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1.
A high percentage of regulatory T cells (Tregs) among tumor-infiltrating lymphocytes weakens the immune response against tumors. 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 receptor-related (GITR), a costimulatory molecule expressed by Teff and Tregs, and by inhibiting the programmed cell death (PD)-1 receptor, an inhibitory molecule expressed by Teff. Patent W02015026684A1 provides a method of treating human tumors 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 antihuman antibodies (Abs) in combination was tested in mixed lymphocyte reactions. Immune checkpoint treatment can break tolerance toward tumors and promote tumor rejection. The patented approach is very interesting and might be successful. The combined use of PD-1 antagonists and GITR agonists is synergic and tumor-centered, 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 antihuman GITR Abs are not agonists.  相似文献   
2.
The magnitude of adaptive T cell responses is controlled by costimulatory molecules, including cell-surface associated members of the tumor necrosis factor receptor (TNF-R) family that modulate T cell receptor (TCR)-dependent activation, and by a network of regulatory T (Treg) cells that downregulate effector T cell functions. The glucocorticoid-induced TNF-R (GITR) is a type I transmembrane protein that is expressed at high levels on CD4+ CD25+ Treg cells and on activated effector T cells. In vitro studies have shown that ligation of GITR with an agonistic monoclonal antibody (mAb) could abrogate the suppressive activity of Treg cells and enhance the survival, proliferation and effector functions of TCR-activated CD4+ and CD8+ T cells. Furthermore, studies in mice demonstrated that mAb-triggered GITR stimulation could also markedly augment antitumor and virus-specific T cell responses in vivo. This has suggested that agonistic anti-GITR mAbs may serve to stimulate T cell immunity for therapeutic purposes. Accordingly, the present patent application reports the generation of a novel agonistic murine mAb to human GITR that is able to reverse Treg-mediated suppression and costimulate T cell activation in vitro. Humanized versions of the mAb are also described, but without providing data on their binding and functional properties. Further studies will be needed to fully appraise the potential utility of these human mAbs for the immunotherapy of cancer or viral infections.  相似文献   
3.
Over the past decade, our understanding of cancer immunotherapy has evolved from assessing peripheral responses in the blood to monitoring changes in the tumour microenvironment. Both preclinical and clinical experience has taught us that modulation of the tumour microenvironment has significant implications to generating robust antitumour immunity. Clinical benefit has been well documented to correlate with a tumour microenvironment that contains a dense infiltration of CD8+CD45RO+ T effectors and a high ratio of CD8+ T cells to FoxP3+ regulatory T cells (Tregs). In preclinical tumour models, modulation of the Glucocorticoid induced TNF receptor (GITR)/GITR ligand (GITRL) axis suggests this pathway may provide the desired biological outcome of inhibiting Treg function while activating CD8+ T effector cells. This review will focus on the scientific rationale and considerations for the therapeutic targeting of GITR for cancer immunotherapy and will discuss possible combination strategies to enhance clinical benefit.  相似文献   
4.
Glucocorticoid-induced tumor-necrosis factor receptor (GITR) and its ligand, GITRL, play significant roles in regulating immune responses. It is clear that human soluble GITRL (hsGITRL) transduces signal activity through multiple oligomerization states. To develop human soluble trimeric GITRL protein as a potential therapeutic target, we explored the link of the isoleucine-zipper (ILZ) motif to the N-terminus of the human soluble GITRL with two leucine sequences. hsGITRL, with the ILZ motif (ILZ-hsGITRL), was firstly expressed in Escherichia coli, which exhibited a predominant trimer when identified by Sephadex G-100 filtration and non-reducing SDS–polyacrylamide gel electrophoresis (SDS-PAGE). The significantly higher biological activity of the ILZ-hsGITRL compared with hsGITRL was confirmed by CD4+ T proliferation, interferon-γ (IFN-γ) secretion and binding activity assay. To reveal and compare the underlying mechanisms, the level of extracellular signal-regulated kinase-1/2 (ERK1/2) phosphorylation was examined, indicating that ILZ-hsGITRL induced more persistent and stronger ERK1/2 activation than hsGITRL. In conclusion, the incorporation of an ILZ motif could markedly improve the costimulation of hsGITRL.  相似文献   
5.
目的研究类风湿关节炎(RA)患者外周血糖皮质激素诱导的肿瘤坏死因子受体家族相关基因(GITR)在CD4^+CD25^+T细胞中的表达及细胞因子IL-6、IL-17的浓度水平变化,探讨两者在RA发病中的作用。方法流式细胞术检测GITR在CD4^+CD25^+T细胞的阳性表达率,ELISA法检测血清中IL-6、IL-17的浓度水平并分析GITR阳性表达率与RA患者DAS28的关系。结果 RA组中的CD4^+CD25^+Treg细胞表面GITR阳性表达率(3.03±1.95)%明显低于健康对照组(7.68±2.01)%,RA组中IL-6,IL-17浓度水平明显高于健康对照组(P〈0.05)。GITR阳性表达率与DAS28呈明显负相关。结论 RA患者GITR+CD4^+CD25^+T细胞阳性表达率低下,与RA发病及疾病的活动性有一定的相关性。  相似文献   
6.
