Ординатура / Офтальмология / Английские материалы / Ocular Therapeutics Eye on New Discoveries_Yorio, Clark, Wax_2007

Pena, J. et al. (1999). Transforming growth factor beta isoforms in human optic nerve heads. Br. J. Ophthalmol. 83, 209–218.

Pernet, V., Di Polo, A. (2006). Synergistic action of brain-derived neurotrophic factor and lens injury promotes retinal ganglion cell survival, but leads to optic nerve dystrophy in vivo. Brain 129, 1014–1026.

Picht, G. et al. (2001). Transforming growth factor beta 2 levels in the aqueous humor in different types of glaucoma and the relation to filtering bleb development. Graefe’s Arch. Clin. Exp. Ophthalmol. 239, 199–207.

Polansky, J. et al. (1979). Human trabecular cells: I. Establishment in tissue culture and growth characteristics. Invest. Ophthalmol. Vis. Sci. 18, 1043–1049.

Quigley, H. et al. (2000). Retrograde axonal transport of BDNF in retinal ganglion cells is blocked by acute IOP elevation in rats. Invest. Ophthalmol. Vis. Sci. 41, 3460–3466.

Rakic, J.M. et al. (2003). Placental growth factor, a member of the VEGF family, contributes to the development of choroidal neovascularization.

Invest. Ophthalmol. Vis. Sci. 44, 3186–3193.

Ritter, M.R. et al. (2006). Myeloid progenitors differentiate into microglia and promote vascular repair in a model of ischemic retinopathy. J. Clin. Invest. 116, 3266–3276.

Rosenfeld, P.J. et al. (2006). Ranibizumab for neovascular age-related macular degeneration. N. Engl. J. Med. 355, 1419–1431.

Ross, R. et al. (1974). A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells. Proc. Natl Acad. Sci. 71, 1207–1210.

Rossi, J. et al. (1999). Retarded growth and deficits in the enteric and parasympathetic nervous system in mice lacking GFR alpha2, a functional neurturin receptor. Neuron. 22, 243–252.

Saika, S., (2006). TGFβ pathobiology in the eye. Lab. Invest. 86, 106–115.

Sakata, R. et al. (2004). Mechanical stretch induces TGF-beta synthesis in hepatic stellate cells. Eur. J. Clin. Invest. 34, 129–136.

Samples, J. et al. (1993). Regulation of the levels of human trabecular matrix metalloproteinases and inhibitor by interleukin-1 and dexamethasone.

Invest. Ophthalmol. Vis. Sci. 34, 3386–3395. Schlotzer-Schrehardt, U. et al. (2001). Role of trans-

forming growth factor-beta 1 and its latent form binding protein in pseudoexfoliation syndrome.

Exp. Eye Res. 73, 765–780.

Schonthal, A.H. et al. (2000). Proliferation of lacrimal gland acinar cells in primary culture. Stimulation by extracellular matrix, EGF, and DHT. Exp. Eye Res. 70, 639–649.

Schuettauf, F. et al. (2004). Adeno-associated viruses containing bFGF or BDNF are neuroprotective against excitotoxicity. Curr. Eye Res. 29, 379–386.

Senger, D. et al. (1983). Tumor cells secrete a vascular permeability factor that promotes accumulations of ascities fluid. Science 219, 983–985.

Sharma, G. et al. (2003). p38 and ERN1/2 coordinate cellular migration and proliferation in epithelial wound healing: evidence of cross-talk activation between MAP kinase cascades. J. Biol. Chem. 278, 21989–21997.

Shelton, D. et al. (1995). Human Trks: molecular cloning, tissue distribution and expression of extracellular domain immunoadhesins. J. Neurosci. 15, 477–491.

Shinoda, I. et al. (1988). Demonstration of a considerable amount of mouse epidermal growth in aqueous humor. Biochem. Int. 17, 243–248.

Shinoda, K. et al. (1999). Comparision of the concentrations of hepatocyte growth factor and vascular endothelial growth factor in aqueous fluid and serum with grades of retinopathy in patients with diabetes mellitus. Br. J. Ophthalmol. 83, 834–837.

Sieving, P.A. et al. (2006). Ciliary neurotrophic factor (CNTF) for human retinal degeneration: Phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proc. Natl Acad. Sci. USA 103, 3896–3901.

Smith, L.E. (2005). IGF-1 and retinopathy of prematurity in the preterm infant. Biol. Neonate 88, 237–244.

