OX40 in the Pathogenesis of Atopic Dermatitis-A New Therapeutic Target.

Atopic dermatitis (AD) is a chronic, heterogeneous, inflammatory disease characterized by skin lesions, pruritus, and pain. Patients with moderate-to-severe AD experience chronic symptoms, intensified by unpredictable flares, and often have comorbidities and secondary complications, which can result in significant clinical burden that impacts the patient's overall quality of life. The complex interplay of immune dysregulation and skin barrier disruption drives AD pathogenesis, of which T-cell-dependent inflammation plays a critical role in patients with AD. Despite new targeted therapies, many patients with moderate-to-severe AD fail to achieve or sustain their individual treatment goals and/or may not be suitable for or tolerate these therapies. There remains a need for a novel, efficacious, well-tolerated therapeutic option that can deliver durable benefits across a heterogeneous AD patient population. Expression of OX40 [tumor necrosis factor receptor superfamily, member 4 (TNFRSF4)], a prominent T-cell co-stimulatory molecule, and its ligand [OX40L; tumor necrosis factor superfamily, member 4 (TNFSF4)] is increased in AD. As the OX40 pathway is critical for expansion, differentiation, and survival of effector and memory T cells, its targeting might be a promising therapeutic approach to provide sustained inhibition of pathogenic T cells and associated inflammation and broad disease control. Antibodies against OX40 [rocatinlimab (AMG 451/KHK4083) and telazorlimab (GBR 830)] or OX40L [amlitelimab (KY1005)] have shown promising results in early-phase clinical studies of moderate-to-severe AD, highlighting the importance of OX40 signaling as a new therapeutic target in AD.

OX40L Inhibition Suppresses KLH-driven Immune Responses in Healthy Volunteers: A Randomized Controlled Trial Demonstrating Proof-of-Pharmacology for KY1005.

The safety, tolerability, immunogenicity, and pharmacokinetic (PK) profile of an anti-OX40L monoclonal antibody (KY1005, currently amlitelimab) were evaluated. Pharmacodynamic (PD) effects were explored using keyhole limpet hemocyanin (KLH) and tetanus toxoid (TT) immunizations. Sixty-four healthy male subjects (26.5 ± 6.0 years) were randomized to single doses of 0.006, 0.018, or 0.05 mg/kg, or multiple doses of 0.15, 0.45, 1.35, 4, or 12 mg/kg KY1005, or placebo (6:2). Serum KY1005 concentrations were measured. Antibody responses upon KLH and TT immunizations and skin response upon intradermal KLH administration were performed. PD data were analyzed using repeated measures analysis of covariances (ANCOVAs) and post hoc exposure-response modeling. No serious adverse events occurred and all adverse events were temporary and of mild or moderate severity. A nonlinear increase in mean serum KY1005 concentrations was observed (median time to maximum concentration (Tmax ) ~ 4 hours, geometric mean terminal half-life (t½) ~ 24 days). Cutaneous blood perfusion (estimated difference (ED) -13.4 arbitrary unit (AU), 95% confidence interval (CI) -23.0 AU to -3.8 AU) and erythema quantified as average redness (ED -0.23 AU, 95% CI -0.35 AU to -0.11 AU) decreased after KY1005 treatment at doses of 0.45 mg/kg and above. Exposure-response analysis displayed a statistically significant treatment effect on anti-KLH antibody titers (IgG maximum effect (Emax ) -0.58 AU, 95% CI -1.10 AU to -0.06 AU) and skin response (erythema Emax -0.20 AU, 95% CI -0.29 AU to -0.11 AU). Administration of KY1005 demonstrated an acceptable safety and tolerability profile and PK analyses displayed a nonlinear profile of KY1005. Despite the observed variability, skin challenge response after KY1005 treatment indicated pharmacological activity of KY1005. Therefore, KY1005 shows potential as a novel pharmacological treatment in immune-mediated disorders.

