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In this paper, we derive a delayed epidemic model to describe the characterization of cytotoxic T lymphocyte (CTL)-mediated immune response against virus infection. The stability of equilibria and the existence of Hopf bifurcation are analysed. Theoretical results reveal that if the basic reproductive number is greater than 1, the positive equilibrium may lose its stability and the bifurcated periodic solution occurs when time delay is taken as the bifurcation parameter. Furthermore, we investigate an optimal control problem according to the delayed model based on the available therapy for hepatitis B infection. With the aim of minimizing the infected cells and viral load with consideration for the treatment costs, the optimal solution is discussed analytically. For the case when periodic solution occurs, numerical simulations are performed to suggest the optimal therapeutic strategy and compare the model-predicted consequences. [ABSTRACT FROM AUTHOR]

In this paper, a delayed human immunodeficiency virus (HIV) model with apoptosis of cells has been studied. Both immunological and intracellular delay have been incorporated to make the model more relevant. Firstly, the model has been investigated using local stability analysis. Next, the global stability analysis of steady states has been performed. The stability switch criteria taking the delay as the bifurcating parameter, leading to Hopf bifurcation has been studied. The transition of the system from order to chaos has been explored, and the analytical results have been verified by numerical simulations. The results thus can be used to describe the extensive dynamics exhibited by the model introduced in this article. The effects of apoptosis on viral load has been studied in the model numerically. [ABSTRACT FROM AUTHOR]

In this paper, the dynamical behaviours for a five-dimensional virus infection model with three delays which describes the interactions of antibody, cytotoxic T-lymphocyte (CTL) immune responses and Beddington-DeAngelis incidence are investigated. The reproduction numbers for virus infection, antibody immune response, CTL immune response, CTL immune competition and antibody immune competition, respectively, are calculated. By using the Lyapunov functionals and linearization method, the threshold conditions on the local and global stability of the equilibria for infection-free, immune-free, antibody response, CTL response and interior, respectively, are established. The existence of Hopf bifurcation with immune delay as a bifurcation parameter is investigated by using the bifurcation theory. Numerical simulations are presented to justify the analytical results. [ABSTRACT FROM AUTHOR]

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

Background: This paper aimed to verify how a supplementation of rower's diet with Astragalus Membranaceus Root (AMR) modulated their immune system response to maximal physical exertion. Methods: The double-blind study included 18 members of the Polish Rowing Team assigned to the supplemented group (n = 10), and the placebo group (n = 8). The participants performed a 2000 m test on a rowing ergometer at the beginning and at the end of the six-week of intensive training camp during which the supplemented group received 500 mg of AMR. Blood samples were obtained prior to, 1 min after completing, and 24 h after the exertion test. The levels of interleukin 2 (IL2), interleukin 4 (IL4), interleukin 10 (IL10), interferon ɤ (IFN-ɣ), and lactic acid were determined. Subpopulations of T regulatory lymphocytes [CD4+/CD25+/CD127−] (Treg), cytotoxic lymphocytes [CD8+/TCRαβ+] (CTL), natural killer cells [CD3−/CD16+/CD56+] (NK), and TCRδγ-positive cells (Tδγ) were determined with flow cytometry. Results: After the camp, the initial NK and Treg levels sustained at the baseline, while Tδγ counts increased relative to the levels in the placebo group. In the supplemented subgroup, a decrease in IL2 level in reaction to maximal exertion clearly deepened while the change in IL-2/IL-10 level induced by the recovery after this exertion clearly increased, relative to the changes in the placebo group. Conclusions: AMR restored the immunological balance in strenuously trained athlets through a stabilization of NK and Treg cells with a positive trend in Tδγ towards Th1 response during restitution by cytokine IL2 modulation. [ABSTRACT FROM AUTHOR]

Cytokines play an important role in immunological responses and protection against Brucella spp. infection. This article gives an overview of the role of various cytokines involved in the outcome of brucellosis. The susceptibility or resistance to the Brucella infection relies on a finely regulated balance of cytokines rhythmically produced by distinct T cell subsets (Th1 and Th2). The Th1 cytokines (e.g. TNF-α, IFN-γ) induce the CD8+ CTL-mediated cytotoxicity against Brucella-infected Mφ (specific cellular immunity), whereas, the Th2 response (e.g. IL-10) activates B lymphocytes for antibody production, facilitating the opsonization of Brucella (specific humoral immunity). This paper further analyses the information available on the assessment of cytokine profiles underscoring the requirement of more research on the cytokine biomarkers and their rhythmic induction in brucellosis, which may be helpful in establishing quick diagnostic tests as well as developing vaccines against brucellosis. Abbreviations: Th: T helper; TNF-α: Tumour necrosis factor-alpha; IFN-γ: Interferon-gamma; CD: Cluster of differentiation; CTL: Cytotoxic T lymphocyte; Mφ: Macrophage; IL: Interleukin [ABSTRACT FROM AUTHOR]

Recently, microneedle arrays (MAs) have been developed for painless inoculation of vaccines and possess many prominent advantages, including convenience for inoculation, and exact delivery of vaccine to the exact epidermal and dermal or mucosal compartments which teem with antigen-presenting cells (APCs). Among different types of MAs, while the micro-environmental stimulus-responsive MAs represent one of the developmental trends in the field, the MAs combined with the conventional vaccines that are based on nonvirulent viruses, such as live attenuated or whole inactivated viruses, and antigen-encoding DNA viral vectors, have developed rapidly into the advanced stages, with certain products already on clinical trials. The pre- and clinical research outcomes showed that the painless MA delivery of the conventional vaccines through mammalian skin or mucosa can not only elicit robust systemic and even mucosal immunity to pathogens but also, in certain circumstances, redirect the immune response toward a specific Th1 pathway, resulting in cytotoxic T lymphocytes (CTL) to erase the cell-hidden pathogens, thanks to the robust adjuvant function of MAs exerted through damaging the contacted cells to release dangerous signals. This paper focuses on reviewing the latest research and advancements in MA delivery of the conventional vaccines that are based on nonvirulent viruses, underlining MA enhancement of the overall vaccine performance and the most advanced MA vaccine products that are relatively close to markets. [ABSTRACT FROM PUBLISHER]

