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1.
Effects of probiotics supplementation and circuit training on immune responses among sedentary young males.
Ibrahim, NS, Ooi, FK, Chen, CK, Muhamad, AS
The Journal of sports medicine and physical fitness. 2018;(7-8):1102-1109
Abstract
BACKGROUND Growing evidence suggests that probiotics may have positive benefits on immune responses following endurance exercise. However, little attention has been given to its possible beneficial effects on immune responses following resistance exercise. METHODS Forty-one healthy sedentary males were recruited and randomised into four groups: sedentary control with placebo (C), probiotics (P), circuit training with placebo (Ex), and circuit training with probiotics (PEx) groups. Participants in the Ex and PEx groups performed a progressive load of circuit training at 3 times/week for 12 weeks. Each circuit comprised 10 exercises with work to rest ratio of 1:2. Participants consumed either multi-strain probiotics or placebo twice daily for 12 weeks. Body height and weight, blood pressure, resting heart rate, saliva and blood samples were collected at pre- and post-tests. RESULTS Saliva flow rate and salivary IgA, α-amylase, lactoferrin and lysozyme responses were not significantly different (P>0.05) between groups and also between pre- and post-test within each group. Similarly, total leukocytes, total lymphocytes, T lymphocytes, T-helper, T-cytotoxic, B lymphocytes, and natural killer cells counts were not significantly affected (P>0.05) by the probiotics and/or circuit training. However, circuit training significantly increased (P<0.05) immune cells count at post-test as compared to pre-test. Yet, a combination of circuit training and probiotics showed no significant (P>0.05) effects on immune cells count. CONCLUSIONS This study did not provide enough support for the positive effects of probiotics on immune responses among sedentary young males following resistance exercise. However, 12 weeks of circuit training enhanced immune cells count.
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2.
Dynamics of virus-specific T cell immunity in pediatric liver transplant recipients.
Arasaratnam, RJ, Tzannou, I, Gray, T, Aguayo-Hiraldo, PI, Kuvalekar, M, Naik, S, Gaikwad, A, Liu, H, Miloh, T, Vera, JF, et al
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2018;(9):2238-2249
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Abstract
Immunosuppression following solid organ transplantation (SOT) has a deleterious effect on cellular immunity leading to frequent and prolonged viral infections. To better understand the relationship between posttransplant immunosuppression and circulating virus-specific T cells, we prospectively monitored the frequency and function of T cells directed to a range of latent (CMV, EBV, HHV6, BK) and lytic (AdV) viruses in 16 children undergoing liver transplantation for up to 1 year posttransplant. Following transplant, there was an immediate decline in circulating virus-specific T cells, which recovered posttransplant, coincident with the introduction and subsequent routine tapering of immunosuppression. Furthermore, 12 of 14 infections/reactivations that occurred posttransplant were successfully controlled with immunosuppression reduction (and/or antiviral use) and in all cases we detected a temporal increase in the circulating frequency of virus-specific T cells directed against the infecting virus, which was absent in 2 cases where infections remained uncontrolled by the end of follow-up. Our study illustrates the dynamic changes in virus-specific T cells that occur in children following liver transplantation, driven both by active viral replication and modulation of immunosuppression.
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3.
Universal CARs, universal T cells, and universal CAR T cells.
Zhao, J, Lin, Q, Song, Y, Liu, D
Journal of hematology & oncology. 2018;(1):132
Abstract
Currently, the two approved T cell products with chimeric antigen receptors (CAR) are from autologous T cells. These CAR T cells approved for clinical use must be generated on a custom-made basis. This case-by-case autologous T cell production platform remains a significant limiting factor for large-scale clinical application due to the costly and lengthy production process. There is also an inherent risk of production failure. The individualized, custom-made autologous CAR T cell production process also posts constriction on the wide application on diverse tumor types. Therefore, universal allogeneic T cells are needed for the preparation of universal CAR T cells that can serve as the "off-the-shelf" ready-to-use therapeutic agents for large-scale clinical applications. Genome-editing technologies including ZFN (zinc finger nuclease), TALEN (transcription activator-like effector nuclease), and CRISPR-Cas9 are being used to generate the universal third-party T cells. In addition, split, universal, and programmable (SUPRA) CARs are being developed to enhance the flexibility and controllability of CAR T cells. The engineered universal T cells and universal CARs are paving the road for a totally new generation of CAR T cells capable of targeting multiple antigens and/ or being delivered to multiple recipients without re-editing of T cells. This may escalate to a new wave of revolution in cancer immunotherapy. This review summarized the latest advances on designs and development of universal CARs, universal T cells, and clinical application of universal CAR T cells.
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4.
Survival of the fittest: Cancer challenges T cell metabolism.