Roles of OX40 and OX40 Ligand in Mycosis Fungoides and Sézary Syndrome.

Mycosis fungoides (MF) and Sézary syndrome (SS), the most common types of cutaneous T-cell lymphoma (CTCL), are characterized by proliferation of mature CD4+ T-helper cells. Patients with advanced-stage MF and SS have poor prognosis, with 5-year survival rates of 52%. Although a variety of systemic therapies are currently available, there are no curative options for such patients except for stem cell transplantation, and thus the treatment of advanced MF and SS still remains challenging. Therefore, elucidation of the pathophysiology of MF/SS and development of medical treatments are desired. In this study, we focused on a molecule called OX40. We examined OX40 and OX40L expression and function using clinical samples of MF and SS and CTCL cell lines. OX40 and OX40L were co-expressed on tumor cells of MF and SS. OX40 and OX40L expression was increased and correlated with disease severity markers in MF/SS patients. Anti-OX40 antibody and anti-OX40L antibody suppressed the proliferation of CTCL cell lines both in vitro and in vivo. These results suggest that OX40-OX40L interactions could contribute to the proliferation of MF/SS tumor cells and that the disruption of OX40-OX40L interactions could become a new therapeutic strategy for the treatment of MF/SS.

OX40L blockade cellular nanovesicles for autoimmune diseases therapy.

Current clinical agents for autoimmunity disorders treatment often cause substantial adverse effects and safety concerns, owing to non-specific immune modulation. Due to the prominent contribution of effector T cells in pathogenesis of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), and preferential location of co-stimulatory receptor-ligand pair OX40-OX40L at the inflamed sites, selectively targeting autoaggressive T cells by blockade OX40-OX40L, might represent an alternative strategy. Herein, we developed a new strategy to antagonize OX40-OX40L interaction by engineering a cell membrane derived nanovesicles (NVs) expressing OX40 receptors (OX40 NVs), and explored their potential for autoimmune disorders therapy. OX40 NVs showed specific binding capability to inflamed HUVECs in vitro, it also possessed distinct arthritic-targeting capacity in RA inflamed joints, and preferential accumulation in IBD inflamed colon. OX40 NVs efficiently suppressed the progression of both RA and IBD diseases through reducing CD4+OX40+ T cells population, and proinflammatory cytokines (i.e., TNF-α and IL-1ß), while reinforcing Tregs immune-suppressive effect, with superior therapeutic efficacy than anti-OX40L. Additionally, dexamethasone (DEX) loading can further enhance the potential of OX40 NVs for RA treatment. Owing to their preferential localization to inflamed sites, and potent immune-suppression ability, targeting OX40-OX40L blockade by OX40 NVs for autoimmune therapy is highly promising.

Immunotherapeutic strategy based on anti-OX40L and low dose of IL-2 to prolong graft survival in sensitized mice by inducing the generation of CD4+ and CD8+ Tregs.

Alloreactive memory cells play a critical role after a second transplant and are difficult to suppress. This study investigated the effect of an immunotherapeutic strategy that combines anti-OX40L, rapamycin (Rapa), and a low dose of IL-2 in a memory cell-based adoptive model. In this model, the median survival time (MST) of the grafts of the combined treatment group was significantly extended compared to that of the control group and other treatment groups. A similar effect was observed regarding a reduction in memory T cells (Tm) and inflammatory cytokines production. Also, the percentages of Foxp3+ regulatory T cells (Tregs) increased in our model. In addition, mounting evidence has shown CD8+CD122+ T cells are also Tregs. We found that the group of CD8+CD122+PD1+ T cells was markedly increased in the combined treatment group, especially in the graft. We further demonstrated that CD8+CD122+PD1+ T cells could suppress activated T cells. Our data suggest that anti-OX40L combined with Rapa and a low dose of IL-2 can suppress Tm, modulate CD4 and CD8 Tregs, and induce long-term heart allograft survival in sensitized mice.