Smith, L.E. et al. (1997). Essential role of growth hormone in ischemia-induced retinal neovascularization. Science 276, 1706–1709.

Soto, I. et al. (2006). Fibroblast growth factor 2 applied to the optic nerve after axotomy up-regulates BDNF and Trk B in ganglion cells by activating the ERK and PKA signaling pathways. J. Neurochem. 96, 82–96.

Takita, H. et al. (2003). Retinal neuroprotection against ischemic injury mediated by intraocular gene transfer of pigment epithelium-derived factor. Invest. Ophthalmol. Vis. Sci. 44, 4497–4504.

Tamm, E. et al. (1999). Modulation of myocilin/TIGR expression in human trabecular meshwork. Invest. Ophthalmol. Vis. Sci. 40, 2577–2582.

Tamm, E. et al. (1996). Transforming growth factorbeta 1 induces alpha-smooth muscle actin expression in cultured human and monkey trabecular meshwork. Exp. Eye Res. 62, 389–397.

Tao, W. (2006). Application of encapsulated cell technology for retinal degenerative diseases. Expert Opin. Biol. Ther. 6, 717–726.

Tervo, T. et al. (1997). Tear hepatocyte growth factor (HGF) availability increases markedly after eximer laser surface ablation. Exp. Eye Res. 64, 501–504.

Tezel, G. et al. (2001). TNF-alpha and TNF-alpha receptor-1 in the retina of normal and glaucomatous eyes. Invest. Ophthalmol. Vis. Sci. 42, 1787–1794.

Tezel, G., Wax, M.B. (2000). Increased production of tumor necrosis factor-alpha by glial cells exposed to simulated ischemia or elevated hydrostatic pressure induces apoptosis in cocultured retinal ganglion cells. J. Neurosci. 20, 8693–8700.

Thanos, C., Emerich, D. (2005). Delivery of neurotrophic factors and therapeutic proteins for retinal diseases. Expert Opin. Biol. Ther. 5, 1443–1452.

Tong, J. et al. (2006). Aqueous humor levels of vascular endothelial growth factor and pigment epitheliumderived factor in polypoidal vasculopathy and choroidal neovascularization. Am. J. Ophthalmol. 141, 456–462.

Tong, J.P., Yao, Y.F. (2006). Contribution of VEGF and PEDF to choroidal angiogenesis: a need for balanced expressions. Clin. Biochem. 39, 267–276.

Tripathi, B., Tripathi, R. (1989). Neural crest origin of human trabecular meshwork and its implications for the pathogenesis of glaucoma. Am. J. Ophthalmol. 107, 583–590.

Tripathi, R. et al. (1992). Detection, quantification and significance of basic fibroblast growth factor in the aqueous humor of man, cat, dog, and pig. Exp. Eye Res. 54, 447–454.

Tripathi, R. et al. (1994). Growth factors in the aqueous humor and their clinical significance. J. Glaucoma 3, 248–258.

Tripathi, R. et al. (1996). Clinical implications of aqueous humor growth factors in glaucoma, in: The Glaucomas (R. Ritch et al., eds), Vol. 1, pp. 71–88. Mosby Year Book, St Louis.

Tripathi, R. et al. (1998). Increased level of vascular endothelial growth factor in aqueous humor of patients with neovascular glaucoma. Opthalmology 105, 232–237.

Tsai, J.C. et al. (2005). Intravitreal administration of erythropoietin and preservation of retinal ganglion cells in an experimental rat model of glaucoma. Curr. Eye Res. 30, 1025–1031.

Turner, C. et al. (2006). The fibroblat growth factor system and mood disorders. Biol. Psy. 59, 1128–1135.

van Adel, B.A. et al. (2005). Ciliary neurotrophic factor protects retinal ganglion cells from axotomyinduced apoptosis via modulation of retinal glia in vivo. J. Neurobiol. 63, 215–234.

van Setten, G. et al. (1989). Epidermal growth factor is a constant component of normal human tear film. Graefe’s Arch. Clin. Exp. Ophthalmology 227, 184–187.

von Bubnoff, A., Cho, K. (2001). Intracellular regulation in vertebrates: pathway or network? Dev. Biol. 239, 1–14.

Ward, M.S. et al. (2007). Neuroprotection of retinal ganglion cells in DBA/2J mice with GDNF-loaded biodegradable microspheres. J. Pharm. Sci. 96, 558–568.