Franchina, DG, He, F, Brenner, D
Cancer letters. 2018;:216-223
Abstract
T cells represent the major contributors to antitumor-specific immunity among the tumor-infiltrating lymphocytes. However, tumors acquire ways to evade immunosurveillance and anti-tumor responses are too weak to eradicate the disease. T cells are often functionally impaired as a result of interaction with, or signals from, transformed cells and the tumor microenvironment, including stromal cells. Among these, nutrients use and consumption is critically important for the control of differentiation and effector mechanisms of T cells. Moreover, Treg cells-skewing conditions often coexist within the cancer milieu, which sustains the notion of immune privileged tumors. Additionally, cancer cells contend with tumor infiltrating lymphocytes for nutrients and can outcompete the immune response. PD1- and CTLA-based immunotherapies partially remodel cell metabolism leading the way to clinical approaches of metabolic reprogramming for therapeutic purposes. Here we shortly discuss T cell fates during anti-tumor immune responses and how signals within tumor microenvironment influence T cell metabolism, altering functions and longevity of the cell.
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5.
Gene-knocked out chimeric antigen receptor (CAR) T cells: Tuning up for the next generation cancer immunotherapy.
Mirzaei, HR, Pourghadamyari, H, Rahmati, M, Mohammadi, A, Nahand, JS, Rezaei, A, Mirzaei, H, Hadjati, J
Cancer letters. 2018;:95-104
Abstract
Recently clinical trials utilizing genetically engineered T cells expressing a chimeric antigen receptor (CAR) that is half monoclonal antibody and half T-cell receptor have demonstrated remarkable response in patients with advanced cancers like relapsed or refractory acute lymphoblastic leukemia (ALL) and lymphoma. Moreover, emerging chimeric genome editing tools such as zinc-finger nucleases (ZNFs), transcription activator-like effector nucleases (TALENs) and clustered regulatory interspaced short palindromic repeat (CRISPR)/Cas composed of sequence-specific DNA binding module(s) linked to a non-specific DNA cleavage domain have made possible to dramatically expand the ability to manipulate cells aim to treat and/or study a wide range of diseases including cancer. Here, we will discuss how joint application of these two chimeras will help us to manipulate CAR T cells aiming to enhance the efficacy of CAR T cell therapy in preclinical and clinical settings.
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DNA damage, metabolism and aging in pro-inflammatory T cells: Rheumatoid arthritis as a model system.
Li, Y, Goronzy, JJ, Weyand, CM
Experimental gerontology. 2018;:118-127
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Abstract
The aging process is the major driver of morbidity and mortality, steeply increasing the risk to succumb to cancer, cardiovascular disease, infection and neurodegeneration. Inflammation is a common denominator in age-related pathologies, identifying the immune system as a gatekeeper in aging overall. Among immune cells, T cells are long-lived and exposed to intense replication pressure, making them sensitive to aging-related abnormalities. In successful T cell aging, numbers of naïve cells, repertoire diversity and activation thresholds are preserved as long as possible; in maladaptive T cell aging, protective T cell functions decline and pro-inflammatory effector cells are enriched. Here, we review in the model system of rheumatoid arthritis (RA) how maladaptive T cell aging renders the host susceptible to chronic, tissue-damaging inflammation. In T cells from RA patients, known to be about 20years pre-aged, three interconnected functional domains are altered: DNA damage repair, metabolic activity generating energy and biosynthetic precursor molecules, and shaping of plasma membranes to promote T cell motility. In each of these domains, key molecules and pathways have now been identified, including the glycolytic enzymes PFKFB3 and G6PD; the DNA repair molecules ATM, DNA-PKcs and MRE11A; and the podosome marker protein TKS5. Some of these molecules may help in defining targetable pathways to slow the T cell aging process.
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7.
Egg-specific IgE and basophil activation but not egg-specific T-cell counts correlate with phenotypes of clinical egg allergy.
