**Acknowledgements**

cells and cells of the immune system. It works as a cell adhesion molecule that recruits nearby circulating leukocytes to the inflamed location. In PDR patients, ICAM-1 is suspected as one of the deteriorating factors, promoting leukostasis and inflammation on nearby retinal tissue. Several experiments show leukostasis as a possible mechanism in diabetic retinal vasculature injury. Cells which are attached, mainly granulocytes and monocytes cause microvascular occlusion and capillary injury [106]. Leukostasis in DR is mainly caused by endothelial activation and increased surface expression of intercellular adhesion molecules (ICAM-1) [107]. Hillier et al. stated that increases in ICAM-1 correlate with the severity of DR in patients [108]. Our study on ICAM-1 showed an increase of ICAM-1 expression in PDR patients with more than 10 years of diabetes history [103]. Yan et al. in their study about the effects of intravitreal ranibizumab injection on ICAM-1 levels in PDR patients, demonstrated a decrease of ICAM-1

Vascular cell adhesion molecule-1 (VCAM-1) is an immunoglobulin supergene family of cellular adhesion molecules that are involved in the transmigration of monocytes, eosinophils, and lymphocytes [105, 110–112]. Oxidative stress, VEGF, and hypercholesterolemia increase the expression of VCAM-1 in the brain and retina [111, 113, 114]. It is released by endothelial cells and is present as an early feature of inflammatory disease [111, 113]. Several studies state that VCAM-1 promotes angiogenesis in PDR patients [105, 112–114]. Burgos et al. demonstrated increases in vitreous concentration of VCAM-1 in PDR patients (26 ng/mL) compared to non-diabetic patients in whom a vitrectomy was performed (22 ng/mL) [104]. These results are also consistent with Mroczek et al. in their study about the influence of glucose control on the activation of the intraocular molecular system [114]. There are also reports of increase VCAM-1 concentration in the retinal vessels and serum

CD200 is a novel immunosuppressive molecule found in neuronal cells. CD200 exists in a cell membrane-bound form and a soluble form. It exerts inhibitory effects on microglia/ macrophages via interaction with the CD200 receptor (CD200R) [115]. DR-related neuronal degeneration also reduces CD200 concentration and further induces microglial activation [6]. Recent study on CD200 revealed that levels of sCD200 in vitreous of patients with PDR are significantly higher compared to that in the vitreous of patients without PDR. Xu et al. showed increases in mean sCD200 levels in the PDR group (182 ± 17.63 pg/mL) compared to non-diabetic patients with other conditions who requires pars plana vitrectomy (56.86 ± 6.573 pg/mL). This study also showed that vitreous levels of sCD200 are higher in PDR patients with DME (266.9 ± 28.82 pg/mL) or traction retinal detachment (TRD) (256.9 ± 34.50 pg/mL) compared to PDR patients without DME (136.9 ± 15.13 pg/mL) or TRD (146.9 ± 15.97 pg/mL). sCD200 level increases also have significant statistical correlations with the increase of several angiogenic and inflammatory molecules such as VEGF, IL-6, IL-8

levels a week after intravitreal injection [109].

82 Early Events in Diabetic Retinopathy and Intervention Strategies

*3.6.2. Vascular cell adhesion molecule-1*

of PDR patients [111, 112].

**3.7. Soluble CD200**

and IL-10 [115].

This article's publication is partially supported by the United States Agency for International Development (USAID) through the Sustainable Higher Education Research Alliance (SHERA) Program for Universitas Indonesia's Scientific Modeling, Application, Research and Training for City-centered Innovation and Technology (SMART CITY) Project, Grant #AID-497-A-1600004, Sub Grant #IIE-00000078-UI-1.
