Ocular immune privilege: the eye takes a dim but practical view of immunity and inammation

J. Wayne Streilein Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts

Abstract: The delicate visual axis that makes precise vision possible is highly vulnerable to the destructive potential of immunogenic inammation. Immune privilege of the eye is the experimental expression of the way in which evolution has coped with the countermanding threats to vision of ocular infections and ocular immunity and inammation. Ocular immune privilege has ve primary features that account for its existence: blood:ocular barriers, absent lymphatic drainage pathways, soluble immunomodulatory factors in aqueous humor, immunomodulatory ligands on the surface of ocular parenchymal cells, and indigenous, tolerance-promoting antigen-presenting cells (APCs). Three manifestations of ocular immune privilege that have received the most extensive study are the intraocular microenvironment, which is selectively anti-inammatory and immunosuppressive; the prolonged acceptance of solid tissue and tumor allografts in the anterior chamber; and the induction of systemic tolerance to eye-derived antigens. Anterior chamber-associated immune deviation is known to arise when indigenous, ocular APCs capture eye-derived antigens and deliver them to the spleen where multicellular clusters of these cells, natural killer T cells, marginal zone B cells, and T cells create an antigen-presentation environment that leads to CD4 and CD8 / T cells, which as regulators, suppress induction and expression of T helper cell type 1 (Th1) and Th2 immune expression systems. The ways the eye inuences local and systemic immune responses to ocular antigens and pathogens carry risks to and benets for mammalian organisms. As loss of sight is a powerful, negative-selecting force, the benets of ocular immune privilege outweigh the risks. J. Leukoc. Biol. 74: 179-185; 2003.
Key Words: anterior chamber regulatory T cells immune deviation transforming growth factor- thrombospondin

tissue barriers and the absence of lymphatic drainage routes, and for the next two decades, this view was unchallenged. However, in the 1970s, Kaplan and Streilein [2, 3] reported on a series of experiments in rodents, the results of which strongly suggested that immune privilege is the product of a deviant systemic, immune response to eye-derived antigens. Research over the subsequent three decades has served to strengthen this view and has called attention to the existence of two types of immune privilege [4 8]: sites and tissues. Immune privileged sites are dened as places within the body where foreign tissue grafts experience extended (often indenite) survival, whereas similar grafts placed in conventional sites are promptly rejected. Immune privileged tissues differ from conventional tissues in that grafts prepared from the former experience extended (often indenite) survival when placed at conventional sites, whereas nonprivileged tissue grafts placed in conventional sites are promptly rejected. The last 30 years of research have also given rise to a consensus view of the meaning of ocular immune privilege. The rationale is as follows: All organs and tissues, even those with special physiologic needs and those unable to regenerate themselves, require immune protection against pathogens. As immune protection against pathogens can damage vital tissues in an innocent bystander manner, immune privilege is regarded as an evolutionary adaptation that enables local protection to be provided by immune effectors that do not disrupt specialized tissue functions or cause the loss of tissue incapable of regeneration. Immune privilege is achieved by dynamic interactions between the immune system and specialized tissues. In the case of the eye, where a precise microanatomy and clear media must be maintained for light images to fall accurately on the retina, immune privilege allows for immune protection of the eye in a manner that is largely devoid of immunogenic inammation.

ANTERIOR CHAMBER OF THE EYE: FEATURES OF AN IMMUNE PRIVILEGED SITE

This review will focus on the anterior chamber as an ocular immune privileged site, but much of what has been learned about the anterior chamber also applies to other ocular compartments that also display immune privilege: the vitreous

INTRODUCTION
More than 50 years have transpired since it was rst proposed by Medawar that the anterior chamber is an immune privileged site [1]. Medawar believed that immune privilege resulted from immunological ignorance because of the existence of blood:
Correspondence: J. Wayne Streilein, M.D., Schepens Eye Research Institute, 20 Staniford St., Boston, MA 02114. E-mail: waynes@vision.eri.harvard.edu Received November 21, 2002; accepted January 28, 2003; doi: 10.1189/ jlb.1102574.

