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Clinical and Experimental Immunology Mar 1972The mitogenic selectivity of four phytomitogens, phytohaemagglutinin (PHA), concanavalin (ConA), lentil mitogen (LM) and pokeweed mitogen (PWM), and a series of...
The mitogenic selectivity of four phytomitogens, phytohaemagglutinin (PHA), concanavalin (ConA), lentil mitogen (LM) and pokeweed mitogen (PWM), and a series of heterologous antilymphocyte sera (ALS) for mouse T and B lymphocytes has been investigated using thymidine uptake as a measure of proliferative activity. The results show that PHA, ConA and LM stimulate T but not B cells whereas PWM activates both T and B cells. Of six mitogenically active ALS, five were T cell specific and one B cell specific. Cortisone resistant (T) cells within the thymus showed a much greater response to all mitogens than unselected thymocytes. However, ConA and LM activated a considerable response in the latter population. Selective activation of T and B cells by aspecific means may be useful both as a clinical tool and as an approach to gaining an understanding of antigen induction of immune responses.
Topics: Animals; Antibody Formation; Antigens; Antilymphocyte Serum; Bursa of Fabricius; Concanavalin A; Hydrocortisone; Lectins; Lymphocytes; Mice; Mitosis; Organ Specificity; Plant Lectins; Plants; Stimulation, Chemical; Thymidine; Thymus Gland; Tritium
PubMed: 5033804
DOI: No ID Found -
Discovery Medicine Dec 2013While cure rates for several cancers have significantly improved, the outcome for patients with advanced solid tumors remains grimly unchanged over the last decades.... (Review)
Review
While cure rates for several cancers have significantly improved, the outcome for patients with advanced solid tumors remains grimly unchanged over the last decades. Thus, there is a need for new therapies that could improve outcome for patients who fail current therapies. Oncolytic vaccinia virus (VV) would be an appealing addition to the current therapies of cancers because of its ability to infect, replicate in, and lyse tumor cells, and spread to other tumor cells in successive rounds of replication. While clinical studies have demonstrated their safety, the antitumor efficacy of oncolytic VVs has been suboptimal. Oncolytic VVs' major mode of action is the destruction of tumor cells, which can subsequently activate a component of the immune system called T cells that can travel to distant sites and target against any tumor they find. At present, virus spread through tumors, as well as the activation of tumor-specific T cells, is limited, explaining the observed suboptimal antitumor activity of current oncolytic VVs. Thus it would be desirable to make the oncolytic VVs more powerful stimulators of immunity through activating resident T cells within the tumors so that they will kill tumor cells and stop new tumors from growing. To activate T cells within tumors, a new molecule called a T-cell engager that couples the T cell and the tumor cell, which increases the effectiveness of the T cells and their activation, has been constructed. This review summarizes the progress of the emerging field of combinations of oncolytic virotherapy and T-cell based therapy.
Topics: Animals; Clinical Trials as Topic; Combined Modality Therapy; Humans; Immune System; Immunotherapy; Lymphocyte Activation; Neoplasms; Oncolytic Virotherapy; Oncolytic Viruses; T-Lymphocytes; Transgenes
PubMed: 24333405
DOI: No ID Found -
The Journal of Experimental Medicine Aug 1979Osteoclast-activating factor (OAF), a powerful stimulator of osteoclastic bone resorption, is released by peripheral blood mononuclear cells on exposure to...