Prolongation of allograft survival by artemisinin treatment is associated with blockade of OX40-OX40L.

OBJECTIVES: It has been demonstrated that artemisinin (ART) possesses multiple immune modulatory effects. However, its role as immunosuppressant in allogeneic transplantation is undetermined. Here, we investigated the effect of ART on co-stimulatory signaling in OX40+ T cells and evaluated ART as a potential immunosuppressant in transplantation. MATERIALS AND METHODS: Allogeneic skin transplantation was performed in C57BL/6 to BALB/c mice. Recipient mice were administrated with vehicle, ART or cyclosporine A daily from day 0 to day 19 post transplantation. Proportions of splenic CD4+OX40+ and CD4+CD44hiCD62Lhi cells, and serum IgG was measured by using flow cytometry. An in vitro lymphocyte stimulation with Con A or LPS under various concentrations of ART was performed, expression of CD4+OX40+ and CD4+CD44hiCD62Lhi cells was evaluated, and interleukin(IL)-6 production was measured by ELISA. RESULTS: In in vivo allogeneic skin transplant model, ART significantly prolongs allogeneic skin survival. Furthermore, our in vitro studies demonstrate that the immune suppression of ART on T cells is associated with a reduction in OX40+ T cells and inhibition of IL-6 secretion. CONCLUSION: Our data indicate that the OX40-OX40L pathway and IL-6 are possibly involved in ART-induced immunosuppression, and ART is a potential novel immunosuppressant.

Combination blockade of OX40L and CD30L inhibits allergen-driven memory TH2 cell reactivity and lung inflammation.

BACKGROUND: The selective reduction of memory TH2 cell responses could be key to affording tolerance and protection from the recurrence of damaging allergic pathology. OBJECTIVE: We asked whether TNF family costimulatory molecules cooperated to promote accumulation and reactivity of effector memory CD4 T cells to inhaled complex allergen, and whether their neutralization could promote airway tolerance to subsequent reexposure to allergen. METHODS: Mice were sensitized intraperitoneally or intranasally with house dust mite and challenged with intranasal allergen after memory had developed. We assessed whether single or combined blockade of OX40L/CD252 and CD30L/CD153 inhibited memory T cells from driving acute asthmatic lung inflammation and protected mice following exposure to allergen at a later time. RESULTS: OX40- or CD30-deficient animals showed strong or partial protection against allergic airway inflammation; however, neutralizing either molecule alone during the secondary response to allergen had little effect on the frequency of effector memory CD4 T cells formed and acute lung inflammation. In contrast, a significant reduction in eosinophilic inflammation was observed when OX40L and CD30L were simultaneously neutralized, with dual blockade inhibiting effector memory TH2 cell expansion in the lungs, whereas formation of peripherally induced regulatory T cells remained intact. Moreover, dual blockade during the secondary response resulted in a tolerogenic state such that mice did not develop a normal tertiary memory TH2 cell and lung inflammatory response when challenged weeks later with allergen. CONCLUSION: Memory T-cell responses to complex allergens are controlled by several TNF costimulatory interactions, and their combination targeting might represent a strategy to reduce the severity of inflammatory reactions following reexposure to allergen.

Safety, tolerability and efficacy of repeated intravenous infusions of KHK4083, a fully human anti-OX40 monoclonal antibody, in Japanese patients with moderate to severe atopic dermatitis.