Watanabe, D. et al. (2005a). Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy. N. Engl. J. Med. 353, 782–792.

Watanabe, D. et al. (2005b). Expression of connective tissue growth factor and its potential role in choroidal neovascularization. Retina 25, 911–918.

Wei, L. (2005). Adenovector pigment epitheliumderived factor (AdPEDF) delivery for wet agerelated macular degeneration. Retina 25, S48–S49.

Weinreb, R. et al. (1997). Prostaglandins increase matrix metalloproteinase release from the human ciliary smooth muscle cells. Invest. Ophthalmol. Vis. Sci. 38, 2772–2780.

Welge-Luessen, U. et al. (1999). Alphaβ-crystalline in the trabecular meshwork is inducible by transforming growth factor-beta. Invest. Ophthalmol. Vis. Sci.

40, 2235–2241.

Welge-Luessen, U. et al. (2000). Induction of tissue transglutaminase in the trabecular meshwork by TGF-β1 and TGF-β2. Invest. Ophthalmol. Vis. Sci. 41, 2229–2238.

Welge-Lussen, U. et al. (2001). Role of tissue growth factors in aqueous humor homeostasis. Curr. Opin. Ophthalmol. 12(2), 94–99

Wilkinson-Berka, J.L. et al. (2004). Inhibition of plate- let-derived growth factor promotes pericyte loss and angiogenesis in ischemic retinopathy. Am. J. Pathol. 164, 1263–1273.

Wilkinson-Berka, J.L. et al. (2006). The role of growth hormone, insulin-like growth factor and somatostatin in diabetic retinopathy. Curr. Med. Chem. 13, 3307–3317.

Wilson, S. et al. (1994). Effect of epidermal growth factor, hepatocyte growth factor and keratinocyte growth factor on proliferation, motility and differentiation of human corneal epithelial cells. Exp. Eye Res. 59, 665–668.

Wilson, S. et al. (1999a). Expression of HGF, KGF, EGF, and receptor messenger RNAs following corneal epithelial wounding. Exp. Eye Res. 68, 377–397.

Wilson, S. et al. (1999b). Stromal-epithelial interactions in the cornea. Prog. Retinal Eye Res. 18, 293–309.

Wilson, S. et al. (2001). The corneal wound healing response cytokine-mediated interaction of the epithelium, stroma and inflammatory cells. Prog. Retinal Eye Res. 20, 625–637.

Wilson, S. et al. (2003). Corneal cells: chatty in development, homeostasis, wound healing and disease.

Am. J. Ophthamol. 136, 530–536.

Wordinger, R. et al. (1998). Cultured human trabecular meshwork cells express functional growth factor receptors. Invest. Ophthalmol. Vis. Sci. 39, 1575–1589.

Wordinger, R. et al. (1999). Expression of alternatively spliced growth factor receptor isoforms in the human trabecular meshwork. Invest. Ophthalmol. Vis. Sci. 40, 242–247.

Wordinger, R. et al. (2000). Human trabecular meshwork cells secrete neurotrophins and express neurotrophin receptors (Trk). Invest. Ophthalmol. Vis. Sci.

41, 3833–3841.

Wordinger, R. et al. (2002). Expression of bone morphogenetic proteins (BMP), BMP receptors, and BMP associated proteins in human trabecular meshwork and optic nerve head cells and tissues. Mol. Vision. 8, 241–250.

Wordinger, R. et al. (2003). Cells of the human optic nerve head express glial cell line-derived neurotrophic factor (GDNF) and the GDNF receptor complex. Mol. Vision 9, 249–256.

Wordinger, R. et al. (2007). Effects of TGF-β2, BMP-4 and gremlin in the trabecular meshwork: implications for glaucoma. Invest. Ophthalmol. Vis. Sci. 48, 1191–1200.

Wozney, J. et al. (1988). Novel regulators of bone formation: molecular clones and activities. Science 242, 1528–1534.

Yamai, L. et al. (2002). Mitogenic and antiapoptotic effects of various growth factors on human corneal fibroblasts. Invest. Ophthalmol. Vis. Sci. 43, 2122–2126.

Yan, Q. et al. (1999). Glial cell line-derived neurotrophic factor (GDNF) promotes the survival of axotomized retinal ganglion cells in adult rats: comparison to and combination with brain-derived neurotrophic factor (BDNF). J. Neurobiol. 38, 382–390.

