Role Of OX40 Research Articles

The role of OX40 ligand/OX40 axis signalling in atopic dermatitis.

Atopic dermatitis (AD) is a heterogeneous inflammatory condition involving multiple immune pathways mediated by pathogenic T cells. OX40 ligand (OX40L) and OX40 are costimulatory immune checkpoint molecules that regulate effector and memory T-cell activity and promote sustained immune responses in multiple immunological pathways, including T helper (Th)2, Th1, Th17 and Th22. As such, OX40L/OX40 signalling between antigen-presenting cells (APCs) and activated T cells postantigen recognition promotes pathogenic T-cell proliferation and survival. Under inflammatory conditions, OX40L is upregulated on APCs, enhancing the magnitude of antigen-specific T-cell responses and secretion of proinflammatory cytokines. In AD, OX40L/OX40 signalling contributes to the amplification and chronic persistence of T-cell-mediated inflammation. Recent therapeutic success in clinical trials has highlighted the importance of the OX40L/OX40 axis as a promising target for the treatment of AD. Here, we discuss the many factors that are involved in the expression of OX40L and OX40, including the cytokine milieu, antigen presentation, the inflammatory environment in AD, and the therapeutic direction influenced by this costimulatory pathway.

An OX-Tra'Ordinary Tale: The Role of OX40 and OX40L in Atopic Dermatitis.

The transmembrane glycoprotein OX40 receptor (OX40) and its ligand, OX40L, are instrumental modulators of the adaptive immune response in humans. OX40 functions as a costimulatory molecule that promotes T cell activation, differentiation, and survival through ligation with OX40L. T cells play an integral role in the pathogenesis of several inflammatory skin conditions, including atopic dermatitis (AD). In particular, T helper 2 (TH2) cells strongly contribute to AD pathogenesis via the production of cytokines associated with type 2 inflammation (e.g., IL-4, IL-5, IL-13, and IL-31) that lead to skin barrier dysfunction and pruritus. The OX40-OX40L interaction also promotes the activation and proliferation of other T helper cell populations (e.g., TH1, TH22, and TH17), and AD patients have demonstrated higher levels of OX40 expression on peripheral blood mononuclear cells than healthy controls. As such, the OX40-OX40L pathway is a potential target for AD treatment. Novel therapies targeting the OX40 pathway are currently in development, several of which have demonstrated promising safety and efficacy results in patients with moderate-to-severe AD. Herein, we review the function of OX40 and the OX40-OX40L signaling pathway, their role in AD pathogenesis, and emerging therapies targeting OX40-OX40L that may offer insights into the future of AD management.

Analysis of the OX40/OX40L immunoregulatory axis combined with alternative immune checkpoint molecules in pancreatic ductal adenocarcinoma.

Immune checkpoint modulation has been a vital therapeutic option in many malignancies, and targeting of novel immune checkpoints, including OX40/OX40L costimulatory signaling, is being assessed in clinical trials. However, little is known about the role of OX40 and OX40L in pancreatic ductal adenocarcinoma (PDAC). Thus, we investigated the clinical significance of OX-40 and OX40L and their associations with alternative immune checkpoints, immune infiltrates, clinicopathological features, and clinical outcomes. We performed multiplexed immunofluorescence staining for OX40, OX40L, CD8, and CD68 using tissue microarrays from 255 patients. Immunohistochemistry data for PD-L1, B7-H3, B7-H4, CD3, and Foxp3 were analyzed. And the RNA sequencing data of OX40/OX40L in The Cancer Genome Atlas and International Cancer Genome Consortium databases were also evaluated. The positive rates for OX40 on tumor cells (TCs) and immune cells (ICs) were 8.6% and 10.2%, respectively, and the positive rates for OX40L on TCs, ICs, and macrophages were 20%, 40.4%, and 12.9%, respectively. OX40 was associated with favorable clinicopathological features. OX40+ on ICs, OX40L+ on TCs, or OX40L+ on macrophages, rather than the total gene and protein levels of OX40/OX40L, were associated with improved survival. OX40+ on ICs and OX40L+ on macrophages were independent factors of clinical outcomes. Moreover, we could more accurately stratify patients through the combination of OX40 on ICs and OX40L on TCs, and patients with OX40+ ICs and OX40L+CK+ showed the best outcome. And we demonstrated that patients with OX40-ICs and low CD8+ T cells infiltration had unfavorable survival. Intriguingly, OX40+ ICs or OX40L+ macrophages demonstrated superior survival in patients with PD-L1 negativity than in those with PD-L1 positivity. Furthermore, OX40+ ICs were correlated with negative B7-H4 on TCs, high densities of CD3 T cells, and high densities of Foxp3 T cells; OX40+ TCs and OX40L+ TCs were associated with low densities of Foxp3 T cells. We identified OX40 and OX40L as promising predictors for prognosis in PDAC.