BACKGROUND: KHK4083, a fully human anti-OX40 monoclonal antibody, is a potential novel therapeutic option for moderate to severe atopic dermatitis (AD), targeting the immunopathogenic pathways. OBJECTIVE: Assess the safety and tolerability of repeated doses of KHK4083 in patients with moderate to severe AD, and investigate the pharmacokinetics and immunogenicity of KHK4083. Additionally, assess the clinical efficacy and pharmacodynamics as exploratory objectives. METHODS: In this phase 1, single-center, open-label, repeated-dose study, a total of 22 patients received KHK4083 10 mg/kg IV on Day 1, Day 15 and Day 29, and were followed until Day 155. RESULTS: There were no deaths, serious adverse events (SAEs), or discontinuations due to adverse events (AEs). Common treatment-emergent AEs were mild or moderate pyrexia (11 patients, 50.0 %), and chills (8 patients, 36.4 %). No clinically meaningful changes in the laboratory values, vital signs, and electrocardiogram recordings were observed. The Cmax was 267 ± 53 µg/mL and the t1/2 was 303 ± 88 h at Day 29. The overall assessment of antibodies against KHK4083 (immunogenicity) showed low positive responses. Continued improvement in the Eczema Area and Severity Index (EASI) and Investigator's Global Assessment (IGA) scores were observed throughout the study. The mean and median percent changes in thymus and activation-regulated chemokine (TARC) continued to decrease over time to -70.4 and -78.8 % until Day 155. CONCLUSION: Repeated intravenous infusion of KHK4083 had an acceptable safety profile in patients with moderate to severe AD. Sustained improvement in the symptoms of AD was observed after completion of KHK4083 treatment.

Statins can suppress DC-mediated Th2 responses through the repression of OX40-ligand and CCL17 expression.

DCs and epithelial cell-derived thymic stromal lymphopoietin (TSLP) have pivotal roles in allergic inflammation. TSLP stimulates myeloid DCs to express OX40-ligand (OX40L) and CCL17, which trigger and maintain Th2 cell responses. We have previously shown that statins, which are HMG-CoA reductase inhibitors, have the ability to suppress type I IFN production by plasmacytoid DCs. Here, we extended our previous work to examine the immunomodulatory effect of statins on allergic responses, particularly the TSLP-dependent Th2 pathway induced by myeloid DCs. We found that treatment of TSLP-stimulated DCs with either pitavastatin or simvastatin suppressed both the DC-mediated inflammatory Th2 cell differentiation and CRTH2+ CD4+ memory Th2 cell expansion and also repressed the expressions of OX40L and CCL17 by DCs. These inhibitory effects of statins were mimicked by treatment with either a geranylgeranyl-transferase inhibitor or Rho-kinase inhibitor and were counteracted by the addition of mevalonate, suggesting that statins induce geranylgeranylated Rho inactivation through a mevalonate-dependent pathway. We also found that statins inhibited the expressions of phosphorylated STA6 and NF-κB-p50 in TSLP-stimulated DCs. This study identified a specific ability of statins to control DC-mediated Th2 responses, suggesting their therapeutic potential for treating allergic diseases.

Central Roles of OX40L-OX40 Interaction in the Induction and Progression of Human T Cell-Driven Acute Graft-versus-Host Disease.

Graft-versus-host disease (GVHD) is one of the major obstacles for the success of allogeneic hematopoietic stem cell transplantation. Here, we report that the interaction between OX40L and OX40 is of critical importance for both induction and progression of acute GVHD (aGVHD) driven by human T cells. Anti-human OX40L monoclonal antibody (hOX40L) treatment could thus effectively reduce the disease severity in a xenogeneic-aGVHD (x-aGVHD) model in both preventative and therapeutic modes. Mechanistically, blocking OX40L-OX40 interaction with an anti-hOX40L antibody reduces infiltration of human T cells in target organs, including liver, gut, lung, and skin. It also decreases IL-21- and TNF-producing T cell responses, while promoting regulatory T cell (Treg) responses without compromising the cytolytic activity of CD8+ T cells. Single blockade of hOX40L was thus more effective than dual blockade of IL-21 and TNF in reducing the severity of aGVHD as well as mortality. Data from this study indicate that OX40L-OX40 interactions play a central role in the pathogenesis of aGVHD induced by human T cells. Therapeutic strategies that can efficiently interrupt OX40L-OX40 interaction in patients might have potential to provide patients with an improved clinical benefit.

