Leukotriene B4 (LTB4) and its receptor in Experimental Autoimmune Uveitis (EAU) and in human retinal tissues: clinical severity and LTB4-dependence of retinal Th17 cells
Nomacopan, a drug originally derived from tick saliva, has dual functions of sequestering leukotriene B4 (LTB4) and inhibiting complement component 5 (C5) activation. It was demonstrated that nomacopan provides therapeutic benefit in experimental autoimmune uveitis (EAU). The 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 significant reduction of effector Th17 cells and inflammatory macrophages.
Increased levels of LTB4 and C5a (produced upon C5 activation) were detected during disease progression. Retinal activated lymphocytes were shown to express LTB4 receptors (R) in vitro and in inflamed draining lymph nodes (dLN). Levels of LTB4R-expressing retinal active/inflammatory macrophages were also increased. Within the dLN CD4+T cell population, 30% expressed LTB4R+ following activation in vitro, while 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-BLT1 pathway as a novel therapeutic approach. In conclusion, 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
