title: OX40, OX40L and Autoimmunity: a Comprehensive Review.
abstract: 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.
authors.affiliation: MRC Centre for Immune Regulation, Institute of Biomedical Research, University of Birmingham, Birmingham, West Midlands, B15 2TT, UK. gwilym.webb@gmail.com.|National Institute for Health Research Birmingham Liver Biomedical Research Unit, University of Birmingham, Birmingham, West Midlands, B15 2TT, UK. gwilym.webb@gmail.com.
authors.forename: Gwilym J
authors.identifier: http://orcid.org/0000-0002-0710-5644
authors.initials: GJ
authors.lastname: Webb
authors.affiliation: National Institute for Health Research Birmingham Liver Biomedical Research Unit, University of Birmingham, Birmingham, West Midlands, B15 2TT, UK.
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Hirschfield
authors.affiliation: MRC Centre for Immune Regulation, Institute of Biomedical Research, University of Birmingham, Birmingham, West Midlands, B15 2TT, UK.
authors.forename: Peter J L
authors.initials: PJ
authors.lastname: Lane
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity / Q000235:genetics; D002448:Cell Adhesion; D002450:Cell Communication; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D007156:Immunologic Memory; D056747:Immunomodulation; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D053278:OX40 Ligand / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011485:Protein Binding; D053262:Receptors, OX40 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D053278:OX40 Ligand; D053262:Receptors, OX40
keywords: Animal models; Immunoregulation; T cells; T-regulatory cells; TNF receptors