Anti-CD73 and anti-OX40 immunotherapy coupled with a novel biocompatible enzyme prodrug system for the treatment of recurrent, metastatic ovarian cancer.

Approximately 75% of ovarian cancer is diagnosed once metastasis to the peritoneal cavity has occurred. A large proportion of patients eventually develop platinum-resistive tumors, which are considered terminal. In order to provide an alternative a novel fusion protein, mCTH-ANXA5, has been developed for the treatment of recurrent, metastatic ovarian cancer. The fusion protein combines annexin V (ANXA5), an ovarian tumor and tumor vasculature targeting protein, with mutated cystathionine gamma-lyase (mCTH), an enzyme that converts selenomethionine (SeMet) into toxic methylselenol, which generates reactive oxygen species and eventual tumor cell death. In order to further enhance the therapeutic efficacy, anti-CD73 and anti-OX40 immunostimulants were combined with mCTH-ANXA5, resulting in an increase of survival by 100% from 12 to 24 days post-therapy and decrease tumor burden in mice with orthotopic metastatic ovarian cancer. Further evaluation of the combination therapy revealed a strong antibody-mediated immune response, and an increased infiltration of cytotoxic T-cells along with a decrease in tumor promoting immune cells. This study demonstrates the efficacy of a synergistic, multi-drug system by attacking the tumor as well as enlisting the body's own defense system to treat the patient.

Combined OX40L and mTOR blockade controls effector T cell activation while preserving Treg reconstitution after transplant.

A critical question facing the field of transplantation is how to control effector T cell (Teff) activation while preserving regulatory T cell (Treg) function. Standard calcineurin inhibitor-based strategies can partially control Teffs, but breakthrough activation still occurs, and these agents are antagonistic to Treg function. Conversely, mechanistic target of rapamycin (mTOR) inhibition with sirolimus is more Treg-compatible but is inadequate to fully control Teff activation. In contrast, blockade of OX40L signaling has the capacity to partially control Teff activation despite maintaining Treg function. We used the nonhuman primate graft-versus-host disease (GVHD) model to probe the efficacy of combinatorial immunomodulation with sirolimus and the OX40L-blocking antibody KY1005. Our results demonstrate significant biologic activity of KY1005 alone (prolonging median GVHD-free survival from 8 to 19.5 days), as well as marked, synergistic control of GVHD with KY1005 + sirolimus (median survival time, >100 days; P < 0.01 compared to all other regimens), which was associated with potent control of both TH/TC1 (T helper cell 1/cytotoxic T cell 1) and TH/TC17 activation. Combined administration also maintained Treg reconstitution [resulting in an enhanced Treg/Teff ratio (40% over baseline) in the KY1005/sirolimus cohort compared to a 2.9-fold decrease in the unprophylaxed GVHD cohort]. This unique immunologic signature resulted in transplant recipients that were able to control GVHD for the length of analysis and to down-regulate donor/recipient alloreactivity despite maintaining anti-third-party responses. These data indicate that combined OX40L blockade and sirolimus represents a promising strategy to induce immune balance after transplant and is an important candidate regimen for clinical translation.

Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases.

TNF blockers are highly efficacious at dampening inflammation and reducing symptoms in rheumatic diseases such as rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, and also in nonrheumatic syndromes such as inflammatory bowel disease. As TNF belongs to a superfamily of 19 structurally related proteins that have both proinflammatory and anti-inflammatory activity, reagents that disrupt the interaction between proinflammatory TNF family cytokines and their receptors, or agonize the anti-inflammatory receptors, are being considered for the treatment of rheumatic diseases. Biologic agents that block B cell activating factor (BAFF) and receptor activator of nuclear factor-κB ligand (RANKL) have been approved for the treatment of systemic lupus erythematosus and osteoporosis, respectively. In this Review, we focus on additional members of the TNF superfamily that could be relevant for the pathogenesis of rheumatic disease, including those that can strongly promote activity of immune cells or increase activity of tissue cells, as well as those that promote death pathways and might limit inflammation. We examine preclinical mouse and human data linking these molecules to the control of damage in the joints, muscle, bone or other tissues, and discuss their potential as targets for future therapy of rheumatic diseases.

