Deficiency of 5-lipoxygenase accelerates renal allograft rejection in mice

Acute renal allograft rejection is associated with alterations in renal ara chidonic acid metabolism, including enhanced synthesis of leukotrienes (LTs ). LTs, the products of the 5-lipoxygenase (5-LO) pathway, are potent lipid mediators with a broad range of biologic activities. Previous studies, usi ng pharmacological agents to inhibit LT synthesis or activity, have implica ted these eicosanoids in transplant rejection. To further investigate the r ole of LTs in acute graft rejection, we transplanted kidneys from CByD2F(1) mice into fully allogeneic 129 mice that carry a targeted mutation in the 5lo gene. Unexpectedly, allograft rejection was significantly accelerated i n 5-LO-deficient mice compared with mild-type animals. Despite the marked r eduction in graft survival, the 5lo mutation had no effect on the hemodynam ics or morphology of the allografts. Although LTB4 levels were reduced, ren al thromboxane B, production and cytokine expression were not altered in 5- LO-deficient allograft recipients. These findings suggest that, along with their proinflammatory actions, metabolites of 5-LO can act to enhance allog raft survival.