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.

The Ox40/Ox40 Ligand Pathway Promotes Pathogenic Th Cell Responses, Plasmablast Accumulation, and Lupus Nephritis in NZB/W F1 Mice

“…Previous reports have also shown elevated Ox40 and Ox40L in SLE patient blood cells, serum, and kidney biopsies (reviewed in Ref. 11). …”

T Cell/B Cell Collaboration and Autoimmunity: An Intimate Relationship

“…CD40 , which provides an essential pathway for GC B cells to perceive T cell help, is implicated in multiple autoimmune diseases (103) as is DBC1 which regulates its downstream signaling (104). OX40L contributes to pathology in a mouse model of SLE (34) and polymorphisms in OX40L ( TNFSF4 ) are associated with several diseases where humoral immunity is known to be perturbed including SLE and RA, leading to the investigation of this pathway as a therapeutic target (105). …”

OX40L blockade protects against inflammation-driven fibrosis

“…The glycoprotein OX40-OX40 ligand (OX40L) pair, which is involved in late T-cell costimulatory signaling and is transiently expressed following antigen recognition, fits these criteria (4). Blocking OX40-OX40L was effective in preventing the development of disease in several in vivo animal models of autoimmune and inflammatory diseases (5). This strategy has not yet been evaluated in fibrotic conditions such as SSc.…”