Role of OX40 and its ligand as costimulatory modulators in cancer immunotherapy

<abstract> Body's defence mechanism has ability to combat tumour cells but tumour cells can circumvent immune system in order to flourish. Therefore, current research focuses on reinvigorating immune system to combat against extensive range of human malignancies through immunotherapy. Recently, immuno-therapy has demonstrated beneficial outcomes in cancers treatment but the main drawbacks are primary and acquired resistance to the therapeutic agents and immune-related toxicities. Therefore, novel immune therapies are direly required. Co-stimulatory molecules such as TNF Receptor Superfamily Member 4 (OX40, CD134) and its ligand TNF Superfamily Member 4 (CD252, OX40L) are expressed on different immune cells. The mutual interaction between OX40 and its ligand (OX40/OX40L) decreases the functional capacity of immunosuppression offered by regulatory T cells (Tregs) and induces the proliferation of T cells against specific antigen enhancing the immune response. Many clinical trials are focusing on OX40/OX40L therapeutic agents to find out whether they have therapeutic effect on cancer treatment. The initial phase trials result of OX40 and its ligands focusing therapeutic agents are encouraging but still not sufficient. This review will concentrate on the cellular and molecular pathways of OX40-mediated T-cell co-stimulation, the expression of OX40 and OX40L in tumours, the implications of their interactions and their under-or over-expression patterns, with particular focus on the function of OX40 in tumours of different origins. Finally, we discuss results of clinical trials of OX40 and OX40L directed pharmacotherapy and the lacunae that need to be filled. </abstract>

Relative Expression of OX40, OX40L mRNA, and OX40L Serum Levels in Women with Recurrent Spontaneous Abortion

ABSTRACTThis study determined the roles of OX40 and OX40L in women with recurrent spontaneous abortion (RSA). We compared the expression of OX40 and OX40L genes in peripheral blood mRNA levels and serum levels of OX40L in women with a history of RSA to the control group. In this case-control study, 40 women with a history of RSA (case group), and 40 others with no history of abortion (control group) were investigated. The expressions of OX40 mRNA and OX40L mRNA were determined in the two groups using the quantitative polymerase chain reaction. Also, the enzyme-linked immunosorbent assay was used to determine the levels of serum OX40L in the two groups. There were no significant differences in the maternal age of women in the two groups (30.1 ± 4.28 years in the case vs. 30.03 ± 4.23 years in the control group). There was no difference in terms of the levels of OX40 and OX40L mRNA between the groups (p = 0.08 and p = 0.56, respectively). In addition, there was no significant correlation between the expression of OX40 and OX40L mRNA levels with age or the number of abortions. The correlation between OX40 and OX40L mRNA levels was not significant. RSA history group turned to show a higher level of serum OX40L than the control group (p = 0.03). In conclusion, our findings demonstrated that the expression of OX40 mRNA and OX40L mRNA was similar between women with a history of RSA and the control group. The elevation of serum OX40L level may be considered as a risk factor for RSA.

OX40 regulates pressure overload-induced cardiac hypertrophy and remodelling via CD4+ T-cells.

