New Roles for LTA4 Hydrolase, LTB4 and BLT1 in Multiple Sclerosis and Experimental Allergic Encephalomyelitis (48.9)

Abstract

Abstract 5-lipoxygenase (5-LO), leukotriene A4 hydrolase (LTA4h), leukotriene B4 (LTB4) and its high affinity receptor BLT1 are known drivers of allergy, adaptive immunity and vascular inflammation, but have unknown roles in human multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). We show that LTA4h and BLT1 are markers of inflammatory perivascular cuffs and actively demyelinating plaques in relapsing-remitting and progressive human MS, as well as spinal cord inflammatory foci in rodent EAE. Encephalitogenic murine CD3+ T cells experienced with proteolipid protein peptide antigen (PLP139-151) migrate to LTB4 and express functional BLT1. Peripheral blood immune cell LTB4 synthetic capacity is markedly primed prior to/during onset of rat and mouse EAE and mouse spleen 5-LO/LTA4h/BLT1 mRNAs are dynamically regulated during the immune response after T cell adoptive transfer. Potent, selective LTA4h inhibitors decrease clinical score and cumulative disease burden in rat antigen-induced and murine adoptive T cell transfer EAE. LTA4h inhibitors are also synergistic in suppressing rat EAE when combined with agents having an orthogonal mode of immunomodulatory action, such as the PDE-IV inhibitor mesopram. The results define new roles for the 5-LO / LTA4h / LTB4 / BLT1 pathway in autoimmunity and disease progression in EAE. Human MS may be a therapeutic target for inhibitors of LTB4 synthesis.