Use of leptin antagonists as anti-inflammatory and anti-fibrotic reagents

Leptin has been implicated as a pro-inflammatory cytokine, involved in the activation of effector T-cells as well as various other components of the innate and adaptive immune response. Leptin-deficient ob/obmice exhibit resistance to several T-cell-mediated autoim­ mune disorders including experimental arthritis, hepatitis and experimental allergic encephalomyelitis. Inhibition of the leptin-induced proimmune response may be useful as a therapeutic tool in T-cell-mediated autoimmune disorder. Herein, we report on the use of our recently developed competitive leptin antagonist as an anti-inflammatory agent in models of acute and chronic T-cell-mediated liver inflammation and chronic liver fibrosis. This beneficial effect may be mediated by both direct T-cell modulatory effects and inhibition of hepatic stellate cell activation and function, leading to alleviation of liver fibrosis. Our results suggest that leptin inhibition may be developed into a rational imm unomodulatory therapeutic modality.