OX40, which belongs to the tumour necrosis factor (TNF)-receptor family, is a costimulatory receptor that can potentiate T-cell receptor signalling on the surface of T-lymphocytes. The role of OX40in non-immune systems, particularly the cardiovascular system, has not been defined. In the present study, we observed a noticeable increase in OX40 expression during cardiac remodelling in rodent heart. In the present study, cardiac hypertrophy was induced by aortic banding (AB) in OX40 knockout (KO) mice and wild-type (WT) mice. After 8weeks, the OX40 KO mice showed significantly attenuated cardiac hypertrophy, fibrosis and inflammation as well as preserved cardiac function compared with the WT mice. Follow-up invitro studies suggested that CD4+ T-lymphocyte proliferation and pro-inflammatory cytokine release were significantly decreased, whereas anti-inflammatory cytokine release was considerably increased in OX40 KO mice compared with WT mice as assessed by Cell Counting Kit-8 (CCK-8) assay and ELISA. Co-culturing neonatal rat cardiomyocytes with the activated supernatant of CD4+ T-lymphocytes from OX40 KO mice reduced the hypertrophy response. Interestingly, OX40 KO mice with reconstituted CD4+ T-lymphocytes presented deteriorated cardiac remodelling. Collectively, our data indicate that OX40 regulates cardiac remodelling via the modulation of CD4+ T-lymphocytes.

New Insights on OX40 in the Control of T Cell Immunity and Immune Tolerance In Vivo

OX40 is a T cell costimulatory molecule that belongs to the TNFR superfamily. In the absence of immune activation, OX40 is selectively expressed by Foxp3(+) regulatory T cells (Tregs), but not by resting conventional T cells. The exact role of OX40 in Treg homeostasis and function remains incompletely defined. In this study, we demonstrate that OX40 engagement in vivo in naive mice induces initial expansion of Foxp3(+) Tregs, but the expanded Tregs have poor suppressive function and exhibit features of exhaustion. We also show that OX40 enables the activation of the Akt and Stat5 pathways in Tregs, resulting in transient proliferation of Tregs and reduced levels of Foxp3 expression. This creates a state of relative IL-2 deficiency in naive mice that further impacts Tregs. This exhausted Treg phenotype can be prevented by exogenous IL-2, as both OX40 and IL-2 agonists drive further expansion of Tregs in vivo. Importantly, Tregs expanded by both OX40 and IL-2 agonists are potent suppressor cells, and in a heart transplant model, they promote long-term allograft survival. Our data reveal a novel role for OX40 in promoting immune tolerance and may have important clinical implications.

Suppression of CCR5-Tropic HIV Type 1 Infection by OX40 Stimulation via Enhanced Production of β-Chemokines

To elucidate the immunological role for the costimulatory molecule OX40 against the early stage of HIV-1 infection, fresh peripheral blood mononuclear cells (PBMCs) from normal donors were stimulated with immobilized anti-CD3 monoclonal antibody (mAb) together with soluble anti-CD28 mAb for 24 h, infected with CCR5-tropic (R5) HIV-1, and then cocultured in the presence or absence of OX40 ligand (OX40L). Results of these studied showed that OX40 stimulation led to a marked reduction in levels of p24, the frequency of intracellular p24(+) cells, as well as HIV-1-mediated syncytium formation. The suppression was reversed by anti-OX40L mAb. The mechanism underlying the R5 HIV-1 suppression was shown to be mediated in part by the CCR5-binding β-chemokines RANTES, MIP-1α, and MIP-1β, since the effect of the OX40 stimulation was reversed by a neutralizing antibody mixture against these three β-chemokines. Thus, OX40 stimulation enhanced the production of these CCR5-binding β-chemokines by the activated PBMCs and subsequently down-modulated CCR5 expression on the activated CD4(+) T cells. Taken together, the present data revealed a new role for OX40 in HIV-1 infection and documents the fact that OX40 stimulation suppresses the infection of primary activated PBMCs with R5 HIV-1 via enhanced production of R5 HIV-1 suppressing β-chemokines.

