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

Rohrer, B., Tao, J., Stell, W.K. (1997). Basic fibroblast growth factor, its highand low-affinity receptors, and their relationship to form-deprivation myopia in the chick. Neuroscience 79, 775–787.

Rose, K., Smith, W., Morgan, I., Mitchell, P. (2001). The increasing prevalence of myopia: implications for Australia. Clin. Experiment. Ophthalmol. 29, 116–120.

Rose, K.A., Morgan, I.G., Smith, W., Mitchell, G. (2002). High heritability of myopia does not preclude rapid changes in prevalence. Clin. Experiment. Ophthalmol. 30, 168–172.

Rosenfield, M., Gilmartin, B. (1998). Chapter 10. Myopia and nearwork: causation or merely association? in: Myopia and Nearwork (M. Rosenfield, B. Gilmartin, eds), pp. 193–206. ButterworthHeinemann, Oxford.

Saw, S.-M., Chia, K.-S., Lindstrom, J.M., Tan, D.T.H., Stone, R.A. (2004). Childhood myopia and parental smoking. Brit. J. Ophthalmol. 88, 934–937.

Saw, S.-M., Chua, W.-H., Hong, C.-Y., Wu, H.-M., Chan, W.-Y., Chia, K.-S., Stone, R.A., Tan, D. (2002a). Nearwork in early-onset myopia. Invest. Ophthalmol. Vis. Sci. 43, 332–339.

Saw, S.-M., Katz, J., Schein, O.D., Chew, S.-J., Chan, T.-K. (1996). Epidemiology of myopia. Epidemiol. Rev. 18, 175–187.

Saw, S.-M., Shih-Yen, E.C., Koh, A., Tan, D. (2002b). Interventions to retard myopia progression in children. Ophthalmology 109, 415–427.

Saw, S.-M., Wu, H.-M., Hong, C.-Y., Chua, W.-H., Chia, K.-S., Tan, D. (2001). Myopia and night lighting in children in Singapore. Br. J. Ophthalmol. 85, 527–528.

Saw, S.-M., Zhang, M.-Z., Hong, R.-Z., Fu, Z.-F., Pang, M.-H., Tan, D.T.H. (2002c). Near-work activity, night-lights, and myopia in the Singapore-China study. Arch. Ophthalmol. 120, 620–627.

Schaeffel, F. (2006). Myopia: the importance of seeing fine detail. Curr. Biol. 16, R257–R259.

Schaeffel, F., Bartmann, M., Hagel, G., Zrenner, E. (1995). Studies on the role of the retinal dopamine/ melatonin system in experimental refractive errors in chickens. Vision Res. 35, 1247–1264.

Schaeffel, F., Glasser, A., Howland, H.C. (1988). Accommodation, refractive error and eye growth in chickens. Vision Res. 28, 639–657.

Schmid, G.F., Papastergiou, G.I., Lin, T., Riva, C.E., Laties, A.M., Stone, R.A. (1999). Autonomic denervations influence ocular dimensions and intraocular pressure in chicks. Exp. Eye Res. 68, 573–581.

Schmid, K.L., Wildsoet, C.F. (2004). Inhibitory effects of apomorphine and atropine and their combination on myopia in chicks. Optom. Vis. Sci. 81, 137–147.

Seddon, J.M., Schwartz, B., Flowerdew, G. (1983). Case-control study of ocular hypertension. Arch. Ophthalmol. 101, 891–894.

Seko, Y., Shimizu, M., Tokoro, T. (1998). Retinoic acid increases in the retina of the chick with form deprivation myopia. Ophthalmic Res. 30, 361–367.

Seko, Y., Shimokawa, H., Tokoro, T. (1995). Expression of bFGF and TGF-beta 2 in experimental myopia in chicks. Invest. Ophthalmol. Vis. Sci. 36, 1183–1187.

Seko, Y., Shimokawa, H., Tokoro, T. (1996). In vivo and in vitro association of retinoic acid with formdeprivation myopia in the chick. Exp. Eye Res. 63, 443–452.

Shaikh, A.W., Siegwart, J.T., Norton, T.T. (1999). Effect of interrupted lens wear on compensation for a minus lens in tree shrews. Optom. Vis. Sci. 76, 308–315.