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cavity and the subretinal space [9, 10]. Although many factors are now known to contribute to the immune privileged status of the anterior chamber, most can be assigned to one of the following unique features of this site: the blood:ocular barrier in the tissues surrounding the chamberthe absence of blood vessels in the cornea and specialized vascular endothelial cells of the vessels within the iris stroma; absence of lymphatic drainage from the anterior chamber (with the minor exception of the uveoscleral pathway), which insures that contents of the anterior chamber are drained directly into the venous circulation; soluble immunomodulatory factors in aqueous humor (AqH) that are released from the cells and tissues surrounding the anterior chamber and secreted by the ciliary body; cellsurface immunomodulatory factors that are constitutively expressed on parenchymal cells (pigment epithelium, corneal endothelium), which line the anterior chamber; and tolerancepromoting antigen-presenting cells (APCs) in iris stroma and (perhaps) in the trabecular meshwork and outow pathways. Together, these features make it possible for the multiple manifestations of ocular immune privilege to exist.

MANIFESTATIONS OF OCULAR IMMUNE PRIVILEGE

Immune privilege manifests itself in three distinctive ways that can be measured experimentally: through the existence of an anti-inammatory and immunosuppressive microenvironment, through the extended survival of allogeneic allografts, and through induction of tolerance to eye-derived antigens. These manifestations are summarized below.

Intraocular microenvironment is selectively antiinammatory and immunosuppressive

AqH, when harvested from normal eyes and tested in vitro, has been shown to suppress activation of a wide variety of cells and molecules involved in inammation and destructive immunity [11, 12]: CD4 T cells (as revealed by inhibition of proliferation and secretion of effector cytokines), polymorphonuclear neutrophilic leukocytes (inhibiting release and destructive potential of the cellular contents), macrophages activated by bacterial lipopolysaccharide and interferon- (IFN- ; reduced production of reactive oxygen intermediates and nitric oxide), natural killer (NK) cells (reduced capacity to lyse appropriate target cells), and complement components C1q and C3 NK cells. Some of these same inhibitory activities are found within the vitreous gel. It should be pointed out that AqH is not a global inhibitor of all inammation and immunity, as fully functional cytotoxic T cells retain their capacity to lyse their specic targets in the presence of AqH, and neutralizing, noncomplement-xing antibodies retain their properties when AqH is present. The virtually continuous layer of pigmented epithelium that lines the posterior surface of the iris, which lies immediately beneath the secretory epithelium of the ciliary body and supports the photoreceptor cell layer of the retina, represents a kind of immunologic barrier for the eye. In part, this is because tight junctions unite retinal pigment epithelium (RPE) into an
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impermeable shield that prevents blood-borne cells and molecules from indiscriminately entering the subretinal space from the choriocapillaris. A similar set of tight junctions unites iris phycoerythrin (PE). Despite this physical barrier, leukocytes especially activated T lymphocytes have been demonstrated to be able to penetrate through pigment epithelial layers, and this appears to be an important pathway by which immunopathogenic T cells enter ocular compartments and cause inammatory diseases. Over the past 15 years, experimental evidence has accumulated to indicate that T cells, which encounter ocular pigment epithelia, are altered by this experience [1315]. RPE and pigmented epithelial cells cultured from iris and ciliary body have all been found to inhibit T cell activation in vitro. In the case of iris PE, inhibition has been found to be dependent on intimate cell contact between PE and T cells, whereas PE from ciliary body and retina secretes soluble factors that suppress T cells. Identication of the cell-surface molecules responsible for iris PE-induced suppression is now under way. RPE are known to secrete transforming growth factor- (TGF- ), thrombospondin (TSP), prostaglandin E2, and probably other immunomodulatory molecules. One way to consider the ocular pigment epithelium as an immune barrier relates to the fact that any T cells that enter the eye must pass through this layer. Inevitably, and as a means of avoiding sight-limiting inammation, invading T cells must be altered by this encounter. Consequently, most, if not all, of the immunopathogenic potential of T cells that approach the eye through the pigment epithelial layer are neutralized. Thus, it may well be that the immune barrier created by ocular pigment epithelia makes an essential contribution to ocular immune privilege. Corneal endothelium provides a somewhat impenetrable barrier between the anterior chamber and the corneal stroma, and corneal endothelial cells have been reported to secrete molecules that suppress lymphocyte activation and to suppress inammation [16, 17]. In addition, corneal endothelial cells express cell molecules on their apical surface, which inhibit complement activation (CD46, CD55, CD59) [18] and promote apoptosis (CD95 ligand) among CD95 cells that encounter them [19]. Circumstantial evidence links CD95L expression on corneal endothelium with enhanced survival of orthotopic corneal allografts in mice [20, 21], presumably as the donorspecic, alloreactive T cells, which could mediate graft rejection, express CD95 and are thus deleted via programmed cell death. Thus, the ability of the intraocular microenvironment to be anti-inammatory and immunosuppressive resides among unique molecular features of the AqH and vitreous gel and the cell-surface properties of ocular parenchymal cells (pigment epithelia, corneal endothelia) that surround intraocular compartments and form a type of immune barrier to blood-borne molecules and cells that threaten the integrity of the visual axis.

