Protective effect of neutralizing anti-IL-18α monoclonal antibody on a mouse model of acute graft-versus-host disease

Graft-versus-host disease (GVHD) is a devastating complication of hematopoietic stem cell transplantation (HSCT), and is characterized by systemic inflammation and tissue damage in multiple organs, such as the liver and small intestine. Interleukin-18 (IL-18), an important pro-inflammatory cytokine, is elevated during the course of acute GVHD (aGVHD), and is associated with the severe clinical manifestations of the disease. The biological activity of IL-18 is based on its interaction with the IL-18 receptor (IL-18R) expressed in a variety of cells. The aim of this study was to assess whether blocking the interaction of IL-18 with IL-18R by the anti-IL-18R alpha antibody could attenuate the severity of aGVHD. We used a well-established mouse bone marrow transplantation (BMT) model (B6 -> BALB/c) to block the IL-18/IL-18R interaction by a neutralizing monoclonal antibody (mAb) against murine IL-18R alpha. Administration of anti-IL-18R alpha mAb had a significant protective effect on the clinical and pathologic manifestations of aGVHD, resulting in a markedly improved survival rate, modified inflammatory response and decreased tissue damage. Interfering with IL-18/IL-18R interaction affected levels of Th1, Th2 and Th17 subsets in the peripheral blood of the aGVHD animals. Additionally, it led to decreased tissue expression of IL-18 and apoptosis-associated molecules (Fas and FasL), and lower phosphorylation levels of p38MAPK in the liver and small intestine. These changes coincided with the decrease in cell apoptosis in aGVHD target organs. Thus, anti-IL-18R alpha therapy may, therefore, represent a new therapeutic interference approach for treating aGVHD.