Shiose, Y., Kitazawa, Y., Tsukahara, S., Akamatsu, T., Mizokami, K., Futa, R., Katsushima, H., Kosaki, H. (1991). Epidemiology of glaucoma in Japan – a nationwide glaucoma survey. Jpn J. Ophthalmol. 35, 133–155.

Siatkowski, R.M., Cotter, S., Miller, J.M., Scher, C.A., Crockett, R.S., Novack, G.D., and the US Pirenzepine Study Group (2004). Safety and efficacy of 2% pirenzepine ophthalmic gel in children with myopia. Arch. Ophthalmol. 122, 1667–1674.

Siegwart, J.T., Jr, Norton, T.T. (1998). The susceptible period for deprivation-induced myopia in tree shrew. Vision Res. 38, 3505–3515.

Singh, K.D., Logan, N.S., Gilmartin, B. (2006). Threedimensional modeling of the human eye based on magnetic resonance imaging. Invest. Ophthalmol. Vis. Sci. 47, 2272–2279.

Smith, E.L., III, Bradley, D.V., Fernandes, A., Boothe, R.G. (1999). Form deprivation myopia in adolescent monkeys. Optom. Vis. Sci. 76, 428–432.

Smith, E.L., Bradley, D.V., Fernandes, A., Hung, L.-F., Boothe, R.G. (2001). Continuous ambient lighting and eye growth in primates. Invest. Ophthalmol. Vis. Sci. 42, 1146–1152.

Smith, E.L., III, Hung, L.-F., Kee, C.-S., Qiao, Y. (2002). Effects of brief periods of unrestricted vision on the development of form-deprivation myopia in monkeys. Invest. Ophthalmol. Vis. Sci. 43, 291–299.

Stambolian, D., Ibay, G., Reider, L., Dana, D., Moy, C., Schlifka, M., Holmes, T., Ciner, E., Bailey-Wilson, J.E. (2004). Genomewide linkage scan for myopia susceptibility loci among Ashkenazi Jewish families shows evidence of linkage on chromosome 22q12.

Am. J. Hum. Genet. 75, 448–459.

Stone, R.A. (1997). Neural mechanisms and eye growth control, in: Myopia Updates: Proceedings of the 6th International Conference on Myopia (T. Tokoro, ed.), pp. 241–254. Springer, Tokyo.

Stone, R.A., Flitcroft, D.I. (2004). Ocular shape and myopia. Ann. Acad. Med. Singapore 33, 7–15.

Stone, R.A., Laties, A.M., Raviola, E., Wiesel, T.N. (1988). Increase in retinal vasoactive intestinal polypeptide after eyelid fusion in primates. Proc. Natl Acad. Sci. USA 85, 257–260.

Stone, R.A., Lin, T., Desai, D., Capehart, C. (1995). Photoperiod, early post-natal eye growth, and visual deprivation. Vision Res. 35, 1195–1202.

Stone, R.A., Lin, T., Iuvone, P.M., Laties, A.M. (1990). Postnatal control of ocular growth: dopaminergic mechanisms. Ciba Foundation Symposium 155, 45–57; discussion 57–62.

Stone, R.A., Lin, T., Laties, A.M. (1991). Muscarinic antagonist effects on experimental chick myopia.

Exp. Eye Res. 52, 755–758.

Stone, R.A., Lin, T., Laties, A.M., Iuvone, P.M. (1989). Retinal dopamine and form-deprivation myopia.

Proc. Natl Acad. Sci. USA 86, 704–706.

Stone, R.A., Liu, J., Sugimoto, R., Capehart, C., Zhu, X., Pendrak, K. (2003). GABA, experimental myopia and ocular growth in chick. Invest. Ophthalmol. Vis. Sci. 44, 3933–3946.

Stone, R.A., Pendrak, K., Sugimoto, R., Lin, T., Gill, A.S., Capehart, C., Liu, J. (2006a). Local patterns of image degradation differentially affect refraction and eye shape in chick. Curr. Eye Res. 31, 91–105.

Stone, R.A., Quinn, G.E., Francis, E.L., Ying, G.-S., Flitcroft, D.I., Parekh, P., Brown, J., Orlow, J., Schmid, G. (2004). Diurnal axial length fluctuations in human eyes. Invest. Ophthalmol. Vis. Sci. 45, 63–70.