Yeh, S. et al. (2003). Apoptosis of ocular surface cells in experimentally induced dry eye. Invest. Ophthalmol. Vis. Sci. 44, 124–129.

You, L. et al. (2000). Neurotrophic factors in the human cornea. Invest. Ophthalmol. Vis. Sci. 41, 692–702.

Yu, S. et al. (2006). Effects of bone marrow stromal cell injection in an experimental glaucoma model.

Biochem. Biophys. Res. Commun. 344, 1071–1079. Yuan, L., Neufeld, A.H. (2000). Tumor necrosis

factor-alpha: a potentially neurodestructive cytokine produced by glia in the human glaucomatous optic nerve head. Glia 32, 42–50.

Zhang, X. et al. (2006). Constitutive signaling pathway activity in trabecular meshwork cells from glaucomatous eyes. Exp. Eye Res. 82, 968–973.

Zhong, L. et al. (2007). Erythropoietin promotes survival of retinal ganglion cells in DBA/2J glaucoma mice. Invest. Ophthalmol. Vis. Sci. 48, 1212–1218.

Zode, G. et al. (2007). Activation of the BMP canonical signaling pathway in human optic nerve head tissue and isolated optic nerve head astrocytes and lamina cribrosa cells. Invest. Ophthalmol. Vis. Sci. In press.

I. INTRODUCTION

As our understanding of the pathophysiology of dry eye disease has expanded, the options for better therapy have also improved. The importance of maintaining a stable tear film is now recognized as important. There is better understanding of the mechanisms that maintain tear film stability and new options to enhance that stability. The role of inflammation in producing symptoms and in damaging the ocular surface has been identified and anti-inflammatory approaches to treatment continue to evolve. Recognition of the importance of hormonal support to the lacrimal and ocular surface system suggests that preventing inflammation and

maintaining a healthy surface is a therapeutic option.

II. HISTORICAL PERSPECTIVE

Dry eye disease is a very common condition in ophthalmic practice with prevalence in the United States documented at approximately 7% in women over the age of 50 and 3.6% in men over the age of 50 (Schaumberg et al., 2003). It occurs more frequently in women beyond menopause and has been reported with higher prevalence in those taking estrogen-only hormonal support therapy (HRT) (Schaumberg et al., 2001). More severe dry eye disease is associated with Sjogren’s syndrome in

which the disease is named keratoconjunctivitis sicca (Sjogren, 1951).

Historically the treatment for dry eye disease has been tear replacement with numerous formulations ranging from simple aqueous solutions to complex polymer combinations formulated to provide extended residence time or emollient effect on the ocular surface (Murube et al., 1998a). The limitation of early tear supplements is that they are primarily palliative, and do not correct the underlying abnormalities of the tear film nor the ocular surface. Additionally, early formulations included surface-active preservatives that were themselves damaging to the tear film stability and ocular surface (Burstein, 1985). With recognition that elevated tear film osmolarity of dry eye could damage ocular surface epithelial cells, formulations that provided hypotonic tear supplementation became available under the brand names Hypotears™ and Theratears™ (Gilbard et al., 1984; Gilbard, 1994a). Refinement of the electrolyte balance to mimic the naturally occurring tear led to development of Theratears™ (Gilbard and Rossi, 1992; Gilbard, 1994b). This formulation is still extensively used today for tear supplementation in all types of dry eye disease.

As our understanding of the pathophysiology of dry eye disease has expanded, the options for better therapeutic measures have also improved. The importance of maintaining a stable tear film is now clear (Bron et al., 2004). There is better understanding of the mechanisms that maintain tear film stability and new options to enhance that stability (Lemp et al., 2005). The role of inflammation in producing symptoms and in damaging the ocular surface has been identified, and anti-inflammatory approaches to treatment continue to evolve (Pflugfelder et al., 2000; Stern et al., 1998). Recognition of the importance of hormonal support to the lacrimal and ocular surface system in both preventing inflammation and maintaining healthy surface cells suggests that selective hormone replacement is a reasonable option.

III. ENHANCED TEAR

STABILIZERS AND OCULAR SURFACE PROTECTANTS

With the recognition of the importance of the lipid layer of the tear film in maintaining tear film stability, several medications containing lipids have been developed and are now available as over-the-counter (OTC) preparations (Bron et al., 2004; Tomlinson, 2006). The early suggestion of Niels Ehler that phospholipid was responsible for the surfactant properties of the tear film was pursued by Frank Holly, PhD, to include lipid in the formulation of tear supplements (Ehlers, 1965; Holly, 1973a,b; Murube et al., 1998b). Although lipidcontaining artificial tears were advocated by some practitioners in the 1970s, there was little general enthusiasm in their application. A newly marketed lipid-containing artificial tear (Freshkote™) is now available as an OTC option and anecdotal reports indicate it is beneficial in relieving symptoms of discomfort in dry eye.