A non‐redundant role for OX40 in the competitive fitness of Treg in response to IL‐2

OX40 stimulation is known to enhance activation of effector T cells and to inhibit induction and suppressive function of Treg. Here we uncovered a novel role of OX40 in sustaining Treg competitive fitness in vivo, during repopulation of lymphopenic hosts and reconstitution of BM chimeras. Defective expansion of OX40-null Treg diminished their ability to suppress inflammation in a model of lymphopenia-driven colitis. OX40-mediated promotion of Treg fitness spanned beyond lymphopenic environments, as endogenous Treg in OX40-null mice showed decreased accumulation during thymic development, enhanced susceptibility to antibody-mediated depletion and defective turnover following thymectomy. In vitro, OX40-deficient Treg were found to be intrinsically hyporesponsive to IL-2, in terms of Stat5 phosphorylation and proliferation, according to elevated SOCS1 content and reduced miR155 expression. Therefore, OX40 is a key factor in shaping Treg sensitivity to IL-2 and promoting their proliferation and survival, toward accurate immune regulation.

OX40 Controls Islet Allograft Tolerance in CD154 Deficient Mice by Regulating FOXP3+ Tregs

The role of OX40 in the islet allograft tolerance, especially in the absence of CD154 costimulation, remains poorly defined. In the present study, we used CD154 deficient mice to critically examine the role of OX40 in the activation of T effector cells and Foxp3+ Tregs and the effect of blocking OX40 on the induction of islet allograft tolerance. We found that blocking OX40 costimulation in CD154 deficient mice induced donor specific tolerance but stimulating OX40 resulted in prompt islet allograft rejection. We also found that OX40 differentially regulates T effector cells and Foxp3+ Tregs, OX40 signaling mediates proliferation of CD154 deficient T effector cells but blocks the induction and suppressor functions of Foxp3+ Tregs. Our data suggest that the role of OX40 in the induction of islet allograft tolerance involves modifying not only the T effector cells but also the Foxp3+ Tregs in CD154 deficient mice.

Novel roles of OX40 in the allograft response

In the past few years, much effort has been focused on the identification of new pathways, new mechanisms, and new therapeutic targets in transplant models. Understanding of T-cell costimulatory molecules remains one of the highly contested areas of research. In this review, we will focus specifically on OX40, and summarize the latest developments on the role of OX40 in transplant models. OX40 regulates multiple aspects of the T-cell response; it delivers a potent costimulatory signal to T effector cells and plays a key role in their survival and proliferation. OX40 also supports the transition of activated T effector cells to memory T cells. Importantly, OX40 signaling inhibits the suppressor functions of forkhead box P3 T regulatory cells and also blocks the induction of new forkhead box P3 T regulatory cells from activated T effector cells. These new findings may have major clinical implications in the induction of transplant tolerance. The current belief is that tolerance to organ transplants involves the apoptotic deletion of T effector cells and the expansion of graft-protective T regulatory cells. Given our recent understanding of OX40, we believe that targeting the OX40 costimulation is therapeutically important in the induction of transplant tolerance.

OX40 costimulation turns off Foxp3+ Tregs

OX40 is a recently identified T-cell costimulatory molecule that belongs to the TNF/TNFR superfamily. OX40 can be expressed by both activated T effector cells and Foxp3(+) Tregs. It is well known that OX40 delivers a potent costimulatory signal to T effector cells, but very little is known about the role of OX40 in regulating the suppressor properties of Foxp3(+) Tregs and the de novo generation of new inducible Foxp3(+) Tregs from T effector cells. In the present study, we found, by using a newly created foxp3gfp knockin model, that OX40 was dispensable for the genesis and suppressor functions of naturally arising CD4(+)Foxp3(+) Tregs, but stimulating OX40 on the Foxp3(+) Tregs abrogated their ability to suppress T effector cell proliferation, IFN-gamma production, and T effector cell-mediated allograft rejection. OX40 costimulation did not significantly affect proliferation and survival of the naturally arising Foxp3(+) Tregs, but profoundly inhibited Foxp3 gene expression. Importantly, OX40 costimulation to T effector cells prevented the induction of new inducible Foxp3(+) Tregs from T effector cells. Our study identified OX40 as a key negative regulator of Foxp3(+) Tregs and may have important clinical implications in models of transplantation and autoimmunity.