Osteoclast-activating factor (OAF), a powerful stimulator of osteoclastic bone resorption, is released by peripheral blood mononuclear cells on exposure to phytohemagglutinin (PHA) or a specific antigen to which the leukocytes have been previously exposed. Both lymphocytes and monocytes are required in the leukocyte population for OAF release to occur. In this study we examined the relationship between the lymphocyte and monocyte in OAF production. Biological activity, as a result of OAF, was assessed by a bioassay based on the release of previously incorporated 45Ca from fetal rodent long bones in organ culture. We found that an enriched lymphocyte population depleted of monocytes by serial adherence does not release OAF after stimulation with PHA, although the cells are activated as assessed by [3H]thymidine and 3H-amino acid incorporation. When conditioned media harvested from adherent cells which did not contain OAF was added to the enriched lymphocytes, OAF release occurred. Media harvested from adherent cells which were cultured with indomethacin (10 microM), an inhibitor of prostaglandin synthesis, did not permit OAF release by activated lymphocytes. When PGE1 and PGE2 (0.1 microM) were added exogenously to the enriched lymphocyte population, OAF release occurred after stimulation with PHA. These results indicate that, (a) the activated lymphocyte is the cell or origin of OAF, (b) prostaglandins produced by monocytes are necessary for OAF production by activated lymphocytes, and (c) monocyte prostaglandins can influence bone resorption indirectly by regulating OAF production as well as directly by osteoclast activation. The interactions of OAF and prostaglandins at bone resorbing sites may be important in inflammatory and neoplastic diseases associated with bone destruction.
Topics: Bone Resorption; Cells, Cultured; Humans; Indomethacin; Lymphocytes; Lymphokines; Monocytes; Osteoclasts; Phytohemagglutinins; Prostaglandins
PubMed: 458377
DOI: 10.1084/jem.150.2.338 -
Toxicological Sciences : An Official... Jul 20102,3,7,8-Tetrachlordibenzo-p-dioxin (TCDD) is a potent suppressor of humoral immunity, disrupting antibody production in response to both T cell-dependent and T...
2,3,7,8-Tetrachlordibenzo-p-dioxin (TCDD) is a potent suppressor of humoral immunity, disrupting antibody production in response to both T cell-dependent and T cell-independent antigens. Among the cell types required for humoral responses, the B cell is highly, and directly, sensitive to TCDD. B cells become antibody-secreting cells via plasmacytic differentiation, a process regulated by several transcription factors, including activator protein-1, B-cell CLL/lymphoma 6 (BCL-6), and B lymphocyte-induced maturation protein 1 (Blimp-1). The overarching conceptual framework guiding experimentation is that TCDD disrupts plasmacytic differentiation by altering the expression or activity for upstream regulators of Blimp-1. Multiparametric flow cytometry was used to investigate TCDD-induced alterations in both activation marker and transcription factor expression following lipopolysaccharide (LPS) activation of purified B cells. TCDD significantly impaired LPS-activated expression of major histocompatibility complex class II, cluster of differentiation (CD)69, CD80, and CD86. Immunosuppressive concentrations of TCDD also suppressed LPS-activated Blimp-1 and phosphorylated c-Jun expression, whereas elevating BCL-6 expression. Because BCL-6 and c-Jun are directly and indirectly regulated by the kinases AKT, extracellular signal-regulated kinase (ERK), and Jun N-terminal kinase (JNK), it was hypothesized that TCDD alters toll-like receptor-activated kinase phosphorylation. TCDD at 0.03 and 0.3 nM significantly impaired phosphorylation of AKT, ERK, and JNK in CH12.LX B cells activated with LPS, CpG oligonucleotides, or resiquimod (R848). In primary B cells, R848-activated phosphorylation of AKT, ERK, and JNK was also impaired by TCDD at 30 nM. These results suggest that impairment of plasmacytic differentiation by TCDD involves altered transcription factor expression, in part, by suppressed kinase phosphorylation.
Topics: Animals; B-Lymphocytes; Base Sequence; Cell Differentiation; Cell Line; Enzyme-Linked Immunosorbent Assay; Female; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Oligonucleotides; Phosphorylation; Polychlorinated Dibenzodioxins; Toll-Like Receptors; Transcription Factors
PubMed: 20348231
DOI: 10.1093/toxsci/kfq095 -
PloS One 2013Galectin-9 (Gal-9) is known for induction of apoptosis in IFN-γ and IL-17 producing T-cells and amelioration of autoimmunity in murine models. On the other hand, Gal-9...