The use of lipids in creating emulsionbased therapy to stabilize the tear film was initiated by development of a vehicle for cyclosporine. The formulation tested very well in clinical trials as a vehicle control in the Phase II and III studies of topical cyclosporine therapy of dry eye disease and it was subsequently marketed as a tear stabilizer. It is available as Refresh Endura™, and is composed of a lipid emulsion of castor oil that also includes glycerin, polysorbate 80, and sodium hydroxide (to adjust the pH). It probably achieves its effect by retarding evaporation from the tear film but has been demonstrated to stabilize the tear film and improve tear breakup time (TBUT) (Di Pascuale et al., 2004).

More recent studies have sought to treat dry eye symptoms and increase lipid layer thickness (LLT) through the application of a metastable lipid emulsion, which is able to mimic the polar and non-polar lipid components of the lipid layer by rapidly

separating into its multiple oil and water phases (Korb et al., 2004; Lemp et al., 2005). In a double-masked, subject-paired study, Korb and associates compared two novel lubricant eye drops on LLT in subjects reporting dry eye symptoms. They found that one eye drop containing Restoryl™, the active ingredient of Soothe™ (Alimera Sciences, Inc.), more than doubled LLT, while the increase with the combination of Polyethylene Glycol 400 0.4%, Propylene Glycol 0.3% in Systane™ (Alcon Laboratories, Inc.) was not significantly greater than that produced by the weakest measurable blink response. Greiner et al. (2005) treated subjects reporting dry eye symptoms with Restoryl™ for one month and found a dramatic increase in LLT within one minute of instillation and also an improvement of dry eye symptoms in all subjects after one month of treatment. Restoryl™ has also been shown to replenish the aqueous layer of the tear film. When applied to the eye, Restoryl™ differentiates into neutral oils (helping to rebuild the lipid layer), interfacial molecules (stabilizing the interface between the lipid and aqueous layers and supporting the mucin layer), and water (helping to restore the aqueous layer) (Lemp et al., 2005).

Protection of the ocular surface has long been a goal of dry eye therapy and numerous preparations have been marketed to achieve this protection with limited success (Murube et al., 1998a,b). A recent approach that has been more successful is built upon a platform of the HP-guar-based molecule (Christensen et al., 2004). The formulation includes borate and HP-guar at a controlled pH. Upon instillation onto the eye there is a resulting pH change that initiates a dispersion of the molecules both to adhere to the ocular surface and to stabilize the tear film. The formulation, marketed as Systane™ (Alcon Laboratories, Inc.) works well alone but has also been demonstrated to enhance the effect of topical cyclosporine in treatment of dry eye disease (Sall et al., 2006).

With the recognition of the damage of increased osmolarity to the ocular surface cells, therapy to protect against this deleterious osmotic stress has been proposed. The attempts to reduce the osmolarity of the tear film by applying hypotonic solutions are limited by the short duration of reduced osmolarity achieved by topical application of a hypotonic solution (Holly and Lamberts, 1981). The goal of actual osmoprotection of the surface cells by compatible osmolytes is evolving however, with the availability of Optive™ (Allergan, Inc.). Based upon the biological concepts of controlling osmotic stress to epithelial cells by applying compatible osmolytes, molecules that are internalized to the cell and serve to counterbalance the external osmotic stress with solutes such as glycerin that are compatible with intracellular structures, the compatible solutes abrogate some of the damage induced by the osmotic stress (Yancey et al., 1982; Yancey, 2005). Since the osmoprotectants are internalized by cells, residence time on the surface of the eye and the duration of benefit is increased beyond the physical residence time of typical artificial tears. The product, which reached the market in late 2006, is a practical and improved artificial tear that holds promise for incremental benefit in patients with signs or symptoms secondary to hyperosmotic ocular surface compromise (Personal communication, Joseph Vehige, OD, Allergan, Inc.).

