Anti-TNFRSF4 (C-terminal) polyclonal antibody

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.

Ligation of OX40 (CD134, TNFRSF4) on activated T cells by its natural ligand (OX40L, CD252, TNFSF4) enhances cellular survival, proliferation, and effector functions such as cytokine release and cellular cytotoxicity. We engineered a recombinant human OX40L IgG4P Fc fusion protein termed MEDI6383 that assembles into a hexameric structure and exerts potent agonist activity following engagement of OX40. MEDI6383 displayed solution-phase agonist activity that was enhanced when the fusion protein was clustered by Fc gamma receptors (Fc gamma Rs) on the surface of adjacent cells. The resulting costimulation of OX40 on T cells induced NFkB promoter activity in OX40-expressing T cells and induced Th1-type cytokine production, proliferation, and resistance to regulatory T cell (Treg)-mediated suppression. MEDI6383 enhanced the cytolytic activity of tumor-reactive T cells and reduced tumor growth in the context of an alloreactive human T cell: tumor cell admix model in immunocompromised mice. Consistent with the role of OX40 costimulation in the expansion of memory T cells, MEDI6383 administered to healthy nonhuman primates elicited peripheral blood CD4 and CD8 central and effector memory T-cell proliferation as well as B-cell proliferation. Together, these results suggest that OX40 agonism has the potential to enhance antitumor immunity in human malignancies. (C) 2018 AACR.