Interruption of OX40L signaling prevents costimulation blockade-resistant allograft rejection.

The potential of costimulation blockade to serve as a novel transplant immunosuppression strategy has been explored for over 20 years, culminating in the recent clinical approval of belatacept for renal transplant patients. Despite improving long-term graft function and survival compared with calcineurin inhibitors, clinical acceptance of belatacept has been hindered by elevated rates of acute rejection. We examined the signaling pathways required to activate costimulation blockade-resistant alloreactive T cells and identified the OX40/OX40L secondary costimulatory pathway as a promising target. We next sought to improve the clinical efficacy of traditional costimulation blockade using belatacept by coupling it with anti-OX40L. Using a murine transplant model, we demonstrate that combined blockade enhances the suppression of alloreactive T cell proliferation and effector functions including both cytokine release and cytotoxic degranulation. We also show that anti-OX40L may be particularly useful in targeting alloreactive memory T cell responses that are relatively unaffected by traditional costimulation blockade regimens. Finally, we translated this therapy to a clinically relevant nonhuman primate renal transplant model, validating the efficacy of this regimen in a potentially novel steroid- and calcineurin inhibitor-free immunosuppression regimen.

OX40L blockade protects against inflammation-driven fibrosis.

Treatment for fibrosis represents a critical unmet need, because fibrosis is the leading cause of death in industrialized countries, and there is no effective therapy to counteract the fibrotic process. The development of fibrosis relates to the interplay between vessel injury, immune cell activation, and fibroblast stimulation, which can occur in various tissues. Immunotherapies have provided a breakthrough in the treatment of immune diseases. The glycoprotein OX40-OX40 ligand (OX40L) axis offers the advantage of a targeted approach to costimulatory signals with limited impact on the whole immune response. Using systemic sclerosis (SSc) as a prototypic disease, we report compelling evidence that blockade of OX40L is a promising strategy for the treatment of inflammation-driven fibrosis. OX40L is overexpressed in the fibrotic skin and serum of patients with SSc, particularly in patients with diffuse cutaneous forms. Soluble OX40L was identified as a promising serum biomarker to predict the worsening of lung and skin fibrosis, highlighting the role of this pathway in fibrosis. In vivo, OX40L blockade prevents inflammation-driven skin, lung, and vessel fibrosis and induces the regression of established dermal fibrosis in different complementary mouse models. OX40L exerts potent profibrotic effects by promoting the infiltration of inflammatory cells into lesional tissues and therefore the release of proinflammatory mediators, thereafter leading to fibroblast activation.

Anti-OX40L alone or in combination with anti-CD40L and CTLA4Ig does not inhibit the humoral and cellular response to a major grass pollen allergen.