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

CD73 is a cell surface 5'nucleotidase (NT5E) and key node in the catabolic process generating immunosuppressive adenosine in cancer. Using a murine monoclonal antibody surrogate of Oleclumab, we investigated the effect of CD73 inhibition in concert with cytotoxic therapies (chemotherapies as well as fractionated radiotherapy) and PD-L1 blockade. Our results highlight improved survival in syngeneic tumor models of colorectal cancer (CT26 and MC38) and sarcoma (MCA205). This therapeutic outcome was in part driven by cytotoxic CD8 T-cells, as evidenced by the detrimental effect of CD8 depleting antibody treatment of MCA205 tumor bearing mice treated with anti-CD73, anti-PD-L1 and 5-Fluorouracil +Oxaliplatin (5FU+OHP). We hypothesize that the improved responses are tumor microenvironment (TME)-driven, as suggested by the lack of anti-CD73 enhanced cytopathic effects mediated by 5FU+OHP on cell lines in vitro. Pharmacodynamic analysis, using imaging mass cytometry and RNA-sequencing, revealed noteworthy changes in specific cell populations like cytotoxic T cells, B cells and NK cells in the CT26 TME. Transcriptomic analysis highlighted treatment-related modulation of gene profiles associated with an immune response, NK and T-cell activation, T cell receptor signaling and interferon (types 1 & 2) pathways. Inclusion of comparator groups representing the various components of the combination allowed deconvolution of contribution of the individual therapeutic elements; highlighting specific effects mediated by the anti-CD73 antibody with respect to immune-cell representation, chemotaxis and myeloid biology. These pre-clinical data reflect complementarity of adenosine blockade with cytotoxic therapy, and T-cell checkpoint inhibition, and provides new mechanistic insights in support of combination therapy. [ABSTRACT FROM AUTHOR]

Conventional treatments for tumors were frequently accompanied by drawbacks and side effects. It might be useful to use the revolutionary microneedle technology which combines photothermal therapy with tumor immunotherapy. In this study, we created a microneedle drug delivery system with mercapto-modified gold nanorods and immune checkpoint blocker anti-PD-1 polypeptide. With good mechanical strength, the microneedle system can efficiently penetrate the skin and deliver drugs. When inserted into human skin, anti-PD-1 peptides and gold nanorods can be released, boosting the capacity of cytotoxic T lymphocytes to destroy tumor cells. Additionally, the elimination of the tumor is aided by the production of heat while being exposed to near-infrared light. This microneedle drug delivery system can enhance the immunological reaction and prolong the survival time of mice. Moreover, it has been demonstrated that the system has mild toxic and side effects on normal tissues and can effectively inhibit the growth of tumors, indicating a bright prospect for the treatment of cancers. [ABSTRACT FROM AUTHOR]

The pathogenesis of donor cell leukemia (DCL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is unclear and likely multifactorial. Leukemic transformation of healthy donor HSCs in recipient's bone marrow microenvironment provides a useful in vivo model for investigating the mechanisms involved in leukemogenesis. Here, we report a rare case of late-onset DCL developing in a recipient. Whole-genome sequencing indicates that donor-derived cells harboring clonal hematopoiesis of indeterminate potential (CHIP)-associated genetic alterations expand and eventually transform to full-blown AML via acquisition of additional somatic mutations within the recipient's bone marrow microenvironment. The 10× single-cell RNA sequencing reveals the abundance of GMP-like cells with a specific transcriptional signature in DCL. Moreover, impaired immune surveillance, including dysfunction of cytotoxic T lymphocytes (CTLs) and decreased number of canonical NK cells, is discovered in DCL. Our data add valuable information to the current understanding of the mechanisms of DCL. [ABSTRACT FROM AUTHOR]

Patients with non-localized joint presentation experienced worse outcomes than those with localized presentation regardless of the treatment protocol, mirroring clinical intuition about the disease outcomes of less differentiated patients [[18]]. The potential of machine learning (ML) for stratifying patients Thanks to advances in genomic technologies and improvements in data management, we should consider a comprehensive, data-driven, ML-based approach to identify new disease signatures and patient groups in JIA. Keywords: Disease classification; machine learning; juvenile idiopathic arthritis; systems medicine; autoimmune diseases EN Disease classification machine learning juvenile idiopathic arthritis systems medicine autoimmune diseases 1 3 3 03/03/21 20210101 NES 210101 1. [Extracted from the article]

Most immune system polymorphisms have undergone molecular evolution largely due to natural selection driven primarily by host-pathogen interactions, showing significant human geographic expansion signs. Killer cell immunoglobulin-like receptors (KIRs) show great genetic and allelic variation among different populations. The aim of this study was to analyse the frequency of KIR genes in a large cohort of healthy Spanish Caucasians (SC) to be able to compare them with other world populations. A total of 609 healthy SC unrelated individuals were analysed and compared with 16 worldwide populations. KIR genotyping was analysed by PCR-SSO technique. Our results showed that all KIR genes were present in the Spanish population. iKIR2D genes of the Spanish population were similar in different European populations like Danish, Finland, Irish and Italian populations, Czech and Turkish populations but very different to Australian, Bornean, Chinese, Indian, Venezuelan, and Russian populations. KIR3DL1 gene frequency in the Australian population was significantly lower than the Spanish population. aKIR genes frequencies of the Spanish population were similar to European populations, but slight differences were found in English, Finnish, Irish and Macedonian populations. In conclusion, our results enrich the Caucasian genetic information resources of the KIR gene pool for genetic susceptibility diseases and forensic anthropological studies. [ABSTRACT FROM AUTHOR]

A novel therapeutic regimen showed that the oncolytic type II herpes simplex virus (oHSV2) was able to prevent colorectal cancer growth, recurrence, and metastasis. However, no study has yet explored whether oHSV2 has an impact on the development of diffuse large B-cell lymphoma (DLBCL). We chose the clinical chemotherapeutic drug doxorubicin (DOX) as a positive control to evaluate the effect of oHSV2 infection on the apoptotic, invasive, and proliferative capacity of DLBCL cells. We next further explored the therapeutic efficacy of oncolytic virus oHSV2 or DOX in DLBCL tumor bearing BALB/c mice, and evaluated the infiltration of CD8 + T cells and CD4 + T cells in tumor tissues. A pathological approach was used to explore the effects of oHSV2 on various organs of tumor bearing mice, including the heart, liver, and kidney. Next, SU-DHL-4 cells were co-cultured with cytotoxic T lymphocytes (CTLs) to mimic the tumor immune microenvironment (TME), to explore the impact of oHSV2 on the immune environment at the cellular level, and then analyzed the relationship between oHSV2 and the PD-1/PD-L1 immune-checkpoint. Subsequently, we further validated the efficacy of combined oHSV2 and PD-L1 treatment on transplanted tumor growth in mice at the in vivo level. DLBCL cells were sensitive to the action of the oncolytic virus oHSV2, and the decline in their proliferative activity showed a time-and dose-dependent manner. oHSV2 and DOX intervention preeminently increased the cell apoptosis, restrained cell proliferation and invasion, with the greatest changes occurring in response to oHSV2 infection. oHSV2 application effectively improved the immune status of the tumor microenvironment, favoring the invasion of CD8 + T and CD4 + T cells, thereby enhancing their antitumor effects. Besides, oHSV2 treatment has a safety profile in the organs of tumor bearing mice and indeed inhibits the PD-1/PD-L1 immune checkpoint in DLBCL. Interestingly, the combination of oHSV2 and PD-L1 antibodies results in more profound killing of DLBCL cells than oHSV2 infection alone, with a significant increase in the proportion of CD4 + T cells and CD8 + T cells. The antitumor effect was the best after combining oHSV2 and PD-L1 antibodies, suggesting that the combination therapy of oHSV2 and PD-L1 would have a better prospect for clinical application. [ABSTRACT FROM AUTHOR]