Berin, MC, Grishin, A, Masilamani, M, Leung, DYM, Sicherer, SH, Jones, SM, Burks, AW, Henning, AK, Dawson, P, Grabowska, J, et al
The Journal of allergy and clinical immunology. 2018;(1):149-158.e8
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Abstract
BACKGROUND Egg allergy is phenotypically heterogeneous. A subset of patients with egg allergy can tolerate egg in an extensively heated form. Inclusion of baked egg (BE) into the diet accelerates resolution of egg allergy. Conversely, BE reactivity is associated with persistent disease. The immune basis of this clinical heterogeneity is unknown. OBJECTIVES We sought to study egg-specific antibody, basophil, and T-cell responses in children with reactivity or tolerance to BE. METHODS All participants underwent double-blind, placebo-controlled challenges to BE, and those who tolerated BE were challenged with unheated egg white protein to confirm clinical egg reactivity. Laboratory studies included serum antibody measurements, basophil activation tests, and CD154-based detection of egg-responsive T cells by using flow cytometry. RESULTS Of the 129 children studied, BE-reactive participants had significantly greater levels of egg-, ovalbumin-, and ovomucoid-specific IgE; lower ratios of egg-specific IgG4/IgE; and increased basophil activation in response to egg. Among all participants, CD154-based profiling revealed egg-responsive T cells producing IL-4 and IL-13 but little IL-10 or IFN-γ, as well as the presence of egg-responsive Foxp3+CD25+CD127low regulatory T cells. Egg-responsive T cells expressed CCR4, CCR6, and CXCR5, indicating capacity for homing to the skin, mucosa, and B-cell follicles. However, neither the frequency nor phenotype of egg-responsive T cells was different in those with tolerance or reactivity to BE. CONCLUSIONS Egg-specific antibody and basophil responses, but not T-cell responses, are greater in those with reactivity versus tolerance to BE. Egg-specific antibody and T-cell responses were highly heterogeneous in this cohort. The clinical implications of this immune heterogeneity will need to be studied longitudinally.
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FACS single cell index sorting is highly reliable and determines immune phenotypes of clonally expanded T cells.
Penter, L, Dietze, K, Bullinger, L, Westermann, J, Rahn, HP, Hansmann, L
European journal of immunology. 2018;(7):1248-1250
Abstract
FACS index sorting allows the isolation of single cells with retrospective identification of each single cell's high-dimensional immune phenotype. We experimentally determine the error rate of index sorting and combine the technology with T cell receptor sequencing to identify clonal T cell expansion in aplastic anemia bone marrow as an example.
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T-cells and their cytokine production: The anti-inflammatory and immunosuppressive effects of strenuous exercise.
Shaw, DM, Merien, F, Braakhuis, A, Dulson, D
Cytokine. 2018;:136-142
Abstract
Strenuous exercise bouts and heavy training are associated with a heightened anti-inflammatory state and a transient suppression of several immune components. In turn, many athletes are susceptible to illness, particularly upper respiratory symptoms (e.g. cough, sore throat, running nose). T-lymphocytes (T-cells) are important for orchestrating the immune response and can be categorised into subsets according to their phenotypical characteristics resulting from polarisation (i.e. type-1, type-2 and regulatory T-cells). Each T-cell subset has a unique functional role, including their capacity to produce pro- and anti-inflammatory cytokines in response to an immune challenge. Prolonged and exhaustive exercise typically reduces peripheral blood type-1 T-cell number and their capacity to produce the pro-inflammatory cytokine, interferon-γ. Moreover, heavy training loads are associated with elevated numbers of resting peripheral blood type-2 and regulatory T-cells, which characteristically produce the anti-inflammatory cytokines, interleukin-4 and interleukin-10, respectively. This appears to increase the risk of upper respiratory symptoms, potentially due to the cross-regulatory effect of interleukin-4 on interferon-γ production and immunosuppressive action of IL-10. Catecholamines significantly influence the number of peripheral blood T-cells in response to exercise. Whereas, glucocorticoids and prostaglandin E2 promote the production of anti-inflammatory cytokines by T-cells. In summary, strenuous exercise bouts and heavy training shifts T-cell immunity towards an anti-inflammatory state. This impairs the ability of the immune system to mount an inflammatory response to an immune challenge, which may weaken defences against intracellular pathogens (e.g. viruses), and increase the risk of infection and viral reactivation.
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A pilot study of peripheral blood BDCA-1 (CD1c) positive dendritic cells pulsed with NY-ESO-1 ISCOMATRIX™ adjuvant.
Davis, ID, Quirk, J, Morris, L, Seddon, L, Tai, TY, Whitty, G, Cavicchiolo, T, Ebert, L, Jackson, H, Browning, J, et al
Immunotherapy. 2017;(3):249-259
Abstract
AIM: Pilot clinical trial of NY-ESO-1 (ESO) protein in ISCOMATRIX™ adjuvant pulsed onto peripheral blood dendritic cells (PBDC), to ascertain feasibility, evaluate toxicity and assess induction of ESO-specific immune responses. PATIENTS & METHODS Eligible participants had resected cancers expressing ESO or LAGE-1 and were at high risk of relapse. PBDC were produced using CliniMACS®plus, with initial depletion of CD1c+ B cells followed by positive selection of CD1c+ PBDC. Patients received three intradermal vaccinations of ESO/IMX-pulsed PBDC at 4-week intervals. RESULTS The process was feasible and safe. No vaccine-induced immune responses were detected. Assays of immunomodulatory cells did not correlate with outcomes. One patient had a long lasting complete remission. CONCLUSION This method was feasible and safe but was minimally immunogenic.