Foreign tissue grafts survive for prolonged, often indenite, intervals without immune rejection
Vast, clinical experience with penetrating keratoplasty collected over more than 50 years indicates that the eye extends immune privilege to corneal grafts [22]. Unlike any other type
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of solid organ transplant, corneal allografts in humans display a very high rate of acceptance, although immunosuppression is only applied topically and in modest dosage. This salutary outcome is reserved, however, for cornea grafts placed in so-called low-risk eyes, i.e., eyes without evidence that includes prior corneal inammation, neovascularization, and caustic burns. When cornea grafts are placed in high-risk eyes, far fewer grafts are accepted, and even extensive, systemic, immunosuppressive therapy is often unable to reverse this deleterious outcome. Experiments in rodent models have clearly indicated that immune privilege is compromised in articially induced high-risk eyes [23], implying that the reason for the high rate of graft failure in human high-risk eyes is a result of the absence of ocular immune privilege. Orthotopic corneal transplants performed in rodent models have provided direct evidence for the important role of ocular immune privilege [24, 25]. Allografts of cornea placed in normal murine eyes are often accepted, sometimes indenitely, although no local or systemic immune-suppressive therapy is administered. The high rate of acceptance in this circumstance has been traced, on the one hand, to the presence of immune privilege in the recipient eye [26] and conversely, to inherent immune privilege of corneal tissue itself [27]. Experimental maneuvers that compromise the privilege of the recipient eye or of the donor graft invariably result in immune rejection of the transplant. Experimental results obtained when other types of histoincompatible tissue grafts are placed in the anterior chamber of the eye point to the same conclusion. Allogeneic tumor cells, which are routinely destroyed before they can form detectable tumors when injected at subcutaneous sites, often form progressively growing tumors when injected into the anterior chamber [28]. If immune privilege is interrupted in the eye before injection of tumor cells, solid tumors usually fail to develop.

tumor-bearing mice contain regulatory T cells that can suppress induction and expression of donor-specic DH when adoptively transferred to nave mice. This pattern of immune responses to tumor alloantigens, ACAID, has proven to be a stereotypic immune response to eye-derived antigens. Thus, if a soluble, heterologous protein antigen such as ovalbumin (OVA) is injected into the anterior chamber, the recipient mice fail to acquire OVA-specic DH when immunized with OVA and complete Freunds adjuvant, to acquire OVA-specic serum, noncomplement-xing antibodies, and to acquire splenic T cells that suppress OVA-specic T helper cell type 1 (Th1) and Th2 responses when transferred into nave mice.

