ICAM-1 Dominant Eye Surface Disorders
|Eye Surface Disorder||Global Prevalence||Countries with Highest Regional Prevalence|
|Dry Eye Disease||5 – 50%2|
|Pterygium||10.2% - 12%3,4||Japan 30.8%4
|Corneal Neovascularization||Up to 37% among contact lens wearers5,6|
|Corneal Graft Rejection||15% of Cornea Transplants 7||Japan 39.6%8|
|Ocular Graft vs Host Disease (GvHD)||35% of Bone Marrow Transplant Patients9|
What is ICAM-1?
ICAM-1 (Intercellular Adhesion Molecule 1) is a protein found in the cell membranes of leukocytes and cells lining the inside of blood and lymphatic vessels (endothelial cells). Also known as CD54, it is an immunoglobulin, that can be activated by a number of other cells of the immune system. Once activated, ICAM-1 allows circulating leukocytes to bind to endothelial cells and then move, or transmigrate, into tissues, as part of the inflammatory response. In recent years, research seems to indicate that ICAM-1 also plays a role in the recruitment of other inflammatory immune cells such as macrophages and granulocytes.1
ICAM-1 driven inflammation is known to play a role in a number of diseases including eye diseases, rheumatoid arthritis, inflammatory bowel disease, autoimmune diseases, allergies and transplant rejection. Consequently ICAM-1 has become a therapeutic target with anti-ICAM-1 therapies being researched and developed in many of these inflammatory diseases.
ICAM-1 in Eye Diseases
ICAM-1 in Dry Eye Disease
Dry eye disease (DED) is a common and multifactorial disease with symptoms of ocular discomfort, visual disturbance, tear film instability, inflammation of and potential damage to the ocular surface.
In patients with DED, cells on the surface of the eye and in some tissues of the tear glands have high levels of ICAM-1. Owing to its known role in the inflammatory process, it was logically suggested that ICAM-1 may play an important role in the cell-mediated immune response and inflammation that occurs in DED.10 ICAM-1 became an area of interest in DED research and an entire pathway of cellular events was hypothesized.
The first ICAM-1 targeting therapy for dry eye disease was launched in 2016 as Lifitegrast (Xiidra®) by Shire. Lifitegrast eye drops do not directly reduce ICAM-1 expression or production, instead they interfere with the interaction between ICAM-1 and another immunological protein, LFA-1. This in turn prevents activation of T-cells and the inflammatory response that is the hallmark of DED. Randomized, placebo-controlled studies have shown a larger reduction in eye dryness as reported by patients, compared to placebo; and to a lesser degree, a larger reduction in objective signs of DED as measured with inferior fluorescein corneal staining scores.11
ICAM-1 in Pterygium
A pterygium is an elevated, superficial, pinkish-red triangular growth on the cornea of the eye, causing symptoms of redness, foreign body sensation, tearing, dryness and itchiness of the eye.
Increased ICAM-1 expression was detected in pterygium epithelium compared to normal conjunctival epithelium, which together with T-lymphocyte infiltration strongly suggests that cellular immunity plays an important role in pterygium formation.12,13
ICAM-1 in Corneal Neovascularization
Corneal angiogenesis or corneal neovascularization (NV) is the presence of blood vessels within the normally avascular corneal stroma. It’s a common histopathologic feature of corneal diseases leading to corneal transplantation.
Antibodies against ICAM-1 reduced leukocyte adhesion and increased leukocyte rolling in New Zealand White rabbits with induced corneal NV. The surface with new corneal blood vessels significantly decreased, suggesting that ICAM-1-mediated adhesion is an early event in the production of new corneal blood vessels.14 Furthermore, FD006 (an anti-VEGFA IgG) was administered by subconjunctival injection to rats with NV induced by alkali burn. FD006 was more effective in reducing corneal NV and lowering ICAM-1 levels than dexamethasone or bevacizumab.15
ICAM-1 in Corneal Graft Rejection
Penetrating keratoplasty (PKP), or corneal transplant, is the most widely practiced type of transplantation in humans, and irreversible immune rejection of the transplanted cornea is the major cause of human allograft failure.
ICAM-1 was induced de novo and strongly expressed in the endothelium of rat corneal allografts undergoing immunological rejection.16 In another rat PKP investigation, intraperitoneal injection of ursolic acid reduced the levels of ICAM-1 and promoted graft survival following corneal allograft transplantation.17
ICAM-1 in Ocular GvHD
Ocular graft-versus-host disease (oGVHD) is a major morbidity factor in recipients of allogeneic hematopoietic stem cell transplantations (allo-HSCT). It can affect multiple ocular structures including the lacrimal gland, conjunctiva, eyelids, and meibomian glands. Clinical features range from DED and inflammatory conjunctival disease to severe complications such as cicatricial entropion and lacrimal gland scarring, corneal ulceration, corneal neovascularization, and fulminant corneal perforation.
