating temperature related to ambient conditions and its relation to energy yield were also studied. Finally, a comprehensive discussion to understand how different mission profiles affect power processing of photovoltaic power converters and the way this characterization can aid in pre-sizing and lifetime analysis of power electronics is presented. [ABSTRACT FROM AUTHOR]

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]

Presents a list of forthcoming articles to be published in the "European Journal of Biochemistry". Functional and structural analysis of photosystem II core complexes from spinach with high oxygen evolution capacity; Immunosuppressive activity of bovine seminal RNase on T-cell proliferation; Fate of interleukin-6 in the rat; DNA sequence of a citrate carrier of Klebsiella pneumoniae.

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]