ACAID: DEFINITION, FEATURES, AND MECHANISMS

An operational denition of ACAID holds that antigenic material placed in or arising from the anterior chamber of the eye elicits a deviant form of systemic immunity, which includes T cells (Tc) and B cells (non-C xing) that eliminate pathogens and virulence factors in the absence of inammation, excludes effector CD4 T cells (Th1 and Th2) and B cells (that secrete complement-xing antibodies) that eliminate pathogens via immunogenic inammation, and includes regulatory T cells that suppress induction and expression of immunogenic inammation 2 to Th1/Th2 cells. It is now clear that ACAID can be induced by diverse types of antigens (soluble, cell-associated, viral, tumor-specic, haptenic, autologous, allogeneic). Unlike most other forms of experimentally induced unresponsiveness, ACAID can be generated in nave and presensitized individuals, and when it is present, it is long-lasting, dominant, and resistant to termination. It is important that ACAID has now been shown to be inducible in mice, rats, rabbits, and monkeys, and there is even circumstantial evidence to indicate that ACAID exists in humans [31, 32].

Eye-derived antigens induce systemic immune deviation (tolerance), which lacks effector cells and molecules that mediate immunogenic inammation [anterior chamber-associated immune deviation (ACAID)]
Mice with allogeneic tumors growing progressively in the anterior chamber display evidence suggesting that the recipients immune systems ability to recognize and respond to transplantation antigens on the tumor cells is unusual [29, 30]. First, mice bearing progressively growing allogeneic tumors in the eye are unable to reject skin grafts genetically identical to the tumor cells. As the skin grafts accepted by these mice are placed on the recipients ank, the alteration of the recipients immune response is systemic, not merely within the tumorcontaining eye. Second, mice with allogeneic, intraocular tumors fail to acquire or display delayed hypersensitivity (DH) directed at the tumors alloantigens. Acceptance of donor-type skin grafts and failure to develop donor-specic DH do not reect, however, a failure of the immune system of the recipient mouse to respond to tumor alloantigens. Sera of tumor-bearing mice contain antibodies directed at tumor alloantigens, and the secondary lymphoid organs of these mice contain primed, donor-specic, cytotoxic T cells. Moreover, the spleens of eye

ACAID: the camero-splenic axis

One of the several remarkable features of ACAID is that the phenomenon cannot be evoked in animals lacking a spleen [33, 34]. In fact, ACAID induction is aborted if the recipient animals spleen is removed surgically before and up to 4 5 days after antigen is injected into the anterior chamber. As a corollary to this time-dependent effect, ACAID is also aborted if the eye in which antigen has been injected is enucleated within 4 5 days. These results indicate that successful ACAID induction requires the antigen-bearing eye and an intact spleen to be in place for at least an initial 4- to 5-day interval, implying that a camero-splenic axis exists for the transfer of immunologically relevant information. Direct evidence for the existence of this axis was obtained from experiments in which blood was removed from mice that had received an anterior chamber injection of antigen 48 h previously [35]. Normal mice that received an intravenous (i.v.) infusion of this blood subsequently developed ACAID to the original antigen, although these mice never received an anterior chamber injection of that antigen. Analysis of blood obStreilein Ocular immune privilege 181

tained at 48 h after anterior chamber antigen injection has revealed that the ACAID-inducing signal (AIS) is an F4/80 monocyte that bears antigenic epitopes but not native antigen itself. The source of the ACAID-inducing F4/80 monocytes is probably the eye itself. Dendritic cells and macrophages have been demonstrated to be present within the eye: immediately adjacent to the pigment epithelium of the iris, the ciliary body, and the retina [36, 37]. Similar cells are also present in the stroma of the iris and ciliary body, where ample macrophages are also found. In fact, F4/80 cells harvested from an eye that received a direct injection of antigen into the anterior chamber 24 h previously are able to induce ACAID when i.v. injected into nave mice [38]. These results suggest that eye-derived antigens are captured by indigenous APCs and are carried, presumably across the trabecular meshwork, via the blood to the spleen, where the subsequent steps in ACAID development take place.

derived peptides that are loaded onto MHC class I and class II molecules expressed on the cell surface. TGF- 2-treated, OVA-pulsed APCs accumulate in the marginal zone of the spleen (but not elsewhere) after i.v. injection into nave mice [44], and once they reach this site, the cells recruit NK T cells [45], additional F4/80 APCs, and nave CD4 and CD8 T cells and proceed to form multicellular clusters that include marginal zone B cells and perhaps T cells [46 48]. Subsequent steps in ACAID development proceed from this point.

