Abstract
Chronic and recurrent uveitis account for approximately 10% of legal blindness in the western world. Autoimmune uveitis is driven by activated CD4+ T cells that differentiate into effector T helper cells (Th1, Th2, and Th17) which release proinflammatory cytokines that damage the retina. In this study we investigated the effect of the methionine aminopeptidase 2 (MetAP2) inhibitor, Lodamin, on T cell activation and differentiation. MetAp2 is an enzyme which regulates cellular protein synthesis and is highly expressed in T cells. Lodamin was found to suppress T cell receptor (TCR) mediated T cell proliferation and reduced the production of Th1 and Th17 cells. Further, Lodamin suppressed overall inflammation in the mouse model of experimental autoimmune uveitis (EAU) by a six fold. This effect was attributed in part to a reduction in retinal proinflammatory cytokines, down regulation of MetAP2 expression in purified lymph node CD4+ T cells, and a general normalization of the systemic immune reaction.
Highlights
Autoimmune uveitis is a complex, sight-threatening condition associated with a multitude of diseases
To investigate the effect of Lodamin on anti-CD3-mediated T cell proliferation, whole splenocytes were stained with carboxyfluoroscein succinimidyl ester (CFSE) and stimulated with soluble anti-CD3 antibody. 72 hours after cell stimulation, splenocytes were stained with anti-CD4 antibody and proliferation of CD4+ cells was assessed by CFSE-dilution using flow cytometry
Human autoimmune uveitis is regarded as a T cell dependent disease
Summary
Autoimmune uveitis is a complex, sight-threatening condition associated with a multitude of diseases. It affects 2 million Americans, accounting for about 10% of the severe visual impairments in the United States [1]. This condition presents either as isolated intraocular inflammation or as part of systemic autoimmune diseases such as Behcet’s disease, sarcoidosis, VogtKoyanagi-Harada (VKH) disease, or ankylosing spondylitis. Naive CD4+ T cells activate and differentiate into Th1 cells upon interleukin 12 (IL-12) stimulation or Th2 upon interleukin-4 (IL-4) stimulation These cell populations contribute to the cellular immune reaction locally in the eye, as well as activate the humoral immune response in a systemic autoimmune reaction
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