Disease relevance of TNFRSF18

• Thus, GITR plays a key role in dominant immunological self-tolerance maintained by CD25(+)CD4(+) regulatory T cells and could be a suitable molecular target for preventing or treating autoimmune disease [1].
• GITR expression on CD4+ T cells has been shown to correlate with the disease course of noninfectious uveitis [2].
• These data indicate that GITR-mediated macrophage activation may promote atherogenesis via the induction of pro-atherogenic cytokines/chemokines, and destabilize the atherosclerotic plaques via the induction of the matrix-degrading enzyme, MMP-9 [3].
• We have measured the levels of GITR and GITRL in plasma from atopic dermatitis patients and found it not to be increased [4].
• In this study, we investigated the effect of an agonistic mAb (DTA-1) against glucocorticoid-induced TNF receptor (GITR) in a murine model of systemic lupus erythematosus-like chronic graft-vs-host disease (cGVHD) [5].

High impact information on TNFRSF18

• Phenotypic and functional analyses demonstrated that they were antigen-specific CD4(+) Treg cells expressing CD25 and GITR molecules and possessing suppressive activity on the proliferative response of naive CD4(+) T cells to anti-CD3 antibody stimulation [6].
• Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance [1].
• This unique function of OX40L was not shared by two costimulatory TNF family members, GITR ligand and 4-1BB ligand [7].
• The constitutive expression of a transfected GITR gene induced resistance to anti-CD3 mAb-induced apoptosis, whereas antisense GITR mRNA expression lead to increased sensitivity [8].
• Thus, GITR is a new member of tumor necrosis factor/nerve growth factor receptor family involved in the regulation of T cell receptor-mediated cell death [8].

Chemical compound and disease context of TNFRSF18

• Glucocorticoid-induced Tumour Necrosis Factor Receptor (GITR) and its Ligand (GITRL) in Atopic Dermatitis [4].
• Enhancement of Teff was achieved by infection of tumor cells with adenovirus expressing glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR), and suppression of Treg, by depletion of CD4+CD25+ naturally occurring Treg by administration of anti-CD25 monoclonal antibody (PC61) or low-dose cyclophosphamide [9].
• Combined regimen of cisplatin, doxorubicin, and alpha-2b interferon in the treatment of advanced malignant pleural mesothelioma: a Phase II multicenter trial of the Italian Group on Rare Tumors (GITR) and the Italian Lung Cancer Task Force (FONICAP) [10].

Biological context of TNFRSF18

• Cotransfection of hGITRL and hGITR in Jurkat T leukemia cells inhibited antigen-receptor-induced cell death [11].
• The hGITR gene mapped to chromosome 1p36, near a cluster of five genes encoding TNFR homologs [1] [6] [11].
• However, the molecular mechanisms of GITR-induced signal transduction that influence physiologic and pathologic immune responses are not well understood [12].
• The protection toward T cell receptor-induced apoptosis was specific, because other apoptotic signals (Fas triggering, dexamethasone treatment, or UV irradiation) were not modulated by GITR transfection [8].
• GITR is also involved in the inhibition of T-cell receptor-induced apoptosis and the upregulation of inducible nitric oxide synthase (iNOS) [2].

Anatomical context of TNFRSF18

• Thus, hGITRL and hGITR may modulate T lymphocyte survival in peripheral tissues [11].
• The ligand for AITR (AITRL) was found to be an undescribed member of the TNF family, which is expressed in endothelial cells [13].
• Using the same approaches, we found GITR is expressed by activated natural killer (NK) cells and T cells [14].
• Yeast two-hybrid assays and studies in HEK293 cells and primary lymphocytes indicated interactions between TRAF2 and GITR mediated by acidic residues in the cytoplasmic domain of the receptor [12].
• GITR resulted to be expressed in normal T lymphocytes from thymus, spleen, and lymph nodes, although no expression was detected in other nonlymphoid tissues, including brain, kidney, and liver [8].

Associations of TNFRSF18 with chemical compounds

• By comparing untreated and dexamethasone-treated murine T cell hybridoma (3DO) cells by the differential display technique, we have cloned a new gene, GITR (glucocorticoid-induced tumor necrosis factor receptor family-related gene) encoding a new member of the tumor necrosis factor/nerve growth factor receptor family [8].
• Tumor necrosis factor receptor (TNFR) family members such as glucocorticoid-induced TNFR (GITR) control T cell activation, differentiation, and effector functions [15].
• Genetic and pharmacological inhibition of GITR-GITRL interaction reduces chronic lung injury induced by bleomycin instillation [16].
• In contrast, in MH134 cells, PC61 induced partial tumor growth delay only when injected prior to tumor cell inoculation, and low-dose cyclophosphamide showed no effect, but GITR, particularly when administered in vitro, inhibited tumor growth [9].

Regulatory relationships of TNFRSF18

• Direct contact between activated CD4(+) T and FLSs also induced the production of MMP-13, and neutralization of hGITR on activated CD4(+) T cells during coculture decreased the amount of MMP-13 produced by FLSs [17].

Other interactions of TNFRSF18

• Here we report the identification of a new member, activation-inducible TNFR family member (AITR), which belongs to this subfamily, and its ligand [13].
• OBJECTIVE: We tested the hypothesis that human glucocorticoid-induced tumor necrosis factor receptor (hGITR/TR11) expressed on the surface of activated CD4(+) T cells is responsible for up-regulating the production of matrix metalloproteinase (MMP)-13 by fibroblast-like synoviocytes (FLSs) [17].
• GITR-induced activation of NF-kappaB is blocked by A20, an NF-kappaB-inducible protein that interacts with TRAFs and functions in a negative feedback mechanism downstream of other TNFRs [12].
• TRAF4 functions as an intermediate of GITR-induced NF-kappaB activation [18].
• In sum, our studies indicate that TRAF5 plays a crucial role in GITR-induced signaling pathways that augment T cell activation [15].

Analytical, diagnostic and therapeutic context of TNFRSF18

• Expressions of hGITR ligand (hGITRL) on the surface of FLSs and hGITR on the surface of human CD4(+) T cells were analyzed by flow cytometry and RT-PCR [17].
• This abrogation of immunosuppression by GITRL-RPE was dependent on GITR-GITRL interaction and could not be mimicked by anti-CD28 antibody [19].
• Immunohistochemistry and in situ hybridization analyses of human atherosclerotic plaques demonstrated that GITR and its ligand are expressed mainly in lipid-rich macrophages [3].
• Immunohistochemistry showed GITR and GITRL were present in few dermal cells of both patients with atopic dermatitis, and normal healthy volunteers, and often locali zed in close proximity to each other [4].
• Attempts to block or eliminate Treg cells have been made by the use of chemotherapy, anti-CD25 or anti-CTLA-4 antibodies, IL-2-toxin chimeric proteins or Glucocorticoid-induced TNF-like Receptor (GITR) and CD134/OX-40 ligands [20].

References