Abnormal DNA methylation is a fundamental characterization of epigenetics in cancer. Here we demonstrate that aberrant DNA methylating can modulate the tumour immune microenvironment in 16 cancer types. Differential DNA methylation in promoter region can regulate the transcriptomic pattern of immune-related genes and DNA hypomethylation mainly participated in the processes of immunity, carcinogenesis and immune infiltration. Moreover, many cancer types shared immune-related functions, like activation of innate immune response, interferon gamma response and NOD-like receptor signalling pathway. DNA methylation can further help identify molecular subtypes of kidney renal clear cell carcinoma. These subtypes are characterized by DNA methylation pattern, major histocompatibility complex, cytolytic activity and cytotoxic t lymphocyte and tumour mutation burden, and subtype with hypomethylation pattern shows unstable immune status. Then, we investigate the DNA methylation pattern of exhaustion-related marker genes and further demonstrate the role of hypomethylation in tumour immune microenvironment. In summary, our findings support the use of hypomethylation as a biomarker to understand the mechanism of tumour immune environment. [ABSTRACT FROM AUTHOR]

Introduction: Bispecific antibody (BiAb)-armed activated T cells (BATs) comprise an adoptive T cell therapy platform for treating cancer. Arming activated T cells (ATC) with anti-CD3 x anti-tumour associated antigen (TAA) BiAbs converts ATC into non-major histocompatibility complex (MHC)-restricted anti-tumour cytotoxic T lymphocytes (CTLs). Binding of target antigens via the BiAb bridge enables specific anti-tumour cytotoxicity, Th1 cytokines release, and T cell proliferation. Clinical trials in breast, prostate, and pancreatic cancer using BATs armed with chemically heteroconjugated BiAbs demonstrated safety, feasibility, induction of anti-tumour immune responses and potential increases in overall survival (OS). Objectives: The primary objective of this study was to develop a recombinant BiAb that confers enhanced anti-tumour activity of BATs against a broad range of solid tumours. Methods: A recombinant anti-epidermal growth factor receptor (EGFR) x anti-CD3 (OKT3) BiAb (rEGFRBi) was designed and expressed in CHO cells, used to arm ATC (rEGFR-BATs), and tested for specific cytotoxicity against breast, pancreatic and prostate cancers and glioblastoma. Results: rEGFR-BATs exhibit remarkably enhanced specific cytotoxicity and T1 cytokine secretion against a wide range of solid tumour cell lines vs. their respective chemically-heteroconjugated BATs. Conclusion: rEGFR-BATs may provide a "universal" T cell therapy for treating a wide range of solid tumours. A (Gly4Ser)6 linker between the variable light and heavy chains of an scFv fused to the N-terminus of a heavy chain antibody confers unexpected stability to the heavy chain fusion protein and supports the efficient expression of the bispecific antibody. Arming of activated T cells with the rEGFRBi greatly enhances the relative cytotoxicity and Th1 cytokine secretion of theT cells relative to a chemically heteroconjugated BiAbs. rEGFR-BATs are promising candidates for the treatment of a broad range of solid tumours. [ABSTRACT FROM AUTHOR]

Hepatocyte-specific knockout of the essential autophagy gene Autophagy-related 7 (Atg7) is sufficient to cause hepatic carcinogenesis. A recent paper by Lee et al. unveils the molecular pathway accounting for hepatic hypertrophy and hyperplasia followed by malignant transformation. This pathway involves the overactivation of the transcription factor yes-associated protein (YAP), which turns out to be an autophagic substrate. Of note, the transcriptional signature activated in mouse hepatocytes lacking Atg7 resembles that found in non-alcoholic steatohepatitis (NASH), as well as in the steatohepatitic subtype of human hepatocellular carcinomas. [ABSTRACT FROM AUTHOR]

Allergic disease represents one of the most prominent global public health crises of the 21st century. Although many different substances are known to produce hypersensitivity responses, metals constitute one of the major classes of allergens responsible for a disproportionately large segment of the total burden of disease associated with allergy. Some of the most prevalent forms of metal allergy – including allergic contact dermatitis – are well-recognized; however, to our knowledge, a comprehensive review of the many unique disease variants implicated in human cases of metal allergy is not available within the current scientific literature. Consequently, the main goal in composing this review was to (1) generate an up-to-date reference document containing this information to assist in the efforts of lab researchers, clinicians, regulatory toxicologists, industrial hygienists, and other scientists concerned with metal allergy and (2) identify knowledge gaps related to disease. Accordingly, an extensive review of the scientific literature was performed – from which, hundreds of publications describing cases of metal-specific allergic responses in human patients were identified, collected, and analyzed. The information obtained from these articles was then used to compile an exhaustive list of distinctive dermal/ocular, respiratory, gastrointestinal, and systemic hypersensitivity responses associated with metal allergy. Each of these disease variants is discussed briefly within this review, wherein specific metals implicated in each response type are identified, underlying immunological mechanisms are summarized, and major clinical presentations of each reaction are described. Abbreviations: ACD: allergic contact dermatitis, AHR: airway hyperreactivity, ASIA: autoimmune/ autoinflammatory syndrome induced by adjuvants, BAL: bronchoalveolar lavage, CBD: chronic beryllium disease, CTCL: cutaneous T-cell lymphoma, CTL: cytotoxic T-Lymphocyte, DRESS: drug reaction with eosinophilia and systemic symptoms, GERD: gastro-esophageal reflux disease, GI: gastrointestinal, GIP: giant cell interstitial pneumonia, GM-CSF: granulocyte macrophage-colony stimulating factor, HMLD: hard metal lung disease, HMW: high molecular weight, IBS: irritable bowel syndrome, Ig: immunoglobulin, IL: interleukin, LMW: low molecular weight, PAP: pulmonary alveolar proteinosis, PPE: personal protective equipment, PRR: pathogen recognition receptor, SLE: systemic lupus erythematosus, SNAS: systemic nickel allergy syndrome, Th: helper T-cell, UC: ulcerative colitis, UV: ultraviolet. [ABSTRACT FROM AUTHOR]