Stone, R.A., Sugimoto, R., Capehart, C., Pendrak, K., Lin, T. (2006b). Anterior segment growth and peripheral neural pathways in chick. Curr. Eye Res. 31, 511–517.

Stone, R.A., Sugimoto, R., Gill, A.S., Liu, J., Capehart, C., Lindstrom, J.M. (2001). Effects of nicotinic antagonists on ocular growth and experimental myopia.

Invest. Ophthalmol. Vis. Sci. 42, 557–565.

Stone, R.A., Wilson, L.B., Ying, G.-S., Liu, C., Criss, J.S., Orlow, J., Lindstrom, J.M., Quinn, G. E. (2006c). Associations between childhood refraction and parental smoking. Invest. Ophthalmol. Vis. Sci. 47, 4277–4287.

Tan, D.T.H., Lam, D.S., Chua, W.H., Shu-Ping, D.F., Crockett, R.S., and the Asian Pirenzepine Study Group (2005). One-year multicenter, double-masked, placebo-controlled, parallel safety and efficacy study of 2% pirenzepine ophthalmic gel in children with myopia. Ophthalmology 112, 84–91.

Thorn, F., Doty, R.W., Gramiak, R. (1981/1982). Effect of eyelid suture on development of ocular dimensions in macaques. Curr. Eye Res. 1, 727–733.

Thorn, F., Grice, K., Held, R., Gwiazda, J. (2000). Myopia: nature, nurture, and the blur hypothesis, in: Myopia Updates II. Proceedings of the 7th International Conference on Myopia, 1998 (L.L.-K. Lin, Y.-F. Shih, P.T. Hung, eds), pp. 89–93. Springer, Tokyo.

Tigges, M., Iuvone, P.M., Fernandes, A., Sugrue, M.F., Mallorga, P.J., Laties, A.M., Stone, R.A. (1999). Effects of muscarinic cholinergic receptor antagonists on postnatal eye growth of rhesus monkeys. Optom. Vis. Sci. 76, 397–407.

Tokoro, T., Fukushita, K., Hayashi, K., Sato, A., Inoue, H., Ii, M. (1984). Lid fusion in monkeys. Acta Soc. Ophthalmol. Jpn 88, 384–392.

Troilo, D., Gottlieb, M.D., Wallman, J. (1987). Visual deprivation causes myopia in chicks with optic nerve section. Curr. Eye Res. 6, 993–999.

Troilo, D., Judge, S.J. (1993). Ocular development and visual deprivation myopia in the common marmoset (Callithrix jacchus). Vision Res. 33, 1311–1324.

Troilo, D., Nickla, D.L., Mertz, J.R., Summers Rada, J.A. (2006). Change in the synthesis rates of ocular retinoic acid and scleral glycosaminoglycan during experimentally altered eye growth in marmosets.

Invest. Ophthalmol. Vis. Sci. 47, 1768–1777.

Troilo, D., Nickla, D.L., Wildsoet, C.F. (2000a). Choroidal thickness changes during altered eye growth and refractive state in a primate. Invest. Ophthalmol. Vis. Sci. 41, 1249–1258.

Troilo, D., Nickla, D.L., Wildsoet, C.F. (2000b). Form deprivation myopia in mature common marmosets (Callithrix jacchus). Invest. Ophthalmol. Vis. Sci. 41, 2043–2049.

Truong, H.-T., Cottriall, C.L., Gentle, A., McBrien, N.A. (2002). Pirenzepine affects scleral metabolic changes in myopia through a non-toxic mechanism. Exp. Eye Res. 74, 103–111.

van Alphen, G.W.H.M. (1986). Choroidal stress and emmetropization. Vision Res. 26, 723–724.

Vannas, A.E., Ying, G.-S., Stone, R.A., Maguire, M.G., Jormanainen, V., Tervo, T. (2003). Myopia and natural lighting extremes: risk factors in Finnish army conscripts. Acta Ophthalmol. Scand. 81, 588–595.

Vessey, K.A., Lencses, K.A., Rushforth, D.A., Hruby, V.J., Stell, W.K. (2005a). Glucagon receptor agonists and antagonists affect the growth of the chick eye: a role for glucagonergic regulation of emmetropiztion?

