Leukotriene B 4 and Its Receptor in Experimental Autoimmune Uveitis and in Human Retinal Tissues: Clinical Severity and LTB 4 Dependence of Retinal Th17 Cells

Am J Pathol. 2021 Feb;191(2):320-334. doi: 10.1016/j.ajpath.2020.10.010. Epub 2020 Nov 4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Products / pharmacology
  • Complement C5a / antagonists & inhibitors
  • Complement C5a / metabolism
  • Disease Models, Animal
  • Female
  • Humans
  • Leukotriene B4 / antagonists & inhibitors
  • Leukotriene B4 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Leukotriene B4 / antagonists & inhibitors
  • Receptors, Leukotriene B4 / metabolism*
  • Retina / immunology
  • Retina / metabolism*
  • Th17 Cells / immunology
  • Uveitis / immunology*
  • Uveitis / metabolism*

Substances

  • Biological Products
  • Receptors, Leukotriene B4
  • Leukotriene B4
  • Complement C5a