This study aims to elucidate the changes in the percentage of GPR56 and/or granzyme B (GZMB) positive cells in rheumatoid arthritis (RA) CD4 and CD8 T lymphocytes, and to explore their clinical value in diagnosing and reflecting the progression of RA. The percentages of GPR56 and/or GZMB positive cells were analyzed in peripheral blood (PB) and spleen T cells in a collagen-induced arthritis (CIA) model established in DBA/1 mice. The percentages of GPR56+ and/or GZMB+ cells were further analyzed in PBs from RA patients and healthy controls. Correlation analysis was performed between clinical indicators and GPR56+, GZMB+, and GPR56+ GZMB+ T cells. Receiver operating characteristic (ROC) curves were used to evaluate the value of GPR56 and GZMB in differentiating active and stable remitting RA. GPR56+ levels were increased in CD4 and CD8 T cells in the PB of CIA mice. The percentages of GPR56+ and GZMB+ cells were increased in both CD4 and CD8 T cell subsets in patients with active RA. GPR56+, GZMB+, and GPR56+ GZMB+ cells were positively correlated with rheumatoid factor and DAS28. ROC analysis revealed that AUCs for GPR56+, GZMB+, and GPR56+ GZMB+ cell percentages to distinguish active RA from stable remission RA were 0.7106, 0.6941, 0.7024, with cut-off values of 16.35, 16.40, 14.80 in CD4 + T cells, and 0.8031, 0.8086, 0.8196 with cut-off values 60.25, 62.15, 40.15 in CD8 + T cells, respectively. GPR56+ and/or GZMB+ T cells are up-regulated in patients with active RA and reflect their condition. The detection of GPR56 and GZMB is helpful for RA disease assessment. [ABSTRACT FROM AUTHOR]

Background: The overall survival of melanoma patients remains poor despite advancements in surgical treatment and targeted therapies. Therefore, there is a need to develop new therapeutic strategies for melanoma. 2-methoxyestradiol (2-ME) is a major metabolite of estrogen that has been shown to have anti-tumor effects against many malignancies. However, the effects and mechanisms of action of 2-ME against melanoma remain unclear. Materials and methods: Melanoma cells (B16) were treated with 2-ME in vitro. Cell proliferation was detected by CCK8 and clone formation, transwell was carried out to measure the migration of B16 cells with or without 2-ME. Flow cytometry was performed to measure the apoptosis and cell cycle. C57BL/6 mice were used for tumor-bearing of B16 cells, tumor volumes were measured once a day, and sacrificed after it was over 2000 mm3, then immunofluorescence was implemented to examine the marker of CD3, CD8 and PD-L1. Results: In our study, we found that 2-ME significantly affected the proliferation, migration, apoptosis, and cell cycle of melanoma in vitro. Our results also showed that 2-ME had strong anti-tumor effects against melanoma in vivo and increased the infiltration of tumor-specific cytotoxic lymphocytes CD8+ T cells in the tumor microenvironment. Besides, PD-L1 expression in tumor cells was significantly higher in the 2-ME-treated group than in the control group, indicating that 2-ME could exhibit stronger anti-tumor effects against melanoma if combined with PD-1 blockade therapy. Conclusion: 2-ME suppresses melanoma in vivo and in vitro and is a promising synergistic enhancer of PD-1 blockade immunotherapy. [ABSTRACT FROM AUTHOR]

Biodegradable elastomeric controlled-release poly (decane-co-tricarballylate) (PDET) based matrices capable of maintaining the stability and bioactivity of Interleukin-2 (IL-2) through the utilization of visible-light curing and solvent-free loading of the cytokine are reported. The elastomeric devices were fabricated by intimately mixing lyophilized IL-2 powder with the acrylated prepolymer before photocrosslinking. The bioactivity of the released protein was assessed by its ability to stimulate the proliferation of the C57BL/6 mouse cytotoxic T lymphocyte, and its concentration was analysed using ELISA. The influence of changes in the polymer's physicochemical and mechanical properties on IL-2 release kinetics and bioactivity were also studied. The increase in the device's surface area and the incorporation of trehalose in the loaded lyophilized mix increased the IL-2 release rate with drug release proceeding via typical zero-order release kinetics. Moreover, the decrease in the degree of acrylation of the prepared devices increased the IL-2 release rate. The bioactivity assay showed that IL-2 retained over 94% of its initial bioactivity throughout 28 days of the release period. A new protein delivery vehicle composed of biodegradable PDET elastomers was demonstrated to be promising and effective for linear, constant, and sustained osmotic-driven release of bioactive IL-2 and other sensitive proteins and hormones. [ABSTRACT FROM AUTHOR]

This is the first investigation on the in vitro cytotoxicological and genotoxicological effects of Kalanchoe pinnata (Lam.) Pers. fresh leaf juice, for establishing a safe and effective quantity for use. Peripheral blood of 6 healthy, non-addicted males between 20 and 25 years of age was used for toxicity assessment by 3-(4, 5-dimethylthazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), mitotic index (MI), sister chromatid exchanges (SCEs) and Cytokinesis Blocked Micronucleus (CBMN) assays. The IC50 of the leaf juice calculated by MTT assay was 155.1 µl. The 50 and70 µl of the juice concentrations were decided after standardization by MI and showed non-significant and significant decrease respectively when compared to control. The SCEs/Cell and SCEs/Chromosome were increased non-significantly (50 µl) and significantly (70 µl),while cell cycle proliferative index, Average generation time and Population doubling time values were non-significant for both doses when compared to the controls. In CBMN assay, the Cytokinesis block proliferation index, cytotoxicity, Micronuclei, Nuclear bud, Nucleoplasmic bridge frequencies and total DNA damage biomarkers showed non-significant changes for both 50 and 70 µl. The changes observed were significant only at 70 µl for MI and SCEs, which were significantly lower than that by positive control indicating a non genotoxic effect. Hence, the fresh leaf juice can be used pharmaceutically as well as traditionally, but for long durations and higher doses should be used with caution, as it can have mutagenic effect at particularly high levels. [ABSTRACT FROM AUTHOR]