Activation of OX40 down-regulates IL-17 production (91.10)

Abstract IL-17 is an important cytokine involved in multiple inflammatory diseases partially through the up-regulation of various pro-inflammatory cytokines and chemokines. The regulation of IL-17 production has been well studied, but the role of OX40 on IL-17 regulation has not been fully illustrated. In this study, we investigated the effect of activation of OX40 on IL-17 production. As expected, stimulation of PHA activated human peripheral blood mononuclear cells (PBMCs) with soluble OX40L increased both Th1 (IFNγ) and Th2 (IL-4 and IL-13) cytokine production. However, addition of soluble OX40L significantly inhibited IL-17 production, and this inhibition was abrogated by IFNγ mAb. IL-23 is a major stimulator for IL-17 and IL-23 enhanced IL-17 production was also inhibited by soluble OX40L in purified human CD4 and CD8 T cells. The downregulation of IL-17 by activation of OX40 was also demonstrated in murine splenocytes from OVA TCR transgenic mice. Blockage of OX40/OX40L interaction with either OX40L antibody or mouse OX40/Fc protein enhanced IL-17 production. In addition, agonistic OX40 antibody inhibited antigen induced IL-17 production and antagonistic OX40 antibody enhanced IL-17 production in splenocytes from OVA transgenic mice. Taken together, our results show that activation of OX40 exerts a negative regulation on IL-17 production. The inhibition is probably mediated through the up regulation of IFNγ production.

OX40 blockade delays disease progression in NOD by inducing qualitative changes in Tregs (131.1)

Abstract Costimulatory interaction between T cells and APCs is crucial for eliciting an immune response. By blocking costimulatory pathways it is possible to prevent or slow disease progression in many autoimmune diseases. We previously investigated the role of OX40/OX40L blockade in T1D. We demonstrated that OX40 blockade suppressed T1D progression when given at late stage but before T1D symptoms. These data are consistent with the role of OX40 as secondary costimulatory molecule. In the present study we investigated the mechanisms by which OX40 blockade suppresses T1D progression in NOD. OX40 blockade marginally reduces expression of CD80 on DCs. There is a reduction in frequency of islet-reactive effector T cells in spleen and LN. Migration of effector T cells to pancreas may be inhibited since greatly reduced lymphocytic infiltrate was observed in the pancreas. Interestingly, OX40 blockade did not enhance Treg numbers in spleen, draining LN or the pancreas. We did not observe a reduction in Tregs in control animals, contrary to previous reports. In addition, FoxP3+ cells were present in and around infiltrated islets, suggesting that the number or location of Tregs may not be defective in NOD. Preliminary data suggests that OX40 blockade induces qualitative changes in Tregs by changing the regulatory mechanisms. Our data suggests that changes in function, rather than number, of Tregs may be crucial for suppressing T1D.

Roles of OX40 in the Development of Murine Experimental Allergic Conjunctivitis: Exacerbation and Attenuation by Stimulation and Blocking of OX40

