Inhibition of 5-lipoxygenase alleviates graft-versus-host disease

Leukotriene B₄ (LTB₄), a proinflammatory mediator produced by the enzyme 5-lipoxygenase (5-LO), is associated with the development of many inflammatory diseases. In this study, we evaluated the participation of the 5-LO/LTB₄ axis in graft-versus-host disease (GVHD) pathogenesis by transplanting 5-LO-deficient leukocytes and investigated the effect of pharmacologic 5-LO inhibition by zileuton and LTB₄ inhibition by CP-105,696. Mice that received allogeneic transplant showed an increase in nuclear 5-LO expression in splenocytes, indicating enzyme activation after GVHD. Mice receiving 5-LO-deficient cell transplant or zileuton treatment had prolonged survival, reduced GVHD clinical scores, reduced intestinal and liver injury, and decreased levels of serum and hepatic LTB₄ These results were associated with inhibition of leukocyte recruitment and decreased production of cytokines and chemokines. Treatment with CP-105,696 achieved similar effects. The chimerism or the beneficial graft-versus-leukemia response remained unaffected. Our data provide evidence that the 5-LO/LTB₄ axis orchestrates GVHD development and suggest it could be a target for the development of novel therapeutic strategies for GVHD treatment.