Antibody responses to single-dose SARS-CoV-2 vaccination in patients receiving immunomodulators for immune-mediated inflammatory disease. Disease activity and humoral response in patients with inflammatory rheumatic diseases after two doses of the Pfizer mRNA vaccine against SARS-CoV-2. In a multicentre observational study including 686 patients, IgG antibody levels against SARS-CoV-2 spike S1/S2 proteins were measured 2-6 weeks after completion of a two-dose regimen, 3 weeks apart, of BNT162b2 mRNA vaccine and compared with those of 121 controls from the general population. [Extracted from the article]

Among severely immunosuppressed patients resistant or refractory cytomegalovirus (CMV) retinitis is not uncommon, and is potentially blinding in the affected eye. Immunotherapy using CMV-specific cytotoxic T lymphocytes (CTLs) is an emerging and promising alternative for the control of resistant or refractory CMV retinitis. However, highly purified CMV-CTLs are still not available in the majority of medical institutions in China because the generation of CMV-CTLs is labor intensive, time-consuming and expensive. This letter describes the clinical responses to a simplified CMV-CTL immunotherapy aimed at controlling drug-resistant CMV retinitis in two immunodeficient patients. Our cases suggest that the simplified CMV-CTL immunotherapy offers a highly efficient and low-cost solution to drug-resistant CMV retinitis. This immunotherapy strategy targeting drug-resistant CMV retinitis is likely to be cost-effective in the context of a specific patient population. [ABSTRACT FROM AUTHOR]

Indoleamine 2,3-dioxygenase (IDO) inhibition has received much attention in cancer immunotherapy due to its role in immune escape in cancer cells. Additionally, changes in the pro-inflammatory cytokine levels can affect tumor growth and metastasis as well as the effectiveness of immunotherapy. The purpose of this study was for the first time to determine the effects of indoximod as an IDO inhibitor on triple-negative breast cancer (TNBC) and to assess the link between the efficacy of indoximod and IFN-γ or TNF-α stimulation. The cytotoxic and apoptotic effects of indoximod alone or IFN-γ or TNF-α induction to mimic an inflammatory environment were evaluated by WST-1, Annexin V, cell cycle analysis, and acridine orange (AO)/ethidium bromide (EtBr) staining. Furthermore, the expression levels of IDO1 and PD-L1 expression were analyzed by RT-PCR. Our results demonstrated that indoximod significantly decreased the TNBC cell viability through apoptotic cell death (p <.05). The combination of indoximod and TNF-α was more effective than indoximod and IFN-γ stimulation or indoximod alone in TNBC cells. Additionally, PD-L1 expression level was significantly up-regulated after treatment with indoximod and TNF-α or IFN-γ combinations (p <.05). Indoximod exhibited a therapeutic potential in TNBC cells and pro-inflammatory cytokines could affect the effectiveness of indoximod. However, further studies are required to identify the role of the IDO-associated signaling pathways, the molecular mechanisms of indoximod induced apoptotic cell death, and the relationship between IDO inhibition by IDO inhibitors and pro-inflammatory cytokine levels. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) is a leading cause of respiratory tract infections in infants. Macroautophagy/autophagy is a catalytic metabolic process required for cellular homeostasis. Although intracellular metabolism is important for immune responses in dendritic cells, the link between autophagy and immunometabolism remains unknown. Here, we show that the autophagy-related protein ATG5 regulates immunometabolism. Atg5-deficient mouse dendritic cells showed increased CD8A+ T-cell response and increased secretion of proinflammatory cytokines upon RSV infection. Transcriptome analysis showed that Atg5 deficiency alters the expression of metabolism-related genes. Atg5-deficient dendritic cells also showed increased activation of glycolysis and the AKT-MTOR-RPS6KB1 pathway and decreased mitochondrial activity, all of which are cellular signatures for metabolic activation. These cells also showed elevated CD8A+ T-cell priming and surface major histocompatibility complex (MHC) class I expression. Our results suggested that ATG5 regulated host immune responses by modulating dendritic cell metabolism. These findings may help develop potential antiviral therapies that alter host immunity by regulating autophagy and immunometabolism. Abbreviations : 2-DG: 2-deoxyglucose; AAK1: AP2 associated kinase 1; AKT: AKT serine/threonine kinase; AM: alveolar macrophage; ATG: autophagy; ATP: adenosine triphosphate; BAL: bronchoalveolar lavage; BMDC: bone marrow dendritic cell; CSF2/GM-CSF: colony-stimulating factor 2 (granulocyte-macrophage); CTL: cytotoxic T lymphocyte; ELISA: enzyme-linked immunosorbent assay; GFP: green fluorescent protein; GSEA: gene-set enrichment analysis; H-2Db: H-2 class I histocompatibility antigen, D-B alpha chain; H-2Kb: MHC class I H2-K-b; HIF1A: hypoxia-inducible factor 1 alpha; IFNG: interferon-gamma; IL: interleukin; ITGAX: integrin alpha X; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MHC: major histocompatibility complex; MTORC1: mammalian target of rapamycin kinase complex 1; PBS: phosphate-buffered saline; PFU: plaque-forming unit; RLR: retinoic acid-inducible-I-like receptor; ROS: reactive oxygen species; RPMI: Roswell Park Memorial Institute; RPS6KB1/S6K: ribosomal protein S6 kinase, polypeptide 1; RSV: respiratory syncytial virus; Th: T helper; TLR: toll-like receptor; Treg: regulatory T cells; UMAP: uniform manifold approximation and projection. [ABSTRACT FROM AUTHOR]

The most interesting study is KEYNOTE 676 [[21]], a randomized controlled phase 3 study testing the combination of pembrolizumab with BCG versus BCG alone in high-risk NMIBC patients, refractory to BCG induction. Bacille Calmette-Guerin (BCG) Intravesical BCG instillation is the gold standard adjuvant therapy in managing high-risk NMIBC. Therefore, by combining BCG therapy to PD-L1 inhibitors (either intravesical or systemic) or to TNF- , we might be able to overcome these resistance mechanisms, inducing a more prolonged response to BCG instillation, preventing relapse, overcoming resistances, and making refractory patients sensible to BCG. Since then, the development of cancer immunotherapies has undergone many technological advances, from the intravesical administration of Bacille Calmette-Guerin (BCG) to the development of targeted monoclonal antibody-based treatments, and lately CAR T-cell immunotherapy. [Extracted from the article]