Invest. Ophthalmol. Vis. Sci. 46, 3922–3931.

Vessey, K.A., Rushforth, D.A., Stell, W.K. (2005b). Glucagonand secretin-related peptides differentially alter ocular growth and the development of form-deprivation myopia in chicks. Invest. Ophthalmol. Vis. Sci. 46, 3932–3942.

Villarreal, M.G., Ohlsson, J., Abrahamsson, M., Sjöström, A., Sjöstrand, J. (2000). Myopisation: the refractive tendency in teenagers. Prevalence of myopia among young teenagers in Sweden. Acta Ophthalmol. Scand. 78, 177–181.

von Noorden, G.K., Lewis, R.A. (1987). Ocular axial length in unilateral congenital cataracts and blepharoptosis. Invest. Ophthalmol. Vis. Sci. 28, 750–752.

Vongphanit, J., Mitchell, P., Wang, J.J. (2002). Prevalence and progression of myopic retinopathy in an older population. Ophthalmology 109, 704–711.

Walline, J.J., Jones, L.A., Mutti, D.O., Zadnik, K. (2004). A randomized trial of the effects of rigid contact lenses on myopia progression. Arch. Ophthalmol. 122, 1760–1766.

Wallman, J. (1993). Retinal control of eye growth and refraction. Prog. Retin. Eye Res. 12, 133–153.

Wallman, J., Adams, J.I. (1987). Developmental aspects of experimental myopia in chicks: susceptibility,

recovery and relation to emmetropization. Vision Res. 27, 1139–1163.

Wallman, J., Adams, J.I., Trachtman, J.N. (1981). The eyes of young chickens grow toward emmetropia.

Invest. Ophthalmol. Vis. Sci. 20, 557–561.

Wallman, J., Turkel, J., Trachtman, J. (1978). Extreme myopia produced by modest change in early visual experience. Science 201, 1249–1251.

Wallman, J., Wildsoet, C., Xu, A., Gottlieb, M.D., Nickla, D.L., Marran, L., Krebs, W., Christensen, A.M. (1995). Moving the retina: choroidal modulation of refractive state. Vision Res. 35, 37–50.

Wallman, J., Winawer, J. (2004). Homeostasis of eye growth and the question of myopia. Neuron 43, 447–468.

Watsky, M., Cooper, K., Rae, J.L. (1991). Sodium channels in ocular epithelia. Pflügers Arch. 419, 454–459.

Weiss, S., Schaeffel, F. (1993). Diurnal growth rhythms in the chicken eye: relation to myopia development and retinal dopamine levels. J. Comp. Physiol. A 172, 263–270.

Wiesel, T.N., Raviola, E. (1977). Myopia and eye enlargement after neonatal lid fusion in monkeys. Nature 266, 66–68.

Wildsoet, C.F. (2003). Neural pathways subserving negative lens-induced emmetropization in chicks – insights from selective lesions of the optic nerve and ciliary nerve. Curr. Eye Res. 27, 371–385.

Wildsoet, C.F., Pettigrew, J.D. (1988a). Experimental myopia and anomalous eye growth patterns unaffected by optic nerve section in chickens: evidence for local control of eye growth. Clin. Vis. Sci. 3, 99–107.

Wildsoet, C.F., Pettigrew, J.D. (1988b). Kainic acidinduced eye enlargement in chickens: differential effects on anterior and posterior segments. Invest. Ophthalmol. Vis. Sci. 29, 311–319.

Wilson, L.B., Quinn, G.E., Ying, G.-S., Francis, E.L., Schmid, G., Lam, A., Orlow, J., Stone, R.A. (2006). The relation of axial length and intraocular pressure fluctuations in human eyes. Invest. Ophthalmol. Vis. Sci. 47, 1778–1784.

Wilson, M.R., Hertzmark, E., Walker, A.M., ChildsShaw, K., Epstein, D.L. (1987). A case-control study of risk factors in open angle glaucoma. Arch. Ophthalmol. 105, 1066–1071.

Winawer, J., Wallman, J. (2002). Temporal constraints on lens compensation in chicks. Vision Res. 42, 2651–2668.

Wong, T.Y., Klein, B.E.K., Klein, R., Knudtson, M., Lee, K.E. (2003). Refractive errors, intraocular pressure, and glaucoma in a white population.