李杰  刘超 《国外医学:内科学分册》2009,36(8):495-496,F0003,F0004
Graves病(GD)是一种自身免疫性甲状腺疾病,其发病机制涉及到细胞免疫与体液免疫的异常。新近的研究发现,调节性T细胞(Treg)能够抑制那些逃避的自身反应性T细胞克隆的活性和功能,在自身免疫性甲状腺疾病发病的发生发展中扮演重要角色。在GD的发病过程中,不仅有自身反应性T细胞的参与,也可有抑制免疫反应的自身反应性Treg的参与。而Treg及其表面表达分子叉头/翅膀状螺旋(Foxp3)基因、糖皮质类固醇激素诱导的肿瘤坏死因子受体家族相关受体(GITR)及细胞毒性T淋巴细胞相关抗原(CTLA)-4的高表达可减少GD等自身免疫性疾病的发生。因此提高Treg的反应性,进而抑制自身免疫,是GD很有希望的治疗策略。  相似文献   
7.
目的 研究FOXF3、GITR在口腔扁平苔藓(OLP)组织中的表达及其意义.方法 采用免疫组化方法检测30例OLP组织和15例口腔正常黏膜(NOM)组织中FOXP3、GITR的表达.结果 NOM组FOXP3和GITR均阴性表达;OLP组FOXP3和GITR表达分别较NOM增加(PGITR在OLP组中的表达存在正相关关系.结论 OLP患者FOXP3和GITR呈现高表达,二者可能参与了OLP的发病.  相似文献   
8.
The glucocorticoid-induced tumour necrosis factor (TNF)-receptor (GITR) affects the functions of regulatory T (T(reg)) and effector T (T(eff)) cells, but the significance of this phenomenon is still unclear. To examine the association of single nucleotide polymorphisms (SNPs) in the GITR gene with the expression of GITR molecules on T cells and with the pathological conditions in patients with autoimmune thyroid disease (AITD), we examined the frequencies of four candidate SNPs in AITD patients and healthy volunteers by restriction enzyme analysis and direct sequence analyses. We also analysed the GITR expression on peripheral T(reg) and T(eff) cells in AITD patients by three-colour flow cytometry. The CC genotype in the rs3753348 C/G SNP was significantly more frequent in patients with mild Hashimoto's disease (HD) than in those with severe HD [P = 0·0117, odds ratio (OR) = 3·13]. The AA genotype in the rs2298213 A/G SNP was significantly more frequent in patients with mild HD than in patients with severe HD (P = 0·010, OR = 4·43). All patients and healthy individuals had the GG genotype in rs60038293 A/G and rs11466696 A/G SNPs. The proportions of GITR(+) cells in T(reg) and T(eff) cells were significantly higher in AITD patients with the CC genotype of the rs3753348 SNP than in those with the GG genotype (P = 0·004 and P = 0·011, respectively). In conclusion, the rs3753348 C/G SNP in the GITR is associated with HD prognosis and expression on T(reg) and T(eff) cells.  相似文献   
9.
糖皮质激素诱导的TNFR家族相关受体(GITR),也被称为TNFRSF18、AITR(人类)。静止T细胞低水平表达GITR,而CD4^+CD25^+调节性T细胞则呈高水平表达。GITR与其配体(GITRL)结合后会增强T细胞激活、增殖、分泌细胞因子、MAPKs和NF-κB激活效应、抑制CD4^+CD25^+Treg细胞的功能,从而加强效应性T细胞的活性,有利于增强抗肿瘤免疫和抗病毒免疫。随着生物学环境的变化,GITR激活Siva或者TRAF,起着促进或诱导凋亡的作用。  相似文献   
10.
Tumor necrosis factor (TNF) was first identified in 1984 as a cytokine with anti-tumor effects in vitro and in vivo. Extensive research since then has shown that there are at least 18 distinct members of the TNF super family and they exhibit 15-25% amino acid sequence homology with each other. These family members bind to distinct receptors, which are homologous in their extracellular domain. These cytokines have been implicated in a wide variety of diseases including tumorigenesis, septic shock, viral replication, bone resorption, rheumatoid arthritis, diabetes, and other inflammatory diseases. TNF blockers have been approved for human use in treating some of these conditions in the United States and other countries. Various members of the TNF super family mediate either proliferation, survival, or apoptosis of cells. Although distinct receptors, all members share a common cell signaling pathway that mediates the activation of nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinases (e.g. c-jun N-terminal kinase). Regulation of cell growth and activation of NF-kappaB and of c-jun N-terminal kinase by the TNF super family is mediated through sequential activation/association of a set of cell signaling proteins named TNF receptor-associated factors, Fas-associated death domain and FADD-like ICE, caspases, receptor-interacting protein, NF-kappaB-inducing kinases, and IkappaBalpha kinases. Both apoptotic and antiapoptotic signals are activated simultaneously by the same cytokine in the same cell. Together these cytokines regulate cell growth/survival/apoptosis in a complex dance of changing partners and overlapping steps.  相似文献   
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