BACKGROUND: IgE-mediated allergy is a common disease characterized by a harmful immune response towards otherwise harmless environmental antigens. Induction of specific immunological non-responsiveness towards allergens would be a desirable goal. Blockade of costimulatory pathways is a promising strategy to modulate the immune response in an antigen-specific manner. Recently, OX40 (CD134) was identified as a costimulatory receptor important in Th2-mediated immune responses. Moreover, synergy between OX40 blockade and 'conventional' costimulation blockade (anti-CD40L, CTLA4Ig) was observed in models of alloimmunity. OBJECTIVE: We investigated the potential of interfering with OX40 alone or in combination with CD40/CD28 signals to influence the allergic immune response. METHODS: The OX40 pathway was investigated in an established murine model of IgE-mediated allergy where BALB/c mice are repeatedly immunized with the clinically relevant grass pollen allergen Phl p 5. Groups were treated with combinations of anti-OX40L, CTLA4Ig and anti-CD40L. In selected mice, Tregs were depleted with anti-CD25. RESULTS: Blockade of OX40L alone at the time of first or second immunization did not modulate the allergic response on the humoral or effector cell levels but slightly on T cell responses. Administration of a combination of anti-CD40L/CTLA4Ig delayed the allergic immune response, but antibody production could not be inhibited after repeated immunization even though the allergen-specific T cell response was suppressed in the long run. Notably, additional blockade of OX40L had no detectable supplementary effect. Immunomodulation partly involved regulatory T cells as depletion of CD25(+) cells led to restored T cell proliferation. CONCLUSIONS AND CLINICAL RELEVANCE: Collectively, our data provide evidence that the allergic immune response towards Phl p 5 is independent of OX40L, although reduction on T cell responses and slightly on the asthmatic phenotype was detectable. Besides, no relevant synergistic effect of OX40L blockade in addition to CD40L/CD28 blockade could be detected. Thus, the therapeutic potential of OX40L blockade for IgE-mediated allergy appears to be ineffective in this setting.

OX40, OX40L and Autoimmunity: a Comprehensive Review.

The tumour necrosis factor receptor OX40 (CD134) is activated by its cognate ligand OX40L (CD134L, CD252) and functions as a T cell co-stimulatory molecule. OX40-OX40L interactions have been proposed as a potential therapeutic target for treating autoimmunity. OX40 is expressed on activated T cells, and in the mouse at rest on regulatory T cells (Treg). OX40L is found on antigen-presenting cells, activated T cells and others including lymphoid tissue inducer cells, some endothelia and mast cells. Expression of both molecules is increased after antigen presentation occurs and also in response to multiple other pro-inflammatory factors including CD28 ligation, CD40L ligation and interferon-gamma signaling. Their interactions promote T cell survival, promote an effector T cell phenotype, promote T cell memory, tend to reduce regulatory function, increase effector cytokine production and enhance cell mobility. In some circumstances, OX40 agonism may be associated with increased tolerance, although timing with respect to antigenic stimulus is important. Further, recent work has suggested that OX40L blockade may be more effective than OX40 blockade in reducing autoimmunity. This article reviews the expression of OX40 and OX40L in health, the effects of their interactions and insights from their under- or over-expression. We then review OX40 and OX40L expression in human autoimmune disease, identified associations of variations in their genes (TNFRSF4 and TNFSF4, respectively) with autoimmunity, and data from animal models of human diseases. A rationale for blocking OX40-OX40L interaction in human autoimmunity is then presented along with commentary on the one trial of OX40L blockade in human disease conducted to date. Finally, we discuss potential problems with clinical use of OX40-OX40L directed pharmacotherapy.

Treatment with anti-OX40L or anti-TSLP does not alter the frequency of T regulatory cells in allergic asthmatics.

OX40-OX40L interactions and thymic stromal lymphopoietin (TSLP) are important in the induction and maintenance of Th2 responses in allergic disease, whereas T regulatory cells (Treg) have been shown to suppress pro-inflammatory Th2 responses. Both OX40L and TSLP have been implicated in the negative regulation of Treg. The effect of anti-asthma therapies on Treg is not well known. Our aim was to assess the effects of two monoclonal antibody therapies (anti-OX40L and anti-TSLP) on Treg frequency using a human model of allergic asthma. We hypothesized that the anti-inflammatory effects of these therapies would result in an increase in circulating Treg (CD4(+) CD25(+) CD127(low) Foxp3(+) cells) frequency. We measured Treg using flow cytometry, and our results showed that neither allergen challenge nor monoclonal antibody therapy altered circulating Treg frequency. These data highlight the need for assessment of airway Treg and for a more complete understanding of Treg biology so as to develop pharmacologics/biologics that modulate Treg for asthma therapy.