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Blockade of the Interaction of Leukotriene B4 with Its Receptor Prevents Development of Autoimmune Uveitis

¹From the Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, Louisville, Kentucky; and the ²Department of Microbiology and Immunology, and ³Tumor Immunobiology Program, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky.

PURPOSE. To investigate the role of leukotriene B4 (LTB4) and its receptor BLT1 in the pathogenesis of mouse uveitis.

METHODS. Experimental autoimmune uveitis (EAU) was induced in B10RIII mice by immunization of interphotoreceptor retinoid binding protein (IRBP; peptide sequence 161-180) or in C57BL/6 (B6) mice by transfer of activated T cells specific for IRBP1-20. The animals were then treated with and without the BLT1 receptor antagonist, CP105696, at the disease onset after immunization or at day 0 or day 6 after T-cell transfer. EAU was also induced in wild-type B6 (WT) and BLT1-deficient (BLT1^–/–) mice by reciprocal transfer of the T cells from B6 to BLT1-deficient mice and vise versa. Clinical signs of inflammation and ocular histology were compared. The chemotactic activity of LTB4 on naïve and IRBP-specific autoreactive T cells as well as effector leukocytes was examined.

RESULTS. The treatment of CP105696, greatly reduced the intensity of ongoing disease. IRBP1-20-specific T cells derived from wild-type B6 mice induced only mild uveitis in syngeneic BLT1-deficient mice and that IRBP1-20-specific T cells derived from BLT1^–/– mice induced milder disease in wild-type B6 mice than those derived from wild-type B6 mice, suggesting that expression of the LTB4 receptor on both activated autoreactive T cells and effector leukocytes was necessary for ocular inflammation to occur. Consistent with these data, transfer of autoreactive T cells from B6 mice to 5-lipoxygenase-deficient (5-LO^–/–) mice, which have a functional defect in LTB4 expression, also failed to induce uveitis in the recipient mice.

CONCLUSIONS. The results demonstrate a critical role for LTB₄ in ocular inflammation and in the development and progression of EAU and suggest a new potential target for therapeutic intervention in this disease.

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