Leukotriene B4 and Its Receptor in Experimental Autoimmune Uveitis and in Human Retinal Tissues: Clinical Severity and LTB4 Dependence of Retinal Th17 Cells

Abstract

Nomacopan, a drug originally derived from tick saliva, has dual functions of sequestering leukotriene B₄ (LTB₄) and inhibiting complement component 5 (C5) activation. Nomacopan has been shown to provide therapeutic benefit in experimental autoimmune uveitis (EAU). Longer acting forms of nomacopan were more efficacious in mouse EAU models, and the long-acting variant that inhibited only LTB₄ was at least as effective as the long-acting variant that inhibited both C5 and LTB₄, preventing structural damage to the retina and a significantly reducing effector T helper 17 cells and inflammatory macrophages. Increased levels of LTB₄ and C5a (produced upon C5 activation) were detected during disease progression. Activated retinal lymphocytes were shown to express LTB₄ receptors (R) in vitro and in inflamed draining lymph nodes. Levels of LTB₄R-expressing active/inflammatory retinal macrophages were also increased. Within the draining lymph node CD4⁺ T-cell population, 30% expressed LTB₄R⁺ following activation in vitro, whereas retinal infiltrating cells expressed LTB₄R and C5aR. Validation of expression of those receptors in human uveitis and healthy tissues suggests that infiltrating cells could be targeted by inhibitors of the LTB₄-LTB4 receptor 1 (BLT1) pathway as a novel therapeutic approach. This study provides novel data on intraocular LTB₄ and C5a in EAU, their associated receptor expression by retinal infiltrating cells in mouse and human tissues, and in attenuating EAU via the dual inhibitor nomacopan.