TGR5 (G protein-coupled bile acid receptor 1, GPBAR-1) is a G protein-coupled receptor with seven transmembrane domains and is widely distributed in various organs and tissues. As an important bile acid receptor, TGR5 can be activated by primary and secondary bile acids. Increased expression of TGR5 is a risk factor for polycystic liver disease and hepatobiliary cancer. However, there is evidence that the anti-inflammatory effect of the TGR5 receptor and its regulatory effect on hydrophobic bile acid confer protective effects against most liver diseases. Recent studies have shown that TGR5 receptor activation can alleviate the development of diabetic liver fibrosis, regulate the differentiation of natural killer T cells into NKT10 cells, increase the secretion of anti-inflammatory factors, inhibit the invasion of hepatitis B virus, promote white adipose tissue browning, improve arterial vascular dynamics, maintain tight junctions between bile duct cells, and protect against apoptosis. In portal hypertension, TGR5 receptor activation can inhibit the contraction of hepatic stellate cells and improve intrahepatic microcirculation. In addition, the discovery of the regulatory relationship between the TGR5 receptor and miRNA-26a provides a new direction for further studies of the molecular mechanism underlying the effects of TGR5. In this review, we describe recent findings linking TGR5 to various liver diseases, with a focus on the mechanisms underlying its effects and potential therapeutic implications. [ABSTRACT FROM AUTHOR]

Morinda officinalis polysaccharides (MOPS) were investigated for their physicochemical properties, monosaccharide composition, and immune-modulating effects in vitro and in vivo. In vitro, MOPS significantly promoted lymphocyte proliferation and increased IFN-γ and IL-4 secretion. In vivo, MOPS acted as adjuvant, which significantly up-regulated HBsAg-specific IgG and IgG isotype levels, promoted antigen-specific T cell proliferation and cytokine (IL-2 and IL-5) production, and induced CTL and NK cytotoxicity. Moreover, MOPS increased DC maturation. Overall, MOPS can serve as an adjuvant to promote humoral and cellular immune responses via promoting DC maturation, suggesting that MOPS may have potentials as a natural immune-enhancing agent. [ABSTRACT FROM AUTHOR]

Oncolytic virotherapy is emerging as a promising new method for cancer treatment. In the present study, we propose and analyze a mathematical model for treatment of cancer by using oncolytic virotherapy. Here, it is assumed that the growth of tumor cells follows logistic growth and the interaction between tumor cells and viruses is of saturation type. Additionally, the removal rates of uninfected and virus-infected tumor cells due to CTL's are also of saturation type. The basic reproduction numbers and different equilibria of the model are computed. The local stability of the equilibria is also discussed. Numerical simulation is also performed and it is found that for some set of parameters model system exhibits periodic oscillations. In this case it is not easy to predict the success of virotherapy. Finally, the model is extended to stochastic model and numerical simulation is performed to compare the results of deterministic and stochastic model. [ABSTRACT FROM AUTHOR]

Immunosurveillance is generally conceived as a mechanism through which the immune system detects and eliminates (pre-)malignant cells, thus reducing the risk of developing cancer. A recent paper by Ovadya et al. demonstrates that knockout of the gene coding for perforin-1 causes accelerated accumulation of senescent cells in multiple mouse organs, thereby speeding up the aging process. These results suggest that immunosurveillance plays a much broader role in maintaining organismal health than it had been suspected. [ABSTRACT FROM AUTHOR]

In immunotherapy dose-finding trials, the optimal dose is usually defined based on both toxicity and response because the relationship between toxicity and response is different than that seen with cytotoxic anti-neoplastic therapies. In immunotherapy trials, toxicity and response often require a longer follow-up time compared to trials with cytotoxic agents. The rapid enrollment design has been proposed for dose-finding trials to find the maximum-tolerated dose where the follow-up for toxicity is long and it is desirable to assign a patient to a dose of a new therapy as soon as the patient is enrolled. We extend the rapid enrollment design to immunotherapy trials to find the optimal dose. We further describe how to use the design in immunotherapy trials with ordered groups where efficacy and safety considerations dictate running dose-finding trials in each group separately as efficacy and toxicity at the same dose can vary across groups. The estimation of the optimal dose in each of the groups can be improved in many, but not all, cases by using the monotonicity of toxicity and response among groups. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to analyze the response of selected components of the immune system in rowers to maximal physical exercise, and to verify if this response can be modulated by supplementation with spirulina (cyanobacterium Spirulina platensis). Method: The double-blind study included 19 members of the Polish Rowing Team. The subjects were randomly assigned to the supplemented group (n = 10), receiving 1500 mg of spirulina extract for 6 weeks, or to the placebo group (n = 9). The participants performed a 2000-m test on a rowing ergometer at the beginning (1st examination) and at the end of the supplementation period (2nd examination). Blood samples were obtained from the antecubital vein prior to each exercise test, 1 min after completing the test, and after a 24-h recovery period. Subpopulations of T regulatory lymphocytes (Tregs) [CD4+/CD25+/CD127-], cytotoxic lymphocytes (CTLs) [CD8+/TCRαβ+], natural killer (NK) cells [CD3-/CD16+/CD56+] and TCRδγ-positive (Tδγ) cells were determined by means of flow cytometry. Results: On the 2nd examination, athletes from the supplemented group showed neither a post-exercise increase in Treg count nor a post-recovery decrease in Tδγ cell count (both observed in the placebo group), and presented with significantly lower values of Treg/CTL prior to and after the exercise. During the same examination, rowers from the placebo group showed a significant post-recovery increase in Treg/(NK + Tδγ + CTL) ratio, which was absent in the supplemented group. Conclusion: The results of this study imply that supplementation with spirulina extract may protect athletes against a deficit in immune function (especially, anti-infectious function) associated with strenuous exercise, and may cause a beneficial shift in "overtraining threshold" preventing a radical deterioration of immunity. [ABSTRACT FROM AUTHOR]

Purpose: Studies of cytotoxic T cells and their respective lineage master regulators have been limited in Hashimoto’s thyroiditis (HT). It is unclear whether their transcriptomes are changed in HT patients and how these changes are associated with the thyroid damage, major clinical manifestations, and disease progression. Methods: We explored the gene expression patterns of selected transcription factors [eomesodermin (EOMES), BACH2, BCL6, TCF1] and cytolytic molecules [granzyme B (GZMB)] in peripheral blood (PB) T cells of 10 healthy controls and 30 HT patients of various subtypes (hypothyroid, untreated HT; L-thyroxine (T4)-treated HT, and spontaneously euthyroid HT) using real-time quantitative PCR. Results: EOMES (Mann-Whitney P = 0.044), GZMB (P = 0.028), and BCL6 mRNA (P = 0.001) were overrepresented in PB T cells from HT and showed levels varying by age, thyroid volume and disease severity. BCL6 transcripts were predominantly enriched in severely affected, hypothyroid cases, both on and off LT4. Increased EOMES RNA expression was associated with advancing age, lower thyroid volumes and higher peak adjusted TSH levels over the course of the disease. The body mass-adjusted, steady-state maintenance dose of LT4 increased with GZMB and BCL6 levels in PB T cells of hypothyroid cases, mostly postmenopausal women having long-standing, non-goitrous and atrophic disease form. Conclusions: Our exploratory results suggest a role for GZMB, EOMES, and BCL6 in the context of HT, thyroid injury, and aggressive/advanced disease forms. Functions enriched within differentially expressed transcripts could be an important new target in understanding the pathogenesis of HT. [ABSTRACT FROM AUTHOR]