Galectin-9 (Gal-9) is known for induction of apoptosis in IFN-γ and IL-17 producing T-cells and amelioration of autoimmunity in murine models. On the other hand, Gal-9 induced IFN-γ positive T-cells in a sarcoma mouse model and in food allergy, suggesting that Gal-9 can have diametric effects on T-cell immunity. Here, we aimed to delineate the immunomodulatory effect of Gal-9 on human resting and ex vivo activated peripheral blood lymphocytes. Treatment of resting lymphocytes with low concentrations of Gal-9 (5-30 nM) induced apoptosis in ∼60% of T-cells after 1 day, but activated the surviving T-cells. These viable T-cells started to expand after 4 days with up to 6 cell divisions by day 7 and an associated shift from naïve towards central memory and IFN-γ producing phenotype. In the presence of T-cell activation signals (anti-CD3/IL-2) Gal-9 did not induce T-cell expansion, but shifted the CD4/CD8 balance towards a CD4-dominated T-cell response. Thus, Gal-9 activates resting T-cells in the absence of typical T-cell activating signals and promotes their transition to a TH1/C1 phenotype. In the presence of T-cell activating signals T-cell immunity is directed towards a CD4-driven response by Gal-9. Thus, Gal-9 may specifically enhance reactive immunological memory.
Topics: CD4-Positive T-Lymphocytes; Cell Death; Dose-Response Relationship, Drug; Galectins; Hepatitis A Virus Cellular Receptor 2; Humans; Immunologic Memory; Leukocytes, Mononuclear; Lymphocyte Activation; Membrane Proteins; Phenotype; Receptors, Antigen, T-Cell; T-Lymphocytes, Helper-Inducer
PubMed: 23741502
DOI: 10.1371/journal.pone.0065616 -
Journal of Translational Medicine Apr 2020Adoptive transfer of virus-specific T cells (VSTs) represents a prophylactic and curative approach for opportunistic viral infections and reactivations after...
BACKGROUND
Adoptive transfer of virus-specific T cells (VSTs) represents a prophylactic and curative approach for opportunistic viral infections and reactivations after transplantation. However, inadequate frequencies of circulating memory VSTs in the T-cell donor's peripheral blood often result in insufficient enrichment efficiency and purity of the final T-cell product, limiting the effectiveness of this approach.
METHODS
This pilot study was designed as a cross-over trial and compared the effect of a single bout (30 min) of high-intensity interval training (HIT) with that of 30 min of continuous exercise (CONT) on the frequency and function of circulating donor VSTs. To this end, we used established immunoassays to examine the donors' cellular immune status, in particular, with respect to the frequency and specific characteristics of VSTs restricted against Cytomegalovirus (CMV)-, Epstein-Barr-Virus (EBV)- and Adenovirus (AdV)-derived antigens. T-cell function, phenotype, activation and proliferation were examined at different time points before and after exercise to identify the most suitable time for T-cell donation. The clinical applicability was determined by small-scale T-cell enrichment using interferon- (IFN-) γ cytokine secretion assay and virus-derived overlapping peptide pools.
RESULTS
HIT proved to be the most effective exercise program with up to fivefold higher VST response. In general, donors with a moderate fitness level had higher starting and post-exercise frequencies of VSTs than highly fit donors, who showed significantly lower post-exercise increases in VST frequencies. Both exercise programs boosted the number of VSTs against less immunodominant antigens, specifically CMV (IE-1), EBV (EBNA-1) and AdV (Hexon, Penton), compared to VSTs against immunodominant antigens with higher memory T-cell frequencies.
CONCLUSION
This study demonstrates that exercise before T-cell donation has a beneficial effect on the donor's cellular immunity with respect to the proportion of circulating functionally active VSTs. We conclude that a single bout of HIT exercise 24 h before T-cell donation can significantly improve manufacturing of clinically applicable VSTs. This simple and economical adjuvant treatment proved to be especially efficient in enhancing virus-specific memory T cells with low precursor frequencies.