To investigate the roles of interaction between OX40 and OX40 ligand (OX40L) in the development of experimental allergic conjunctivitis (EC) in mice. BALB/c mice actively immunized with short ragweed pollen (RW) were intraperitoneally injected on days 0, 2, 4, 6, and 8 with agonistic anti-OX40 Ab, blocking anti-OX40L Ab, or normal rat (nr)IgG. On day 10, the mice were challenged with RW in eye drops, and 24 hours later their conjunctivas, spleens, and blood were harvested for analyses. For examination of the effects of the Abs during the late induction (or effector) phase, actively immunized mice were treated with the Abs just before or at the same time as the challenge. In addition, splenocytes from RW-primed mice were transferred into syngeneic naïve mice, and the recipients were treated with Abs twice (on days 2 and 4). On day 4, the mice were challenged with RW and evaluated. When the treatments were performed during the induction phase, anti-OX40 Ab treatment significantly increased clinical EC and eosinophil infiltration into the conjunctiva, whereas anti-OX40L Ab treatment significantly reduced eosinophil infiltration. Compared with splenocytes from nrIgG-treated mice, splenocytes from anti-OX40 Ab-treated mice proliferated vigorously against RW and produced significantly higher amounts of IL-2, -4, and -5 by RW stimulation but a significantly lesser amount of IFN-gamma after Con A stimulation. In contrast, splenocytes from anti-OX40L Ab-treated mice produced significantly less IL-5 with RW stimulation and IL-2 and IL-5 with Con A stimulation, whereas significantly more IFN-gamma was induced by Con A stimulation. Treatment with anti-OX40 and anti-OX40L Abs during the late induction or effector phase of EC did not affect eosinophil infiltration. Blocking of the interaction between OX40 and OX40L in vivo inhibits the development of EC. In contrast, forced stimulation of OX40 in vivo significantly exacerbates EC by activating T cells, especially Th2 cells. These effects were noted only in the induction phase of EC, suggesting that the interaction between OX40 and OX40L is important in the generation of Th2 immune responses in the development of EC.

Critical, but Conditional, Role of OX40 in Memory T Cell-Mediated Rejection

Memory T cells can be a significant barrier to the induction of transplant tolerance. However, the molecular pathways that can regulate memory T cell-mediated rejection are poorly defined. In the present study we tested the hypothesis that the novel alternative costimulatory molecules (i.e., ICOS, 4-1BB, OX40, or CD30) may play a critical role in memory T cell activation and memory T cell-mediated rejection. We found that memory T cells, generated by either homeostatic proliferation or donor Ag priming, induced prompt skin allograft rejection regardless of CD28/CD154 blockade. Phenotypic analysis showed that, in contrast to naive T cells, such memory T cells expressed high levels of OX40, 4-1BB, and ICOS on the cell surface. In a skin transplant model in which rejection was mediated by memory T cells, blocking the OX40/OX40 ligand pathway alone did not prolong the skin allograft survival, but blocking OX40 costimulation in combination with CD28/CD154 blockade induced long-term skin allograft survival, and 40% of the recipients accepted their skin allograft for >100 days. In contrast, blocking the ICOS/ICOS ligand and the 4-1BB/4-1BBL pathways alone or combined with CD28/CD154 blockade had no effect in preventing skin allograft rejection. OX40 blockade did not affect the homeostatic proliferation of T cells in vivo, but markedly inhibited the effector functions of memory T cells. Our data demonstrate that memory T cells resisting to CD28/CD154 blockade in transplant rejection are sensitive to OX40 blockade and suggest that OX40 is a key therapeutic target in memory T cell-mediated rejection.

OX40 Costimulation Synergizes with GM-CSF Whole-Cell Vaccination to Overcome Established CD8+ T Cell Tolerance to an Endogenous Tumor Antigen

T cell costimulation via OX40 is known to increase CD4+ T cell expansion and effector function and enhances the development of T cell memory. OX40 costimulation can also prevent, and even reverse, CD4+ T cell anergy. However, the role of OX40 in CD8+ T cell function is less well defined, particularly in the setting of immune tolerance. To determine the effects of OX40 costimulation on the induction of the host CD8+ T cell repertoire to an endogenous tumor Ag, we examined the fate of CD8+ T cells specific for the immunodominant rat HER-2/neu epitope, RNEU420-429, in FVB MMTV-neu (neu-N) mice, which express rat HER-2/neu protein in a predominantly mammary-restricted fashion. We show that the RNEU420-429-specific T cell repertoire in neu-N mice expands transiently after vaccination with a neu-targeted GM-CSF-secreting whole-cell vaccine, but quickly declines to an undetectable level. However, OX40 costimulation, when combined with GM-CSF-secreting tumor-targeted vaccination, can break established CD8+ T cell tolerance in vivo by enhancing the expansion, and prolonging the survival and effector function of CD8+ T cells specific for RNEU420-429. Moreover, we demonstrate that OX40 expression is up-regulated on both CD4+ and CD8+ T cells shortly after administration of a GM-CSF expressing vaccine. These studies highlight the increased efficacy of OX40 costimulation when combined with a GM-CSF-secreting vaccine, and define a new role for OX40 costimulation of CD8+ T cells in overcoming tolerance and boosting antitumor immunity.