Familial hemophagocytic lymphohistiocytosis (FHL) is caused by biallelic variants in genes regulating granule secretion in cytotoxic lymphocytes. In FHL3–5, the affected genesUNC13D, STX11andSTXBP2have further been shown to regulate the secretion of platelet granules, giving rise to compromised platelet function. Therefore, we aimed to investigate platelet degranulation in patientsheterozygousfor variants inUNC13D, STX11andSTXBP2. During the work-up of patients referred to the Coagulation Unit, Skåne University Hospital, Malmö, Sweden and the Department of Hematology, Rigshospitalet, Copenhagen, Denmark due to bleeding tendencies, 12 patients harboring heterozygous variants inUNC13D, STX11orSTXBP2were identified using targeted whole exome sequencing. Transmission electron microscopy (TEM) was used to assess the secretion of platelet dense granules following thrombin stimulation. Platelet degranulation, activation and aggregation were further assessed by flow cytometry (FC) and light transmission aggregometry (LTA) with lumi-aggregometry. In total, eight out of twelve (67%) patients showed impaired degranulation by at least one of the assays (TEM, FC and LTA). In the 12 patients, eight different heterozygous variants were identified. One variant was strongly associated with impaired degranulation, while four of the variants were associated with impaired granule secretion to a slightly lesser extent. One additional variant was found in six out of the twelve patients, and was associated with varying degrees of degranulation impairment. Accordingly, six out of the eight (75%) identified variants were associated with impaired platelet degranulation. Our results suggest that heterozygous variants inUNC13D, STX11andSTXBP2are sufficient to cause platelet secretion defects resulting in increased bleeding. [ABSTRACT FROM PUBLISHER]

Immune cell-based therapies are emerging as a promising tool to tackle malignancies, both solid tumors and selected hematological tumors. Vast experiences in literature have documented their safety and added survival benefits when such cell-based therapies are combined with the existing treatment options. Numerous methodologies of processing andin vitroexpansion protocols of immune cells, such as the dendritic cells, natural killer (NK) cells, NKT cells, αβ T cells, so-called activated T lymphocytes, γδ T cells, cytotoxic T lymphocytes, and lymphokine-activated killer cells, have been reported for use in cell-based therapies. Among this handful of immune cells of significance, the NK cells stand apart from the rest for not only their direct cytotoxic ability against cancer cells but also their added advantage, which includes their capability of (i) action through both innate and adaptive immune mechanism, (ii) tackling viruses too, giving benefits in conditions where viral infections culminate in cancer, and (iii) destroying cancer stem cells, thereby preventing resistance to chemotherapy and radiotherapy. This review thoroughly analyses the sources of such NK cells, methods for expansion, and the future potentials of taking thein vitroexpanded allogeneic NK cells with good cytotoxic ability as a drug for treating cancer and/or viral infection and even as a prophylactic tool for prevention of cancer after initial remission. [ABSTRACT FROM PUBLISHER]

Purpose:Melanoma is an aggressive form of skin cancer. The aim of the study was to evaluate the influence of UVA radiation and psoralens: 5-methoxypsoralen (5-MOP) or 8-methoxypsoralen (8-MOP) on melanoma cells viability. Materials and methods:The amelanotic C32 and melanotic COLO829 human melanoma cell lines were exposed to increasing concentrations of psoralens (0.1–100μM) in the presence or absence of UVA radiation. Cell viability was evaluated by the WST-1 assay. Results:We demonstrated that 8-MOP, in contrast to 5-MOP, has no cytotoxic effect on both melanoma cell lines. Simultaneous exposure of cells to 8-MOP and UVA radiation caused significant cytotoxic response in C32 cells where the EC50value was estimated to be 131.0μM (UVA dose: 1.3 J/cm2) and 105.3μM (UVA dose: 2.6 J/cm2). The cytotoxicity of 5-MOP on both C32 and COLO829 cells was significantly augmented by UVA radiation – the EC50was estimated to be 22.7 or 7.9μM (UVA dose: 1.3 J/cm2) and 24.2 or 7.0μM (UVA dose: 2.6 J/cm2), respectively. Conclusions:The demonstrated high cytotoxic response after simultaneous exposure of melanoma cells to psoralens and UVA radiation in vitro suggests the usefulness of PUVA therapy to treat melanoma in vivo. [ABSTRACT FROM AUTHOR]

Purpose: Malignant gliomas are the most common tumors in the central nervous system with a poor prognosis. Recently, CD4+cytotoxic T cells (CTLs) are being increasingly recognized as possessing antitumor capacity. However, their presence, activity and regulation in glioma have not been investigated in detail.Methods: To examine this, 72 grade II and grade III Han Chinese glioma patients and 30 Han Chinese healthy controls were investigated.Results: We found that compared to healthy controls, glioma patients had significantly upregulated frequencies of circulating CD4+CTLs, identified by the expression of granzyme A (GzmA), granzyme B (GzmB) and/or perforin. The stimulated CD4+CTLs in grade II and grade III glioma patients also had less proliferative ability than those in healthy controls, a feature of suppression that progressed with tumor grade. The frequencies of GzmB-expressing circulating CD4+CTLs were directly associated with prognosis. We hypothesized that the programed death 1 (PD-1)/PD-ligand 1 (L1) interaction possibly contributed to the suppression of CD4+CTLs in grade II and grade III glioma, since an upregulation of PD-1 was observed on CD4+CTLs in glioma compared to those in the healthy individuals. Blockade of the PD-1/PD-L1 interaction with neutralizing antibodies significantly increased the proliferation and granzyme or perforin production by CD4+CTLs in grade II and grade III glioma patients.Conclusions: These data suggest that the CD4+CTLs in grade II and grade III glioma patients contribute to antitumor immunity and could be suppressed by PD-1 signal transduction. [ABSTRACT FROM AUTHOR]