Ophthalmology 110, 211–217.

Wong, T.Y., Klein, B.E.K., Klein, R., Tomany, S.C., Lee, K.E. (2001). Refractive errors and incident cataracts: the Beaver Dam Eye Study. Invest. Ophthalmol. Vis. Sci. 42, 1449–1454.

Wu, H.-M., Seet, B., Yap, E.P.-H., Saw, S.-M., Lim, T.-H., Chia, K.-S. (2001). Does education explain ethnic differences in myopia prevalence? Optom. Vis. Sci. 78, 234–239.

Xu, H., Huang, K., Gao, Q., Gao, Z., Han, X. (2001). A study on the prevention and treatment of myopia with nacre on chicks. Pharmacol. Res. 44, 1–6.

Xu, L., Wang, Y., Li, Y., Wang, Y., Cui, T., Li, J., Jonas, J. B. (2006). Causes of blindness and visual impairment in urban and rural areas in Beijing.

Ophthalmology 113, 1134–1141.

Younan, C., Mitchell, P., Cumming, R.G., Rochtchina, E., Wang, J.J. (2002). Myopia and incident cataract and cataract surgery: the Blue Mountains Eye Study.

Invest. Ophthalmol. Vis. Sci. 43, 3625–3632.

Zadnik, K. (1997). Myopia development in childhood.

Optom. Vis. Sci. 74, 603–608.

Zadnik, K., Jones, L.A., Irvin, B., Kleinstein, R.N., Manny, R.E., Shin, J.A., Mutti, D.O. (2000). Myopia and ambient night-time lighting. CLEERE Study Group. Collaborative longitudinal evaluation of ethnicity and refractive error. Nature 404, 143–144.

Zadnik, K., Mutti, D.O. (1998). Chapter 2. Incidence and distribution of refractive anomalies, in: Borish’s Clinical Refraction (W.J. Benjamin, ed.), pp. 30–46. W.B. Saunders Company, Philadelphia.

Zaknik, K., Mutti, D.O. (1995). How applicable are animal myopia models to human juvenile onset myopia? Vision Res. 35, 1283–1288.

Zhong, X., Ge, J., Smith, E.L.I., Stell, W.K. (2004). Image defocus modulates activity of bipolar and amacrine cells in macaque retina. Invest. Ophthalmol. Vis. Sci. 45, 2065–2074.

Zhu, X., Winawer, J., Wallman, J. (2003). Potency of myopic defocus in spectacle lens compensation.

Invest. Ophthalmol. Vis. Sci. 44, 2818–2827.

I. BASIC PRINCIPLES OF

REGIONAL IMMUNITY IN THE EYE AND OCULAR IMMUNE

PRIVILEGE

The eye has only one known function – to facilitate the unfettered transmission of light from the external environment to the photoreceptors of the retina and from there on to the visual cortex where the signals are translated into images. Although the eye is only a few centimeters in diameter, it is an enormously complex organ that is composed of a multitude of tissues and cells, many of which are found nowhere else in the body. This remarkable organ is an extension of the brain, and, like the brain,

has limited regenerative properties. Two of the crucial components of the eye that are necessary for normal vision – the corneal endothelium and the photoreceptor layer of the retina – are also incapable of regeneration. Accordingly, traumatic events, such as inflammation, can inflict irreparable damage to these tissues, resulting in blindness. Yet, the consequences of ocular infection with microbial pathogens could be equally threatening to the visual apparatus and the host. This immunological conundrum was recognized over 30 years ago by J. Wayne Streilein, who characterized the immune response in the eye as “a dangerous compromise between the immune system and the eye” (Streilein, 1987). The immune

response to ocular antigens must be a measured one that balances protective immunity to pathogens with the potential injury to innocent bystander ocular cells that cannot regenerate. Thus, the nature of the ocular immune response is an expression of this compromise.

A. Mucosal Immunity

The ocular surface is repeatedly exposed to a variety of air-borne particles and pathogens that could elicit either inflammation or infection. Mucosal surfaces represent the most common portal of entry for pathogens, as they occupy over 400 ft2 of surface area in the human body and far exceed the surface area of the skin (Staats et al., 1994). Like other mucosal surfaces, the ocular surface displays a highly specialized regional immunity.