Topics: Hematopoietic Stem Cell Transplantation; High-Intensity Interval Training; Immunotherapy, Adoptive; Pilot Projects; T-Lymphocytes
PubMed: 32238166
DOI: 10.1186/s12967-020-02301-3 -
Scientific Reports Nov 2018The success of immunotherapeutic vaccines is often limited by their inability to activate the cytotoxic T lymphocyte (CTL)-inducing Th1 pathway. We investigated the...
The success of immunotherapeutic vaccines is often limited by their inability to activate the cytotoxic T lymphocyte (CTL)-inducing Th1 pathway. We investigated the ability of self-assembled nanogels (CHP or CH-CDex) to activate this pathway, and characterised them chemically and biologically. Once loaded with antigen (ovalbumin, OVA) their OVA encapsulation and dissociation rates suggested the possibility of effective antigen delivery. The DC2.4 dendritic cell line took up either vaccine time-dependently, but both vaccines required CpG DNA for class I MHC presentation. The nanogel vaccines interacted with RAW264.7, a Balb/c mouse-derived macrophage cell line, and co-localised with lysosomes, suggesting their endocytotic internalization in RAW264.7. Both vaccines activated CTLs better than OVA alone. Unlike OVA alone, the nanogel vaccines induced IgG2a antibody production in mice, whereas the former induced IgG1 antibodies. OVA-nanogel delivery to the draining lymph nodes (DLNs) was higher than that for OVA alone, reaching a deeper medullary area. Furthermore, Langerin CD103 DCs interacted with the nanogel vaccines effectively, which is a subset of cross-presentation DC, in the DLNs. The nanogel vaccines each had good anti-tumour efficacy in OVA tumour-bearing mice compared with the OVA alone. Thus, CHP and CH-CDex nanogels should be investigated further because of the great potential they offer for immunotherapy.
Topics: Animals; Antigen Presentation; Antigens; Disease Models, Animal; Gels; Humans; Lymph Nodes; Lymphocyte Activation; Lymphocytes; Mice; Nanostructures; Neoplasms; Ovalbumin; Polysaccharides; T-Lymphocytes, Cytotoxic; Vaccines; Xenograft Model Antitumor Assays
PubMed: 30405172
DOI: 10.1038/s41598-018-34885-8 -
The Journal of Experimental Medicine Jan 2017Group 2 innate lymphoid cells (ILC2s) and type 2 helper T cells (Th2 cells) are the primary source of interleukin 5 (IL-5) and IL-13 during type 2 (allergic)...
Group 2 innate lymphoid cells (ILC2s) and type 2 helper T cells (Th2 cells) are the primary source of interleukin 5 (IL-5) and IL-13 during type 2 (allergic) inflammation in the lung. In Th2 cells, T cell receptor (TCR) signaling activates the transcription factors nuclear factor of activated T cells (NFAT), nuclear factor κB (NF-κB), and activator protein 1 (AP-1) to induce type 2 cytokines. ILC2s lack a TCR and respond instead to locally produced cytokines such as IL-33. Although IL-33 induces AP-1 and NF-κB, NFAT signaling has not been described in ILC2s. In this study, we report a nonredundant NFAT-dependent role for lipid-derived leukotrienes (LTs) in the activation of lung ILC2s. Using cytokine reporter and LT-deficient mice, we find that complete disruption of LT signaling markedly diminishes ILC2 activation and downstream responses during type 2 inflammation. Type 2 responses are equivalently attenuated in IL-33- and LT-deficient mice, and optimal ILC2 activation reflects potent synergy between these pathways. These findings expand our understanding of ILC2 regulation and may have important implications for the treatment of airways disease.