Aronni et al. examined the cytology samples of 7 patients with chronic GVHD-related keratoconjunctivitis and 5 normal controls.18 They determined that ICAM-1 expression in the conjunctiva is higher in GVHD patients in association with conjunctival goblet cell decrease.18 Similarly, Abud et al. found that in 24 patients with oGVHD treated with topical tacrolimus 0.05%, the ocular surface epithelial expression of ICAM-1 decreased significantly along with decreased corneal fluorescein staining.19
Dipyridamole vs ICAM-1
What is Dipyridamole?
Dipyridamole (DIP) is a synthetic pyrimidopyrimidine derivative used in clinical medicine as a coronary vasodilator since the beginning of 1960s. DIP inhibits platelet activation, is an anti-thrombotic agent, and is used for the prevention of secondary stroke events in combination with aspirin.20
- Anti-aggregant (US FDA Approved in 1961)
- Anti-influenza (Russia)
Notable Off-Label Uses
- Colon cancer adjuvant therapy
- Diabetic Nephropathy
- Hypophosphatemia in renal transplant patients
- Diabetic Retinopathy
- Ocular Surface Disorders (Topical)
- Insomnia (Oral)
Dipyridamole lowers ICAM-1 expression
Beyond its well established antiplatelet and vasodilatory properties, Dipyridamole’s anti-inflammatory properties have become an area of interest in recent years in the development of new treatments.
Compelling contemporary research now indicates that Dipyridamole may also improve injuries to endothelial cells in the brain caused by inflammation and metabolic insults. In a 2010 study,21 samples of these cells that line the insides of blood vessels in the human brain, were subjected to inflammatory injury through exposure to TNF-α, causing an up to 5-fold increase in ICAM-1 levels. Interestingly, treatment with Dipyridamole (5 uM) significantly attenuated ICAM-1 levels by almost 50%, providing a welcome proof-of-principle that DIP can ameliorate endothelial cell reactions to inflammatory stress.
Dipyridamole has potent anti-inflammatory properties, and works via its effect on adenosine - one of the body’s natural endogenous anti-inflammatory agents. Produced inside cells, once excreted, adenosine quickly disappears as it is taken up by adjacent cells. Dipyridamole acts as an adenosine transport inhibitor, slowing this uptake, and effectively raising levels of extracellular adenosine.
In a 2015 study22, streptozotocin was used to induce diabetes in rats, which caused increased levels of ICAM-1 and several other inflammatory proteins, as well as decreased adenosine levels. When Dipyridamole was administered to the rats, three significant effects were seen: Dipyridamole restored adenosine levels, lowered ICAM-1 levels, and restored the normal balance between pro- and anti-inflammatory cytokines. The same effects were seen in a sample of human cells treated in the same way. By increasing endogenous levels of adenosine, Dipyridamole reduced inflammation and cell death, in vivo and in vitro
Dipyridamole in Ocular Surface Disorders
LFA-1/ICAM-1 Interaction as a Therapeutic Target in Dry Eye Disease.
Pflugfelder SC et al. J Ocul Pharmacol Ther. 2017 Jan/Feb;33(1):5-12.
ICAM-1 expression predisposes ocular tissues to immune-based inflammation in dry eye patients and Sjögrens syndrome-like MRL/lpr mice.
Gao J et al. Experimental Eye Research. 2004 Apr; 78(4):823-35.
The roles of T-lymphocyte subpopulations (CD4 and CD8), intercellular adhesion molecule-1 (ICAM-1), HLA-DR receptor, and mast cells in etiopathogenesis of pterygium.
Beden U et al. Ocul Immunol Inflamm. 2003 Jun;11(2):115-22.
Pterygium: nonsurgical treatment using topical dipyridamole - a case report.
Carlock BH et al. Case Rep Ophthalmol. 2014 Mar 25;5(1):98-103.
Topical Dipyridamole for Treatment of Pterygium and Associated Dry Eye Symptoms: Analysis of User-Reported Outcomes.
Rogosnitzky M et al. Presented at: Israel Society for Vision and Eye Research; March 9-10, 2016; Kfar Maccabia, Israel. Programs and Abstracts 36th Annual Meeting, Israel Society for Vision and Eye Research (ISVER).March 9-10, 2016 2016(Abstract 76):119.
Ocular Applications of Dipyridamole: A Review of Indications and Routes of Administration.
Rogosnitzsky M et al. J Ocul Pharmacol Ther. 2016 Mar;32(2):83-9.
Upregulation of ICAM-1 Expression in the Conjunctiva of Patients with Chronic Graft-Versus-Host Disease.
Aronni S et al. European Journal of Ophthalmology. 2006 Jan; 16(1):17-23.
- ICAM-1. (n.d.). In Wikipedia. Retrieved May 12, 2019, from https://en.wikipedia.org/wiki/ICAM-1
- The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). The ocular surface. 2007;5(2):75-92.
- Liu L, Wu J, Geng J, Yuan Z, Huang D. Geographical prevalence and risk factors for pterygium: a systematic review and meta-analysis. BMJ Open. 2013;3(11).
- Rezvan F, Khabazkhoob M, Hooshmand E, Yekta A, Saatchi M, Hashemi H. Prevalence and risk factors of pterygium: a systematic review and meta-analysis. Survey of ophthalmology. 2018;63(5):719-735.