Antigens introduced through mucosal surfaces, which include the gastrointestinal tract, respiratory tract, and the ocular surface (especially the conjunctiva), are processed by components of the common mucosal immune system. The ensuing immune response to mucosal antigens is characterized by the preferential production of secretory IgA antibody and frequently the down regulation of T-cell-mediated immune responses. The mucosal immune response seems well suited for the unique demands that are imposed on these tissues, which are repeatedly exposed to a wide array of antigens in the foods we ingest and in the air we breathe. Chronic immunemediated inflammation at mucosal surfaces would disable the function and integrity of these important tissues. Thus, restraining T-cell-mediated immunity has obvious benefits, yet an immunological blind spot at mucosal surfaces has obvious liabilities. To compensate for this vulnerability, the common mucosal immune system promotes the generation of immune effector elements that reduce the likelihood of inflammation and collateral damage to normal tissues. The most notable of these are secretory IgA

antibodies that are preferentially induced and accumulate in mucosal secretions such as the mucus blankets of the respiratory and GI tracts, and the tears that coat the ocular surface.

We can infer the importance of secretory IgA based on the prodigious amount that is produced each day. More IgA is produced than all of the other immunoglobulins combined, it accounts for 70% of the immunoglobulin secreted by the mammalian immune system each day (Mazanec et al., 1993; Staats et al., 1994). Why does the immune system preferentially select secretory IgA as the dominant immunoglobulin to be expressed at mucosal surfaces? The structural and functional properties of secretory IgA provide clues to answer this question. IgA antibodies are produced by B cells and are assembled as dimers before entering the lumen of the gut via transcyotosis through an epithelial cell. While in the epithelial cell, a molecule called secretory component (SC) is added. SC stabilizes the IgA dimer and protects it from degradation by the digestive enzymes in the GI tract.

Secretory IgA is well suited for protecting mucosal surfaces from invading pathogens, as it is effective in blocking the adhesion and entry of bacterial and viral pathogens at epithelial surfaces (Mazanec et al., 1993; Staats et al., 1994). Interestingly, IgA has only a limited capacity to activate the complement cascade. This is important for the homeostasis of mucosal surfaces such as the ocular surface, as activation of the complement cascade generates proinflammatory products and collateral injury to juxtaposed tissues. Thus, secretory IgA can effectively prevent adhesion of microbial pathogens to epithelial surfaces of mucosal tissues without provoking inflammation and promoting the generation of injurious oxygen species and proteases by inflammatory cells.

Each day we ingest an enormous array of complex proteins that are potentially immunogenic and capable of eliciting inflammation, yet with some notable exceptions, such as inflammatory bowel disease,

we do not normally suffer from immunemediated gastroenteritis or bronchitis. The ocular surface is also exposed to a continuous onslaught of air-borne particles that are potentially immunogenic, yet inflammation of the ocular surface is relatively rare, bacterial keratitis and allergic conjunctivitis notwithstanding. Environmental immunogens do not normally elicit immune-mediated inflammation due in large part to a remarkable immunoregulatory phenomenon termed mucosal tolerance, which is induced by antigens encountered at mucosal surfaces (Mowat et al., 2004). Mucosal tolerance is characterized by the generation of regulatory T-cells that suppress immune-mediated inflammation, yet allow the production of copious quantities of secretory IgA antibodies. Mucosal tolerance is also induced when antigens are introduced at other mucosal sites, such as the ocular surface (Egan et al., 2000).

Mucosal immunity at the ocular surface represents an elegant compromise between the eye and the immune apparatus, in which the unique immunological demands of the ocular surface are met by an immune response that provides a high degree of protection from pathogens while minimizing the risk of inflammation.

B. Immune Privilege in the Anterior

Chamber

Theremarkableimmunologicalproperties of the anterior chamber (AC) were recognized over 100 years ago by the Dutch ophthalmologist van Dooremaal, who observed the prolonged survival of mouse skin grafts placed into the AC of the dog eye (van Dooremaal, 1873). Another 75 years passed before the full impact of this observation was appreciated, when Medawar also noted the curious survival of foreign skin grafts placed into rabbit eyes, and coined the term “immune privilege” to describe this immunological phenomenon (Billingham et al., 1951). Although immune privilege is widely

recognized, it is often misunderstood. In simplest terms, ocular immune privilege is the condition in which certain immunological processes are silenced, excluded, or reduced in the eye. Immune privilege is not restricted to the eye, but is also present in several other body sites including the brain, hair follicle, hamster cheek pouch, and the pregnant uterus (Head and Billingham, 1985; Niederkorn, 2003, 2006; Niederkorn and Wang, 2005; Paus et al., 2005).