Objective: To evaluate expression of glucocorticoid-induced tumor necrosis factor receptor (GITR), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and IL-10 in peripheral blood mononuclear cells (PBMCs) of 20 women with unexplained recurrent spontaneous abortion (URSA) compared to 20 normal non-pregnant women (NNP) during luteal phase in the window of implantation. Methods: Quantitative real-time PCR (qRT-PCR) was performed using the Taqman method for expression of GITR and SYBR Green method for expression of CTLA-4 and IL-10. Results: Expression of CTLA-4 in the NNPs (median; interquartile range; 3; 1.8–10) was significantly higher than the URSAs (0.72; 0.26–3.81,p = 0.015). Expression of GITR in the NNPs (53; 10–139) was significantly higher than the URSAs (6; 3–27,p = 0.005). However, IL-10 expression in the URSAs was significantly higher than the NNPs, did not meet a significant value. A significant correlation was found between CTLA-4 and GITR expression in the study population (p = 0.0001). Conclusions: Expression of CTLA-4 and GITR were significantly down-regulated in the URSAs compared to NNPs at the window of implantation, which shows the essential role of Treg cells in creating an immunological privileged site for fetus as an allograft at the maternal–fetal interface by high expression levels of CTLA-4 and GITR during a normal pregnancy. [ABSTRACT FROM PUBLISHER]

Purpose: The aim of this study was to investigate the specific anti-tumour immunity of cytotoxic T lymphocytes (CTL) activated by high-intensity focused ultrasound (HIFU) after adoptive transfer in a murine tumour model.Materials and methods: H22 tumour-bearing mice were treated by either HIFU or sham-HIFU, while naïve syngeneic mice were used as controls. They were sacrificed and the spleens were harvested 14 days after HIFU. T lymphocytes were obtained from the spleens, and then adoptively transferred into 40 mice each bearing a 3-day implanted H22 tumour. On day 14 after adoptive transfer, 10 mice were sacrificed in each group for assessment of the number of tumour-infiltrating T lymphocytes and interferon-gamma (IFN-γ) secreting cells. The remaining 30 mice were continuously observed for 60 days, and tumour growth, progression and survival were recorded.Results: HIFU significantly increased peripheral blood CD3+, CD4+levels and CD4+/CD8+ratio (P < 0.05), CTL cytotoxicity (P < 0.01) and IFN-γ and TNF-α secretion (P < 0.01) in H22 tumour-bearing mice. Adoptive transfer of HIFU-activated T lymphocytes into the autologous tumour-bearing mice induced a significant increase of tumour-infiltrating T lymphocytes and IFN-γ-secreting cells (P < 0.001). Compared to the control and sham-HIFU groups, HIFU-activated lymphocytes elicited significant inhibition ofin vivotumour growth (P < 0.01) and progression (P < 0.0001), and longer survival time in the tumour-bearing mice (P < 0.001).Conclusions: HIFU could enhance CTL’s specific antitumour immunity. Adoptive transfer of HIFU-activated T lymphocytes could increase local antitumour immunity, and elicit stronger inhibition on tumour growth and progression, with more survival benefit in the autologous tumour-bearing mice. [ABSTRACT FROM PUBLISHER]

Purpose of the study: Cytotoxic-T lymphocyte antigen-4 (CTLA-4) has been shown to play an important role in the development and progression of thyroid associated ophthalmopathy (TAO). A number of case-control studies focused on the association betweenCTLA-4+49A/G polymorphism and risk for TAO. But the results were not always consistent. So we performed a meta-analysis to evaluate the precise association between this polymorphism and risk for TAO. Materials and methods: All publications on the association betweenCTLA-4+49A/G polymorphism and TAO were searched in the following electronic databases: PubMed, Embase, the Cochrane library and Chinese Biomedical Literature Database, with the last report up to May 2014. This meta-analysis was assessed by Review Manager 5.1. Results: A total of 14 studies were involved in this meta-analysis, including 1128 cases and 2539 controls. Overall, we found a significant association betweenCTLA-4+49A/G polymorphism and TAO (G versus A: OR = 1.64, 95% CI = 1.40–1.92,p < 0.00001; GG versus AG + AA: OR = 2.02, 95% CI = 1.59–2.57,p < 0.00001; GG + AG versus AA: OR = 2.01, 95% CI = 1.66–2.43,p < 0.00001; GG versus AA: OR = 2.74, 95% CI = 1.83–4.10,p < 0.00001; AG versus AA: OR = 1.75, 95% CI = 1.42–2.15,p < 0.00001). The results were not materially altered after the studies which did not fulfill Hardy–Weinberg equilibrium were excluded. Significant association was also detected in both Caucasian and Asian populations in subgroup analysis divided by different ethnicity. Conclusion: Our meta-analysis supports the association between theCTLA-4+49A/G polymorphism and TAO. [ABSTRACT FROM PUBLISHER]

Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells target infected or transformed cells with perforin-containing cytotoxic granules through immune synapses, while platelets secrete several types of granules which contents are essential for thrombosis and hemostasis. Recent work has culminated in the notion that an exocytic SNARE complex, based on a very similar set of components, is primarily responsible for exocytosis of the diverse granules in these different cell types. Granule exocytosis is, in particular, uniquely dependent on the atypical Q-SNARE syntaxin 11, its interacting partners of the Sec/Munc (SM) family, and is regulated by Rab27a. Mutations in these exocytic components underlie disease manifestations of familial hemophagocytic lymphohistiocytosis (FHL) subtypes, characterized by hyperactivation of the immune system, as well as platelet granule secretion defects. Here we discuss the key discoveries that led to the converging notion of the syntaxin 11-based exocytosis machinery for cytotoxic granules and platelet-derived granules. [ABSTRACT FROM AUTHOR]

The use of dendritic cells (DC) in cancer immunotherapy is based on their potent abilities to present antigens, so they can act as 'natural adjuvants' to enhance immunogenicity of tumor antigens and stimulate specific cytotoxic T-cells. Large amounts of DC can be generated from bone marrow, neonatal cord blood, and peripheral blood CD34+ hematopoietic stem cells, or from peripheral blood monocytes. The DC can then be pulsed with tumor antigens and re-infused. In vitro, antigen-pulsed DC can stimulate allogeneic T-cell proliferation and induction of autologous specific cytotoxic T-cells; in vivo, the cells inhibit the growth of tumors or protect hosts (i.e. mice) from development of inoculated tumors. The results of preliminary clinical trials have shown that DC vaccines are safe and elicit immune responses; however, the rates of clinical responses are low. It has become quite clear that one key reason for unsatisfactory clinical results is tumor-induced immunosuppression. Among the factors contributing to this type of immunosuppression are populations of regulatory cells including: T-regulatory (Treg) cells, myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAM), and DC expressing 2,3-dioxygenase indoleamine (IDO-DC). This review presents an overview of the current understanding about populations of regulatory cells and the most current research efforts directed to overcome immunosuppressive activity due to the tumor microenvironment. [ABSTRACT FROM AUTHOR]