Differential gene expression in TGF- -treated APCs

The preceding information provides a partial description of the changes that are induced by TGF- 2 in conventional APCs. We have conducted differential gene expression experiments to extend our knowledge of the genes participating in the ACAIDinducing phenotype of TGF- 2-treated cells [49]. Among the more than 40 up-regulated genes and 50 expressed sequence tags following TGF- treatment are the following proteins: murine macrophage elastase, coagulation factor X, ubiquitin fusion protein, integral membrane protein 1, RW1 protein, macrophage-inammatory protein-2 (MIP-2), CDC-10, Cu2 transporting ATPase, TSP, rjs/Herc 2, type I IFNs (IFN- , IFN- ), and Oryctolagus cuniculus translation-initiation factor. Our attention has been rst focused on TSP, IFNs, and MIP-2 because of the capacity of these molecules to down-regulate IL-12 production by APCs (TSP, IFNs) and to recruit NK T cells (MIP-2). Faunce et al. [50] have already demonstrated that MIP-2 secretion by blood-borne cells as well as splenic marginal zone F4/80 cells following anterior chamber injection of antigen is required for NK T cells to be recruited to the site. Sonoda et al. [45] have reported that NK T cells are absolutely required for ACAID induction, and others have implicated B cells and T cells in ACAID [45 48].

In vitro generation of ACAID-inducing cells

Fortunately, it is possible to create an AIS in vitro by exposing conventional APCs to AqH before or during antigen pulsing. When injected into nave mice, these AqH-treated APCs in duce ACAID [39]. The factor in AqH that is able to confer ACAID-inducing properties on conventional APCs in vitro is TGF- 2, the isoform exclusively produced within the eye. Actually, treatment of conventional APCs with amniotic uid and cerebrospinal uid also converts the cells into AIS [40], and this reects the fact that these uids also contain large amounts of TGF- . It is pertinent that AqH, amniotic uid, and cerebrospinal uid are all derived from tissue sites that have been characterized experimentally as immune privileged.

ANALYSIS OF ACAID-PROMOTING FEATURES OF TGF- -TREATED APCs In vitro functional properties of TGF- -treated APCs
The ability to generate ACAID-inducing APCs in vitro has made it possible to learn about the molecules and strategies that these cells use to activate T cells in vitro and by extrapolation, to generate the unique spectrum of antigen-specic T cells observed in the spleens of mice with ACAID following anterior chamber injection of antigen. The following has been learned [41 43]. APCs treated in vitro with active TGF- 2 and pulsed with a soluble antigen, OVA, create a microenvironment (supernatant) that is rich in active TGF- , TSP, tumor necrosis factor (TNF- ), type I IFNs, and interleukin (IL)-10. By contrast, this microenvironment is selectively decient in IL-12. APCs treated in vitro with active TGF- 2 and pulsed with OVA up-regulate CD40 poorly, and this failure persists even in the presence of responding T cells. Such APCs express normal levels of major histocompatibility complex (MHC) class I and class II molecules, B7-1 and B7-2, and intercellular adhesion molecule-1 and enhanced levels of surface CD1. TGF- 2treated, OVA-pulsed APCs readily process and present OVA182 Journal of Leukocyte Biology Volume 74, August 2003