Immune privilege is the product of multiple anatomical, physiological, and immunological features of the eye that restrict the induction and expression of immune responses. The AC has limited lymphatic channels and thus the egression of antigen and antigen presenting cells to regional lymph nodes is limited. The aqueous humor (AH) that fills the AC contains a potpourri of soluble molecules with remarkable anti-inflammatory and immunosuppressive properties; these include: (a) transforming growth factor-β; (b) alpha melanocyte stimulating hormone; (c) calcitonin gene-related peptide; (d) somatostatin; (e) soluble FasL;

(f) vasoactive intestinal peptide; (g) macrophage migration inhibitory factor; and (h) complement regulatory proteins. The cells lining the interior of the eye are decorated with membrane-bound molecules such as complement regulatory proteins, which inactivate the complement cascade. Other membrane-bound molecules such as FasL and tumor necrosis factor-related apoptosisinducing ligand (TRAIL) control the expression of immune-mediated inflammation by inducing apoptosis of immune cells that infiltrate the eye.

Immune privilege of the eye is also maintained by a dynamic immunoregulatory process that is elicited when antigens are introduced into the AC. The ensuing systemic immune responses deviate from conventional immune responses that are induced when antigens are introduced into other body sites. This immunological phenomenon has been termed anterior cham- ber-associated immune deviation (ACAID)

and is characterized by an active, antigenspecific suppression of immune-mediated inflammation (Streilein and Niederkorn, 1981). ACAID results in the suppression of Th1 inflammation – most notably, delayed type hypersensitivity (DTH) – that inflicts collateral injury to innocent bystander cells. The induction and expression of ACAID are extraordinarily complicated and involve the participation of at least four organ systems: (a) eye; (b) thymus; (c) spleen; and

(d) sympathetic nervous system. ACAID also requires the participation of CD4 T cells, CD8 T cells, B cells, F4/80 macrophages, γδ T cells, and NKT cells (Niederkorn, 2006).

The importance of ACAID in maintaining immunological homeostasis in the eye has been inferred, but not formally proven. ACAID can be induced in primates (Eichhorn et al., 1993), and thus it is highly possible that it also exists in humans. If we accept orthotopic corneal transplantation in mice as a relevant model for human penetrating keratoplasty, then we must also conclude that ACAID is clinically relevant, as numerous studies have shown that the long-term survival of corneal allografts is intimately correlated with the development of ACAID to the donor histocompatibility antigens expressed on the corneal transplant (Niederkorn, 1999a,b). Likewise, if we consider the rodent IRBP model of experimental autoimmune uveitis (EAU) to be relevant to human disease, we are compelled also to conclude that ACAID is clinically relevant, because AC injection of IRBP induces ACAID and mitigates EAU (Hara et al., 1992).

C. Immune Privilege of Corneal

Allografts

Corneal transplants have been successfully performed on humans for over 100 years (Niederkorn, 1999a,b). In the United States alone, over 40,000 corneal transplants are performed each year, and in first time, uncomplicated cases, a success rate

of 90% is observed. This exceptionally high acceptance rate is especially noteworthy considering that HLA matching is not typically performed and systemic immunosuppressive drugs are not employed, except in high risk cases in which the graft bed is vascularized or the host has rejected a previous corneal transplant. Animal studies further demonstrate the remarkable properties of corneal transplants. Studies in rat and mouse models of penetrating keratoplasty routinely show that, in the absence of any immunosuppressive drugs, MHCmismatched corneal allografts enjoy indefinite survival in over 50% of the hosts (Niederkorn, 1999a,b). By contrast, other categories of organ allografts, such as skin transplants, undergo rejection in 100% of the hosts. This disparity is even more pronounced in corneal transplants in which the cornea donor and the host differ only at a single MHC class I locus. In this case, less than 30% of the corneal allografts will undergo rejection, while all skin grafts transplanted across the same genetic barrier are rejected (Niederkorn, 2001).

