Abstract
Purpose :
Ischemic retinopathies, such as retinopathy of prematurity (ROP) and diabetic retinopathy (DR) are important causes of vision loss and blindness globally. The pathological processes of these diseases are primarily driven by angiogenic factors, such as vascular endothelial growth factor (VEGF) and angiopoietin 2, which cause retinal vessels to become proliferative and leaky. Retinal inflammation has emerged as an essential factor in driving the development of DR and ROP. Our discovery that anti-inflammatory regulatory T cells (Tregs) are recruited into the retina to protect the vasculature has opened the possibility that boosting the protective arm of the adaptive immune system has therapeutic potential in ischemic retinopathies. Compelling evidence from other disease settings suggests that low dose interleukin (IL-2) can specifically expand and activate Tregs. However, this therapeutic approach has not been evaluated in ischemic retinopathies. We hypothesize that low dose IL-2 can reduce retinal vasculopathy and inflammation via an increase in Tregs.
Methods :
Two robust mouse models of ischemic retinopathy were studied: oxygen-induced retinopathy (OIR) and streptozotocin (STZ)-induced type-1 diabetes. OIR was induced in Foxp3-red fluorescent protein (RFP) mice (C57Bl6/J background). To induce DR, 6-7 weeks old Foxp3-RFP mice were made diabetic with STZ and studied for 26 weeks. Low dose IL-2 (2500IU, R&D systems) was given via intraperitoneal (IP) injections for 5 consecutive days starting once every 3 days until the end of the experiment.
Results :
Here, we demonstrate that in mice with OIR and DR, low dose IL-2 increased the number of Tregs in blood and lymphoid tissues compared to untreated controls, and importantly Tregs were recruited into retinal tissue. The increase in the number of Tregs was associated with reduced retinal neovascularization, vascular leakage and VEGF levels in OIR. Similarly, in mice with DR, low dose-IL-2 reduced retinal vascular leakage and VEGF. Interestingly, effector CD8+ T cells, which injure the retina (unpublished findings) were increased in lymphoid tissues and the blood of OIR mice and low dose IL-2 prevented the increase of CD8+ T cells in OIR.
Conclusions :
This study highlights the therapeutic potential of low dose IL-2 in ischemic retinopathies in which the balance between Tregs and effector T cells is altered.
This is a 2020 ARVO Annual Meeting abstract.