- Brennan NA, Coles ML, Comstock TL, Levy B. A 1-year prospective clinical trial of balafilcon a (PureVision) silicone-hydrogel contact lenses used on a 30-day continuous wear schedule. Ophthalmology. 2002 Jun. 109 (6):1172-7.
- Sweeney DF. Have silicone hydrogel lenses eliminated hypoxia?. Eye Contact Lens. 2013 Jan. 39(1):53-60.
- Dunn SP, Gal RL, Kollman C, et al. Corneal Graft Rejection Ten Years after Penetrating Keratoplasty in the Cornea Donor Study. Cornea. 2014;33(10):1003-1009.
- Ono T, Ishiyama S, Hayashidera T, et al. Twelve-year follow-up of penetrating keratoplasty. Japanese journal of ophthalmology. 2017;61(2):131-136.
- Jacobs R, Tran U, Chen H, et al. Prevalence and risk factors associated with development of ocular GVHD defined by NIH consensus criteria. Bone marrow transplantation. 2012;47(11):1470-1473.
- Pflugfelder SC, Stern M, Zhang S, et al. LFA-1/ICAM-1 Interaction as a Therapeutic Target in Dry Eye Disease. J Ocul Pharmacol Ther. 2017;33(1):5-12.
- Xiidra® Prescribing Information. December 2017. Accessed May 2019. Available at https://www.shirecontent.com/PI/PDFs/Xiidra_USA_ENG.pdf
- Beden U, Irkec M, Orhan D, et al. The roles of T-lymphocyte subpopulations (CD4 and CD8), intercellular adhesion molecule-1 (ICAM-1), HLA-DR receptor, and mast cells in etiopathogenesis of pterygium. Ocul Immunol Inflamm. Jun 2003;11(2):115-122.
- Tekelioglu Y, Turk A, Avunduk AM, et al. Flow cytometrical analysis of adhesion molecules, T-lymphocyte subpopulations and inflammatory markers in pterygium. Ophthalmologica. 2006;220(6):372-378.
- Becker MD, Kruse FE, Azzam L, et al. In vivo significance of ICAM-1--dependent leukocyte adhesion in early corneal angiogenesis. Invest Ophthalmol Vis Sci. Mar 1999;40(3):612-618.
- Wang Q, Yang J, Tang K, et al. Pharmacological characteristics and efficacy of a novel anti-angiogenic antibody FD006 in corneal neovascularization. BMC Biotechnol. Feb 27 2014;14:17.
- Figueiredo FC, Pendergrast DG, Zhang L, et al. An improved method for examining the corneal endothelium during graft rejection in the rat. Exp Eye Res. Dec 1998;67(6):625-630.
- Wang B, Wu J, Ma M, et al. [Ursolic acid inhibits corneal graft rejection following orthotopic allograft transplantation in rats]. Nan Fang Yi Ke Da Xue Xue Bao. Apr 2015;35(4):530-535.
- Aronni S, Cortes M, Sacchetti M, et al. Upregulation of ICAM-1 expression in the conjunctiva of patients with chronic graft-versus-host disease. Eur J Ophthalmol. Jan-Feb 2006;16(1):17-23.
- Abud TB, Amparo F, Saboo US, et al. A Clinical Trial Comparing the Safety and Efficacy of Topical Tacrolimus versus Methylprednisolone in Ocular Graft-versus-Host Disease. Ophthalmology. Jul 2016;123(7):1449-1457.
- Melani A, Cipriani S, Corti F, et al. Effect of intravenous administration of dipyridamole in a rat model of chronic cerebral ischemia. Ann N Y Acad Sci. Oct 2010;1207:89-96.
- Guo S, Stins M, Ning M, et al. Amelioration of inflammation and cytotoxicity by dipyridamole in brain endothelial cells. Cerebrovasc Dis. Aug 2010;30(3):290-296.
- Elsherbiny NM, Al-Gayyar MM, Abd El Galil KH. Nephroprotective role of dipyridamole in diabetic nephropathy: Effect on inflammation and apoptosis. Life Sci. Dec 15 2015;143:8-17.
- Wang Li Qiang MM. Preparation and Clinical Application of Dipyridamole Eye Drops. Chinese Journal of Hospital Pharmacy. 1996:138-139.
- Carlock BH, Bienstock CA, Rogosnitzky M. Pterygium: nonsurgical treatment using topical dipyridamole - a case report. Case Rep Ophthalmol. Jan 2014;5(1):98-103.
- Rogosnitzky M, Bienstock, CA, Issakov, Y, Frenkel, A. Topical dipyridamole for treatment of pterygium and associated dry eye symptoms: Analysis of user-reported outcome. Presented at: Israel Society for Vision and Eye Research; March 9-10, 2016; Kfar Maccabia, Israel. Programs and Abstracts 36th Annual Meeting, Israel Society for Vision and Eye Research (ISVER). March 9-10, 2016 2016(Abstract 76):119.