The simplest explanation offered for the immune privilege of corneal allografts was based on the conspicuous absence of both blood and lymph vessels in the graft bed, which ostensibly prevented egression of donor histocompatibility antigens and antigen presenting cells to the regional lymph node and the trafficking of blood-borne effector lymphocytes into the corneal allograft. Although appealing in its simplicity, this explanation alone cannot explain the corneal allograft’s capacity to elude immune rejection. For example, corneal allografts transplanted into clear, avascular graft beds are promptly rejected if the hosts have been previously immunized with donor alloantigens. Likewise, clear, long-standing corneal allografts will undergo immune rejection if the host is subsequently sensitized with a donor skin graft (Ross et al., 1991).

Studies in rodent models of keratoplasty have revealed that the immune privilege of corneal allografts is due to a combination of

anatomical, physiological, and immunological properties of the corneal allograft and the graft bed and the immunomodulatory properties of the AC and AH, which are in direct contact with the corneal allograft. These properties conspire to restrict both the induction and expression of immune responses to the donor’s histocompatibility antigens that are displayed on the corneal transplant.

Unlike other tissues, the central portion of the cornea that is typically used for transplantation is devoid of mature, MHC, class II, positive antigen presenting Langerhans cells (LC). However, virtually any injury or perturbation of the corneal epithelium will induce the appearance of mature, MHC, class II, positive donor LC into the corneal epithelium (Niederkorn, 1999a,b). The presence of donor LC renders the corneal transplant highly immunogenic, resulting in the induction of potent cell-mediated immune responses to the donor histocompatibility antigens and a steep increase in the incidence and tempo of graft rejection (Niederkorn, 1999a,b).

A second mechanism that contributes to the immune privilege of the corneal transplantation is the graft’s capacity to induce ACAID. Animal studies have convincingly demonstrated that: (a) corneal allografts induce ACAID; (b) grafts that fail to induce ACAID are invariably rejected; and (c) the induction of ACAID by AC injection of donor cells prior to the application of corneal allografts greatly enhances corneal allograft survival, even in high risk hosts (Niederkorn, 1999a,b, 2002).

A third mechanism that promotes corneal allograft survival is the capacity of the corneal graft to disarm immune effector elements that arrive at the graft/host interface. Cells of the corneal epithelium and endothelium are decorated with two molecules of the tumor necrosis factor family, FasL and TRAIL, which have the capacity to induce apoptosis of host inflammatory cells. Thus, immune effector cells that express Fas receptor, such as activated T-lymphocytes,

encounter FasL, which is expressed on the corneal allograft, and as a result, the lymphocytes undergo programmed cell death (apoptosis) before they can attack the foreign corneal transplant. Experiments in mice have shown that in certain donor–host combinations, only 50% of the corneal allografts undergo rejection. However, rejection climbs to 100% if the corneal allografts are prepared from donor mice that do not express functional FasL on their tissues, such as the cornea (Stuart et al., 1997; Yamagami et al., 1997). The cornea also expresses cell membrane-bound complement regulatory proteins that disable elements of the complement cascade and prevent the activity of complement-fixing antibodies directed at the corneal transplant. Thus, even if the host mounts a robust antibody response to the donor’s histocompatibility antigens, the capacity of such antibodies to cause harm is neutralized by the complement regulatory proteins that are expressed on the corneal transplant and are also present in soluble form in the AH.

One hundred years of successful keratoplasties are a testament to the immune privilege of corneal allografts. However, this immune privilege is imperfect and can fail, resulting in corneal allograft rejection. Nonetheless, immune rejection of a corneal allograft does not challenge the validity of corneal immune privilege any more than the presence of an autoimmune disease indicates that the immune system is incapable of distinguishing self from non-self. That is, immune privilege of corneal allografts, like the immune system’s tolerance to the antigens on all of the cells in our body, is effective most of the time. However, it occasionally fails. Our immune system is constantly exposed to a universe of potential antigens, and the overwhelming majority of the time it is able to mount a measured response that distinguishes pathogens (nonself) from our own cells (self). The more we understand about immune privilege, the better prepared we are to restore it when it fails and the better able we are to