Anti-TNFRSF4 Monoclonal antibody, clone BDU46 [APC]

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.

CD134 (TNFRSF4) is a member of the TNFR superfamily, which is specifically expressed on T cells. Previous studies have shown that blocking of CD134L-CD134 interaction reduces the percentage of activated T cells and prevents effector T cell-mediated graft rejection in heart transplantation. However, the role of microRNA-regulated inhibition of the CD134 signal in cardiac transplantation of T-regulatory (Treg) cells is not clear. In this study, we found microRNA 744 (miR-744) agomir administration enhanced the expression levels of miR-744 in CD4(+) CD25(+) Treg cells from heart transplantation mice. Moreover, miR-744 agomir administration significantly enhanced the expression levels of CD62L and Ki67 in CD4(+) CD25(+) Treg cells from heart transplantation mice and further enhanced immunosuppressive function of Treg cells following coculture with CD4(+) CD25(-) T cells for different ratios. In addition, miR-744 agomir treatment significantly prolonged survival time and reduced rejection response of heart allografts in vivo, which are involved in downregulation of TNFRSF4 expression. These results provided a novel molecular mechanism of ameliorating heart allograft rejection in Treg cells, which could be used in the treatment of heart allograft rejection clinically.