1,720,998 research outputs found
Modulation of tumour immunity: a patent evaluation of WO2015026684A1
No full textA high percentage of regulatory T cells (Tregs) among tumour-infiltrating lymphocytes weakens the immune response against tumours. The anergy of effector T cells (Teff) can be reversed by immune checkpoint treatment, which inhibits Tregs and boosts the activation of Teff. Both effects can be obtained by triggering the glucocorticoid-induced TNF related (GITR) receptor, a co-stimulatory molecule expressed by Teff and Tregs, and by inhibiting the programmed cell death (PD)-1 receptor, an inhibitory molecule expressed by Teff. Patent W02015/026684A1 provides a method of treating human tumours using a combination of a molecule triggering GITR and another inhibiting PD-1. The treatment approach was tested on three murine models of cancer, and the synergic effect of anti-human antibodies (Abs) in combination was tested in mixed lymphocyte reactions. Immune checkpoint treatment can break tolerance towards tumours and promote tumour rejection. The patented approach is very interesting and might be successful. The combined use of PD-1 antagonists and GITR agonists is synergic and tumour-centred, and adverse events might be less problematic than expected. A crucial point in translating the murine studies to humans is the differences between murine and human GITR and the evidence that some anti-human GITR Abs are not agonist
GITR/GITRL: More than an effector T cell co-stimulatory system
No full textGlucocorticoid-induced TNFR-related protein (GITR) is a member of the TNFR superfamily, expressed in several cells and tissues including T lymphocytes, NK cells and antigen-presenting cells (APC). GITR activation, upon interaction with its ligand (GITRL), functions as a co-activating signal. GITRL is mainly expressed on APC and GITR/GITRL interaction is important for the development of immune response. This review summarizes recent results about the GITR/GITRL system, focusing on the interplay between APC, effector and regulatory T cells
GILZ as a mediator of the anti-inflammatory effects of glucocorticoids
Full text linkGlucocorticoid-Induced Leucine Zipper (GILZ) is a dexamethasone-inducible gene that mediates glucocorticoid (GC) actions in a variety of cell types, including many cells of immune system. In particular, GILZ can control T cell activities such as activation and differentiation, mainly through its ability to homo- and hetero-dimerize with partner proteins like NF-κB, Ras and C/EBP. These protein-protein interactions control the regulation of proinflammatory target genes. A number of in vitro and in vivo studies using mouse models of inflammatory diseases demonstrate an anti-inflammatory role for GILZ. Here we summarize those studies that make GILZ eligible as an anti-inflammatory protein through which glucocorticoids can act. These findings permit the future development of pharmacological tools that mimic the therapeutic effects of GCs while avoiding the detrimental ones
Pharmacological modulation of GITRL/GITR system: therapeutic perspectives
No full textGlucocorticoid-induced TNFR-related (gitr) is a gene coding for a member of the TNF receptor superfamily. GITR activation by its ligand (GITRL) influences the activity of effector and regulatory T cells, thus participating in the development of immune response against tumours and infectious agents, as well as in autoimmune and inflammatory diseases. Notably, treating animals with GITR-Fc fusion protein ameliorates autoimmune/inflammatory diseases while GITR triggering, by treatment with anti-GITR mAb, is effective in treating viral, bacterial and parasitic infections, as well in boosting immune response against tumours. GITR modulation has been indicated as one of the top 25 most promising research areas by the American National Cancer Institute, and a clinical trial testing the efficacy of an anti-GITR mAb in melanoma patients has been started. In this review, we summarize results regarding: (i) the mechanisms by which GITRL/GITR system modulates immune response; (ii) the structural and functional studies clearly demonstrating differences between GITRL/GITR systems of mice and humans; (iii) the molecules with pharmacological activities including anti-GITR mAbs, GITR-Fc and GITRL-Fc fusion proteins, GITRL in monomer or multimer conformation; and (iv) the possible risks deriving from GITRL/GITR system pharmacological modulation. In conclusion, GITR triggering and inhibition could be useful in treating tumours, infectious diseases, as well as autoimmune and inflammatory diseases. However, differences between mouse and human GITRL/GITR systems suggest that further preclinical studies are needed to better understand how safe therapeutic results can be obtained and to design appropriate clinical trials
How Glucocorticoids Affect the Neutrophil Life
Full text linkGlucocorticoids are hormones that regulate several functions in living organisms and synthetic glucocorticoids are the most powerful anti-inflammatory pharmacological tool that is currently available. Although glucocorticoids have an immunosuppressive effect on immune cells, they exert multiple and sometimes contradictory effects on neutrophils. From being extremely sensitive to the anti-inflammatory effects of glucocorticoids to resisting glucocorticoid-induced apoptosis, neutrophils are proving to be more complex than they were earlier thought to be. The aim of this review is to explain these complex pathways by which neutrophils respond to endogenous or to exogenous glucocorticoids, both under physiological and pathological conditions
L-GILZ binds and inhibits nuclear factor κB nuclear translocation in undifferentiated thyroid cancer cells
No full textProto-oncogene mutations and abnormal activation of mitogen-activated protein kinase (MAPK) signalling are recurrently found in thyroid cancers. Some thyroid neoplasms respond to drugs that inhibit MAPK pathway activation. Previously, we showed that pharmacological inhibition of MAPK in thyroid cancer cells inhibits cell proliferation and upregulates L-GILZ (long glucocorticoid-induced leucine zipper), a protein with anti-oncogenic and antiproliferative activity, and that L-GILZ is partially responsible for the antiproliferative activity of MAPK inhibitors. Here, we demonstrate that pharmacological inhibition of MAPK in the anaplastic thyroid cancer cell line CAL-62 upregulated L-GILZ, which bound nuclear factor κB (NF-κB) and inhibited its nuclear translocation. These data demonstrate a unique L-GILZ-mediated molecular mechanism that, by trapping NF-κB in the cytoplasm, contributes to the inhibition of proliferation induced by drugs targeting the MAPK transduction cascade. Enhanced knowledge of the mechanism of action of MAPK pathway-inhibiting drugs may improve their clinical use
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