Advances in tear supplementation and modulation of the effects of a disturbed tear film by enhancing the properties of the tear film or protecting the ocular surface will continue to be an important part of the management of dry eye, particularly in the patient with very mild disease or the patient with episodic dry eye that is aggravated by environmental conditions or physical activities that challenge tear film stability, such as work with computers and video games, but also in the patient with chronic dry eye disease (Tsubota and Nakamori, 1993).

IV. ANTI-INFLAMMATORY

MEDICATIONS

Recognition of the pathogenetic role of inflammation in dry eye disease is a major advance in our understanding of this common clinical condition (Pflugfelder et al., 2000). Not only is there strong evidence of immune mediated inflammation in some types of dry eye disease (Stern et al., 1998), but the event of increased osmolarity of the tear film has also been identified as an inducer of inflammation (Luo et al., 2005; Pflugfelder et al., 1999; Niederkorn et al., 2006). The inflammatory state has been correlated with damage to both the lacrimal tissue and ocular surface epithelium through increased programmed cell death (apoptosis) of those tissues.

The expression of inflammatory markers in both the ocular surface tissues and tears of dry eye patients has been documented (Stern et al., 1998). Expression of the immune activation marker HLA-DR, as detected by flow cytometry analysis, is significantly increased in conjunctival epithelial cells from dry eye patients compared with those of normal subjects (Brignole et al., 2000). Expression of this marker occurs in conjunctival epithelial cells that have been exposed to inflammatory cytokines produced by activated T-cells, including inter- feron-γ (IFN-γ). Similar levels of HLA-DR have been detected in samples from subjects with Sjögren’s and non-Sjögren’s syndrome keratoconjunctivitis sicca (Brignole et al., 2000; Stern et al., 2002). Proinflammatory cytokines such as IL-1α, IL-1β , IL-6, IL-8, TNF-α and TGF-β1, are elevated in the tears and/or conjunctival epithelium of patients with dry eye (Pflugfelder et al., 1999; Solomon et al., 2001; Turner et al., 2000).

Apoptosis has also been implicated in the pathogenesis of dry eye disease. Molecular markers of apoptosis are increased in the conjunctival epithelia of dry eye patients compared with those of normal control subjects (Stern et al., 1998; Strong et al., 2005). Studies in the canine variant of dry eye

disease demonstrated that anti-inflammatory therapy with cyclosporine could reduce the apoptosis, as well as the other aspects of inflammation (Gao et al., 1998b).

In consideration of the accumulating information implicating inflammation as an integral part of the pathophysiology of dry eye disease, several anti-inflammatory medications have been evaluated for therapy of chronic dry eye.

A. Corticosteroids

Therapy with topical steroids has been demonstrated to decrease the inflammation and improve the integrity of the ocular surface in patients with dry eye disease (Marsh and Pflugfelder, 1999; Pflugfelder et al., 2004). Unpreserved topical methylprednisolone delivered as a 1% solution not only reduces signs of inflammation, but also improves regularity of the ocular surface as measured by computerized videokeratoscopy (Marsh and Pflugfelder, 1999). In a randomized, masked clinical trial, topical loteprednol etabonate 0.5% was better than placebo in reducing the signs and symptoms of dry eye (Pflugfelder et al., 2004). The anti-inflammatory effect of corticosteroids is well known and there is evidence that steroids also ameliorate apoptosis (Bourcier et al., 2000). Unfortunately, long-term topical corticosteroid therapy can be associated with cataract formation and with elevation of intraocular pressure in susceptible patients, and thus protracted therapy cannot be advocated. It is more likely that short-term pulse therapy with corticosteroids will be safer and more likely utilized to control dry eye disease in conjunction with other management strategies.

B. Cyclosporin A

Although initially explored as an antifungal agent, cyclosporine A demonstrated excellent immunomodulatory properties and has been used in treating allograft rejection for numerous organ systems, including

kidney, heart, lung and liver transplantation (DeBakey, 1984). Observations made during the use of topical cyclosporine to treat canine dry eye prompted intensive investigation into the human ocular use of the medication (Kaswan, 1994). Subsequent studies identified utility of topical cyclosporine to suppress inflammation and restore tear function and health of the ocular surface (Gao et al., 1998a).

Treatment with topical cyclosporine has been shown to reduce cell surface markers of activated T-lymphocytes and apoptotic cells in conjunctival biopsies of dry eye patients treated with the drug (Figures 6.1 and 6.2). Biopsies of the conjunctiva of patients treated with topical cyclosporine demonstrated reduction in the numbers of lymphocytes (Kunert et al., 2000). The elevated levels of expression of inflammatory