Roles of OX40 in the Pathogenesis and the Control of Diseases

OX40 belongs to the tumor necrosis factor receptor superfamily, and its expression is restricted to activated T-cells. Ligation of OX40 during T-cell-dendritic cell interaction is crucial for clonal expansion of antigen-specific T-cells and generation of T-cell memory. The ligand of OX40 (OX40L) is expressed not only on dendritic cells but also on other cell types, such as B-cells, vascular endothelial cells, natural killer cells, and mast cells. The pathophysiological relevance of this broad distribution needs further investigation. In particular, OX40L on vascular endothelial cells may play a role in inflammatory vasculitis as well as in atherosclerotic change. Recent studies with animal models have indicated the critical involvement of OX40 in the pathogenesis of a variety of immunologic abnormalities of inflammatory, autoimmune, infectious, allergic, and allotransplantation-related diseases. Blockade of OX40-OX40L interaction has been shown to prevent, cure, or ameliorate these diseases. In contrast, activation of OX40 is known to break an existing state of tolerance in malignancies, leading to a reactivation of antitumor immunity. These findings clearly suggest that the OX40/OX40L system is one of the most promising targets of immune intervention for treatment of these diseases.

Human genetic evidence that OX40 is implicated in myocardial infarction

We recently showed that genetic variants in OX40L are associated with myocardial infarction (MI) and severity of coronary artery disease in human. A number of studies also suggest a possible role for OX40 (the OX40L receptor) as a factor contributing to atherosclerosis. In the present study, the OX40 gene was screened for variants associated with precocious MI, using individuals with MI before the age of 60 and controls. Despite the fact that the OX40 gene is highly conserved between species and that relatively few common genetic variants were encountered, an association with MI was seen for a polymorphism in intron 5 (rs2298212). In silico investigation suggested that genetic variation (rs2298211), linked to this intronic variant, is possibly affecting spliceosome function. Our results provide evidence that variants in human OX40 might influence susceptibility to MI. The relevance of these findings is supported by the vital functions fulfilled by OX40 in mammals as reflected by the high level of evolutionary conservation.

Expression of OX40 (CD134) on CD4+ T-cells from patients with myasthenia gravis

Myasthenia gravis (MG) is commonly regarded as the prototype of an antibody-mediated, organ-specific autoimmune disease. Antibodies against the acetylcholine receptor (AChR) on the muscle endplate trigger its typical clinical manifestations of weakness and fatiguability. T-B cell interactions are thought to play a crucial role in the pathogenesis of MG. OX40 (CD134), a costimulatory molecule that is expressed on activated CD4+ T-cells, might contribute to the development or pathogenesis of immune-mediated diseases such as rheumatoid arthritis and graft-versus-host disease. In the present study, we investigated the expression of OX40 on CD4+ T-cells from patients with MG and healthy individuals. Results from 36 MG patients and 28 healthy controls revealed that more freshly isolated CD4+ T-cells from MG patients expressed OX40 than cells from healthy individuals. High levels of antibodies against the AChR, thymic hyperplasia and onset at an early age were associated with elevated expression of OX40. Upon activation by various concentrations of anti-CD3 antibodies, CD4+ T-cells from MG patients showed a tendency toward higher levels of OX40 expression than cells from healthy individuals. Given the role of OX40 in the immune system, we conclude that OX40 might contribute to the development of MG.