Key Points
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Conventional immunotherapies for autoimmune, allergic and inflammatory diseases prevent disease symptoms by inducing immunosuppression, but at the same time, cause opportunistic infections and cancer. Therefore, an ideal immunotherapeutic strategy for a T-cell-mediated disease would directly target the antigen-specific T cells that are responsible for the disease pathogenesis.
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Optimal activation of naive T cells requires not only interaction between the T-cell receptor and antigen–MHC complexes, but also co-stimulation provided by co-stimulatory ligands expressed by antigen-presenting cells. Among several co-stimulatory receptors, signals through CD28 and OX40 are indispensable for T cells to respond to antigen and for the generation of antigen-specific memory T cells.
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Targeting the T-cell co-stimulatory molecules CD28 and OX40 is a promising strategy to control T-cell-mediated immune disorders, by regulating the T cells that cause disease. Whereas CD28 blockade mainly suppresses the generation of effector T cells from naive T cells, OX40 blockade inhibits the survival and activation of effector T cells generated from either naive or memory T cells in many models.
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As CD28 blockade is unable to effectively suppress effector T-cell function or reactivation of memory T cells, this blockade might be insufficient to prevent ongoing symptoms in certain T-cell-mediated diseases. By contrast, blockade of OX40–OX40 ligand (OX40L) interactions alone inhibits ongoing effector T-cell responses, and therefore might be a favourable strategy in certain clinical settings for T-cell-mediated diseases.
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The presence of OX40+ lymphocytes and OX40L+ cells at the sites of inflammation in T-cell-mediated disorders, such as autoimmunity, allergic and inflammatory diseases, and graft-versus-host disease, indicates the possible involvement of OX40–OX40L interactions in the pathogenesis of these diseases. In fact, targeting OX40 using OX40-specific monoclonal antibodies, OX40–immunoglobulin fusion proteins or OX40-specific immunotoxin is therapeutic in terms of reducing even ongoing disease symptoms in several animal models of these diseases.
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Targeting OX40 in mouse models of disease is effective not only for autoimmune and allergic diseases, but also for tissue inflammation during viral infection without delaying viral clearance, indicating additional benefits of targeting OX40 as an anti-inflammatory therapy, as well as an immunosuppressive regimen.
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Deliberate ligation of OX40 induces favourable antitumour effects in cancer-bearing hosts by enhancing effector T-cell functions, and can be augmented with protocols that involve other stimulatory molecules, such as granulocyte–macrophage colony-stimulating factor, 4-1BB-specific antibody and IL-12.
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Therapeutic reagents that target OX40 and OX40L will soon be tested in phase I clinical trials for T-cell-mediated diseases and patients with certain types of cancer.
Abstract
An emerging immunotherapeutic strategy for T-cell-mediated diseases is to directly target antigen-specific T cells that are responsible for the clinical effects, without causing general widespread immunosuppression. A T-cell co-stimulatory molecule, OX40, which is transiently expressed after antigen recognition, fits these criteria in several immune-mediated diseases. In vivo blockade of OX40 signalling specifically suppresses the function of recently activated autoantigen-specific T cells, leading to inhibition of autoimmune disease without severe immunosuppression. In addition, deliberate ligation of OX40 in tumour-bearing hosts enhances anticancer immunity. We discuss how targeting OX40 is potentially an ideal strategy for immune-based therapies in several human diseases.
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Acknowledgements
We thank L.C. Ndhlovu, J. Borst and N. Killeen for critical reviewing of the manuscript.
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Competing interests
Andrew D. Weinberg is the inventor on three United States patents pertaining to OX40: the patent numbers are 5,759,546; 6,312,700 and 6,566,082. They relate to using reagents to OX40 to inhibit autoimmune disease, diagnose T-cell disorders and enhance antigen-specific immune responses by OX40 ligation in vivo.
Glossary
- IMMUNOTOXIN
-
An antibody that is chemically or genetically modified to produce a hybrid molecule that has an antibody-binding domain and toxin that can kill a cell once internalized.
- CONTACT HYPERSENSITIVITY
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A delayed-type hypersensitivity in which T cells respond to antigens that are introduced by contact with the skin. In common animal models, hapten treatment of the skin induces this hypersensitivity, which is measured by swelling of the sensitized skin, such as ear thickness.
- EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS
-
(EAE). An experimental model for the human disease multiple sclerosis. Autoimmune disease is induced in experimental animals by immunization with myelin antigen or peptides that are derived from myelin. The animals develop a paralytic disease with inflammation and demyelination in the brain and spinal cord.
- INFLAMMATORY BOWEL DISEASE
-
(IBD). A chronic condition of the intestine that is characterized by severe inflammation and mucosal destruction. The most common forms in humans are ulcerative colitis and Crohn's disease. Animal models indicate that they result from dysregulation of the local immune response to normally harmless commensal bacteria.
- GRAFT-VERSUS-HOST DISEASE
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(GVHD). Tissue damage in a recipient of allogeneic transplanted tissue (usually a bone-marrow transplant) that results from the activity of donor T cells that recognize the recipient's tissue as foreign. GVHD varies markedly in severity, but can be life-threatening in severe cases. Typically, damage to the skin and gut mucosa leads to clinical manifestations.
- BLOOD–BRAIN BARRIER
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The central nervous system (CNS) is known to be an immune-privileged site such that no lymphocytes can cross from the blood to the brain. In certain diseases, such as multiple sclerosis, the endothelial-cell wall that protects this barrier is broken down and, when this occurs, lymphocytes can pass freely into the CNS.
- NON-OBESE DIABETIC MICE
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(NOD mice). A strain of mice that normally develops idiopathic autoimmune diabetes that closely resembles type 1 diabetes in humans. The target antigen(s) recognized by the pathogenic CD4+ T cells that initiate disease is expressed by pancreatic islet cells, but its identity is unknown.
- GRAFT VERSUS LEUKAEMIA
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(GVL). Hosts with leukaemia who receive an allogeneic bone-marrow transplant have far fewer disease relapses than individuals obtaining autologous bone-marrow transplants. This is due to the transplanted T cells recognizing alloantigens expressed by the leukaemia.
- CD4+CD25+ REGULATORY T CELLS
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(TReg cells). A specialized subset of CD4+ T cells that can suppress other T-cell responses. These cells are characterized by expression of the interleukin-2 receptor α-chain (CD25) and some T-cell-activation markers. The transcription factor FOXP3 is specifically expressed by these cells and contributes to the suppressive function.
- IMMUNOGENIC TUMOURS
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The immunogenicity of a tumour is defined by its ability to enhance immune responses after irradiation and subcutaneous vaccination into naive mice. Highly immunogenic tumours will allow 100% of the vaccinated hosts to be protected against live tumour challenge 30 days after immunization, whereas less immunogenic tumours elicit poorer immune responses, resulting in 50% or less of hosts that succumb to live tumour challenge after immunization.
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Sugamura, K., Ishii, N. & Weinberg, A. Therapeutic targeting of the effector T-cell co-stimulatory molecule OX40. Nat Rev Immunol 4, 420–431 (2004). https://doi.org/10.1038/nri1371
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DOI: https://doi.org/10.1038/nri1371
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