Topics: Animals; Drug Synergism; Homeostasis; Interleukin-33; Leukotrienes; Lymphocyte Activation; Lymphocytes; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; NFATC Transcription Factors; Signal Transduction
PubMed: 28011865
DOI: 10.1084/jem.20161274 -
IUBMB Life Mar 2019Tilorone hydrochloride, a low-molecular-weight synthetic compound, induces interferon production and has been reported to have both antiviral and antitumor activities....
Tilorone hydrochloride, a low-molecular-weight synthetic compound, induces interferon production and has been reported to have both antiviral and antitumor activities. Here, we have demonstrated the ability of tilorone to activate NK cells and specific subpopulations of cytotoxic CD4+ and CD8+ T lymphocytes that recognize immune-evasive tumor cells and kill them via the FasL-Fas interaction. We have also performed a comparative analysis of characteristics between lymphocytes activated in the fraction of human peripheral blood mononuclear cells (PBMCs) upon treatment with different stimulants of the immune response: tilorone, innate immunity protein Tag7, and cytokine IL-2, a regulator of adaptive immunity. The results show that all the three stimulants, regardless of their nature, activate lymphocytes that are identical with respect to the spectrum of target cells, phenotype, and mechanism of cytotoxic action However, these stimulants induce different mechanisms of lymphocyte activation at early stages of the immune response. © 2018 IUBMB Life, 71(3):376-384, 2019.
Topics: Animals; Antineoplastic Agents; Cell Line; Coculture Techniques; Culture Media, Conditioned; Cytokines; Cytotoxicity, Immunologic; Fas Ligand Protein; Fibroblasts; Gene Expression Regulation, Leukemic; HeLa Cells; Humans; Immunity, Innate; Interleukin-2; K562 Cells; Killer Cells, Natural; Lymphocyte Activation; Mice; Primary Cell Culture; T-Lymphocytes, Cytotoxic; Tilorone; fas Receptor
PubMed: 30537230
DOI: 10.1002/iub.1985 -
Immunological Reviews Aug 2008Inhibitory receptors specific for major histocompatibility complex (MHC) class I molecules govern the capacity of natural killer (NK) cells to attack class I-deficient... (Review)
Review
Inhibitory receptors specific for major histocompatibility complex (MHC) class I molecules govern the capacity of natural killer (NK) cells to attack class I-deficient cells ('missing-self recognition'). These receptors are expressed stochastically, such that the panel of expressed receptors varies between NK cells. This review addresses how the activity of NK cells is coordinated in the face of this variation to achieve a repertoire that is self-tolerant and optimally reactive with diseased cells. Recent studies show that NK cells arise in normal animals or humans that lack any known inhibitory receptors specific for self-MHC class I. These NK cells exhibit self-tolerance and exhibit functional hyporesponsiveness to stimulation through various activating receptors. Evidence suggests that hyporesponsiveness is induced because these NK cells cannot engage inhibitory MHC class I molecules and are therefore persistently over-stimulated by normal cells in the environment. Finally, we discuss evidence that hyporesponsiveness is a quantitative trait that varies depending on the balance of signals encountered by developing NK cells. Thus, a tuning process determines the functional set-point of NK cells, providing a basis for discriminating self from missing-self, and at the same time endowing each NK cell with the highest inherent responsiveness compatible with self-tolerance.
Topics: Animals; Antigens, CD; Antigens, Surface; Cell Adhesion Molecules; Cytotoxicity, Immunologic; Histocompatibility Antigens Class I; Humans; Killer Cells, Natural; Lectins, C-Type; Lymphocyte Activation; Mice; Mice, Transgenic; NK Cell Lectin-Like Receptor Subfamily B; Receptors, Immunologic; Receptors, KIR; Self Tolerance; Signaling Lymphocytic Activation Molecule Family; T-Lymphocytes, Regulatory; Trans-Activators
PubMed: 18759922
DOI: 10.1111/j.1600-065X.2008.00658.x