Abstract

Graft-versus-host disease (GVHD) is one of the major hurdles for the success of solid organ and bone marrow transplantation. Numerous strategies to control alloreactive donor T cell responses have been used in the clinic with limited success. In this study, we investigated the effectiveness of anti-human OX40L monoclonal antibody (ahOX40L) in the prevention and treatment of acute GVHD (aGVHD) in a human xenogeneic model. NOD/SCID/γc−/−NOD.Cg-PrkdcscidIl2rgtm1Sug/Jic mice were transplanted with human PBMCs. Animals were treated with ahOX40L or control antibody either when human PBMCs were inoculated or at the onset of aGVHD. Clinical manifestations and immune profiles of human lymphocytes were monitored over time. ahOX40L treatment significantly alleviated disease severity and prolonged survival in both preventative and therapeutic models. Serological examination of circulating human PBMCs over the course of aGVHD revealed that ahOX40L treatment controls proliferation of CD45+CD3+ T cells, particularly CD8+ T cell expansion, resulting in an increased CD4+/CD8+ T cell ratio. In addition, ahOX40L treatment greatly reduced the infiltration of OX40-expressing CD3+ T cells in the target organs. In line with this, T cells in mice treated with ahOX40L decreased expression of tissue homing receptors. We further observed that ahOX40L treatment significantly down-regulated IL-21 and TNFα but increased IL-10 expression by T cells. Importantly, ahOX40L treatment was more effective in reducing aGVHD-associated mortality compared with neutralizing IL-21, TNFα or IL-21 plus TNFα. Altogether, our data support the clinical development of ahOX40L for the prevention and treatment of aGVHD.