Disease relevance of TNFRSF4

• Soluble OX40 is detectable in serum of subpopulations of healthy donors and patients with autoimmune disease and cancer [1].
• A marked increase in the percentage of CD134/ CD137+ T cells at disease onset may indicate the need for more aggressive therapy in Graves' disease and for a greater duration than the standard 3-year period [2].
• After infection with LCMV and influenza virus, OX40-/- mice retain primary and memory cytotoxic T cell responses with normal expansion and decline of specific CTL [3].
• The HTLV-I tax protein transcriptionally modulates OX40 antigen expression [4].
• We found that the degree of infiltration by CD25(+) and intratumoral OX40(+) lymphocytes showed a tendency to decrease in thicker melanomas [5].

High impact information on TNFRSF4

• The OX40 and its ligand gp34, which are induced by HTLV-I infection and directly mediate the adhesion between HTLV-I-infected T cells and vascular endothelial cells, may be critically involved in the localization and proliferation of HTLV-I-infected cells in vivo [6].
• OX40 signals promote T-cell expansion after the hypo-responsive phenotype is induced and restore normal functionality [7].
• The OX-40 protein was selectively upregulated on encephalitogenic myelin basic protein (MBP)-specific T cells at the site of inflammation during the onset of experimental autoimmune encephalomyelitis (EAE) [8].
• Expression of the human OX-40 antigen was also found in peripheral blood of patients with acute graft-versus-host disease and the synovia of patients with rheumatoid arthritis during active disease [8].
• The unique expression of the OX-40 molecule may provide a novel therapeutic strategy for eliminating autoreactive CD4+T cells that does not require prior knowledge of the pathogenic autoantigen [8].

Chemical compound and disease context of TNFRSF4

• These results suggest that immunostaining for OX40/CD134 may be helpful in subclassification of peripheral T-cell lymphomas and that the patterns of TNF receptor family expression in these tumors may parallel those seen within nonneoplastic helper T-cell subsets [9].
• Four patients with rhinitis and two patients with ACD were available for studying the immunophenotype and the TCR-Vbeta repertoire of bacampicillin induced lymphoblasts as well as the cytokine profiles and expression of the activation markers CD23 and CD134 in primary PBMC cultures [10].

Biological context of TNFRSF4

• Moreover, CD134 ligand, like G-CSF, maintained anti-apoptotic Mcl-1 levels and inhibited cleavage of the pro-apoptotic Bcl-2 family members Bid and Bax in these cells, suggesting that CD134-mediated signals block apoptosis pathways proximal to mitochondria activation [11].
• BACKGROUND: CD134 (OX40) is a member of the tumor necrosis factor receptor superfamily that is expressed as a late event in T-cell activation and contributes to the generation of immunologic memory [12].
• Pimecrolimus inhibits up-regulation of OX40 and synthesis of inflammatory cytokines upon secondary T cell activation by allogeneic dendritic cells [13].
• Taken together, pimecrolimus inhibits T cell proliferation and Th1 cytokine synthesis and also prevents the up-regulation of the OX40 co-receptor on primed T cells indicating its potential in the therapy of chronic inflammation and autoimmunity [13].
• We generated OX40-/- mice and found that the formation of extrafollicular plasma cells, germinal centers, and antibody responses was independent of OX40 [3].

Anatomical context of TNFRSF4

• The OX40-OX40 ligand pathway is involved in the subsequent expansion of memory antigen-specific T cells [14].
• Molecular transfer of CD40 and OX40 ligands to leukemic human B cells induces expansion of autologous tumor-reactive cytotoxic T lymphocytes [14].
• Functional expression of CD134 by neutrophils [11].
• OX40 expression is observed on activated T cells, while OX40L is expressed in antigen-presenting cells [15].
• The involvement of costimulatory markers OX40/4-1BB/4-1BBL leads to the enhancement of signals which are necessary for lymphocyte activation in addition to the antigen-specific signal and may prevent anergy [2].

Associations of TNFRSF4 with chemical compounds

• CD134 (OX40) is a member of the tumor necrosis factor (TNF) receptor superfamily expressed on activated T cells [11].
• In the present study, we compared the potency of pimecrolimus and cyclosporin A (CyA) to inhibit cytokine synthesis of alloantigen-primed T cells and the expression of CD134 (OX40), an inducible co-receptor molecule thought to be critical for the survival and expansion of inflammation-mediating T cells [13].
• The expression of TNFRSF4, one of the genes in this family, was found to be 48 times higher in allergen-challenged cells than in diluent-challenged cells [16].
• Human peripheral blood lymphocytes sensitised to PPD respond to in vitro stimulation with increased expression of CD69 and CD134 activation antigens and production of Th-1 type cytokines [17].

Regulatory relationships of TNFRSF4

• Reverse transcriptase-PCR analysis showed that expression of RANTES mRNA was induced after incubation with soluble OX40 and this induction was inhibited by anti-gp34 mAb [18].
• HUVECs expressing high levels of gp34 were stimulated with recombinant soluble OX40 or mock control and subjected to analysis using cDNA expression arrays [18].

Other interactions of TNFRSF4

• Pimecrolimus inhibited surface expression of OX40 and prevented the up-regulation of CD25 and CD54 with a 10-fold higher potency compared to CyA [13].
• The analysis of OX40/4-1BB expression in patients with newly recognized Graves' disease revealed a statistically significant increase in the percentage of CD134+ T cells (7% vs 1.4%, p <0.001) and CD137+ T cells (3.2% vs 0.8%, p <0.04) compared to the control group [2].
• Through interactions with OX40 ligand, OX40 delivers potent costimulatory signals to T cells [1].
• Activation of OX40 signal transduction pathways leads to tumor necrosis factor receptor-associated factor (TRAF) 2- and TRAF5-mediated NF-kappaB activation [19].
• The effects of OX40 costimulation on Th cell differentiation are observed in the presence of optimal and suboptimal CD28 stimulation [20].

Analytical, diagnostic and therapeutic context of TNFRSF4

• CONCLUSIONS: These results show that CD134-CD134L interaction plays an important role in the co-stimulatory cascade and that blockade of this molecular interaction may be of therapeutic value in helping to prevent allograft rejection [12].
• With this ELISA, the existence of naturally occurring soluble forms of OX40 (sOX40) could be demonstrated for the first time [1].
• Identification of a soluble OX40 isoform: development of a specific and quantitative immunoassay [1].
• In the present study, we identified the rat ligand for OX40 (OX40L) by molecular cloning [21].
• The heterodimer of OX40 and 4-1BB was identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under nonreduced conditions and was associated with the tumor receptor-associated factor (TRAF) family proteins in a unique manner [22].

References