TSP: ORGANIZER OF THE ACAIDPROMOTING PROPERTIES OF TGF- TREATED APCs

Our reasons for exploring a role for TSP in ACAID induction rest on the unique features of this molecule [51]. TSP-1, -2, -3, and -4 are a family of multimeric, multidomain glycoproteins that are constitutively present in platelet granules and can be produced by many different cell types depending on environmental cues. TSP-1 functions as an extracellular matrix molecule, where it dictates cell adhesion and migration of leukocytes and adventitial cells such as broblasts. TSP-1 is constitutively present in AqH, and the TSP-1 gene is active in ocular pigment epithelial cells and corneal endothelium [52 54]. As TSP-1 is also a very potent angiostatic agent, it has received considerable attention as one of the molecules responsible for inhibiting angiogenesis in the normal eye. There are features of TSP-1 expression that make it an attractive candidate for participation in conferring ACAIDinducing properties on APCs. TSP is an immediate early gene found in APCs treated with TGF- 2 [49]. Moreover, APCs treated with TSP display a pattern of up-regulated genes that
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resembles that induced by TGF- 2: TGF- , TNF- , p75 TNF receptor (R), type I IFNs, type I IFN R. Like TGF- 2, TSP treatment of APCs leads to down-regulation of the genes for IL-12 and CD40 [41, 42, 49]. More importantly, antigen-pulsed APCs treated with TSP in vitro, instead of TGF- , induce ACAID when injected i.v. into nave mice. In a corollary experiment, conventional APCs were harvested from mice whose TSP gene had been disrupted. When these cells were treated in vitro with TGF- , little production of active TGF- was observed. In addition, TSP knockout cells, which were treated with TGF- 2, pulsed with antigen, and then injected i.v. into normal, wild-type mice, failed to induce ACAID. Together, these results indicate that TSP plays a key role in the process by which TGF- 2APCs induce ACAID.

that eye-derived APCs that carry antigen to the spleen cause similar perturbations in T cells that they encounter in the marginal zone.

CONCLUDING REMARKS AND PERSPECTIVE

Immune privilege within the eye is an evolutionary adaptation designed to protect the eye from sight-destroying inammation. The strategies used, some of which are known and described above, are effective at limiting inammation and modifying innate and adaptive immunity. As inammation and immunity are important mechanisms for protecting against invading pathogens, there are likely to be risks associated with the eye-dependent alterations. Some of these risks and some of the benets are described below.

Proposed mode of action of TSP in ACAID induction

TSP, by virtue of the receptors and other molecules it is capable of binding, is particularly well suited for orchestrating the interactions between APCs and T cells that lead to ACAID [55]. First, TSP binds CD36, a receptor well expressed on the surface of APCs, and by virtue of its ability to bind latent TGF- , TSP can tether latent TGF- to the APC surface. Second, when TSP binds latent TGF- , it promotes its conversion to active TGF- and subsequently acts to maintain the cytokine in its active state. In this manner, TSP endows the APC with a nanoenvironment highly enriched for active TGF- . APCs also express CD47, a receptor that binds TSP and as a consequence, sends negative signals, which inhibit IL-12 gene activation and IL-12 production, to the nucleus. T cells also express CD47, which offers the potential that TSP could act as a trimolecular bridge (CD36 TSPCD47) that would enhance the stability of interactions between T cells and APCs. In this context, it is relevant that TSP has been reported to bind CD47 on T cells and to cause the deviation of signal transduction proceeding from the T cell receptor away from the Th1 phenotype.

The perils of loss of ocular immune privilege

There are experimental situations and presumed clinical circumstances in which ocular immune privilege is lost cognately or inadvertently. The deleterious consequences of this loss may be revealed as follows: Allogeneic corneal grafts are no longer protected from immune rejection; intraocular tumors elicit immune responses of a vigor and type that destroy the tumor but also cause phthisis; irretrievable damage to the visual axis (corneal stroma, endothelium, lens, vitreous) occurs secondary to acute viral infection or pathogen-associated intraocular inammation; and autoimmunity to strong ocular antigens is triggered, leading to anterior or posterior uveitis and glaucoma secondary to intraocular inammation.

The perils of maintaining ocular immune privilege

The fact that ocular immune privilege exists implies that it carries a biologic cost, as immune responses to eye-derived antigens and immune responses expressed in the eye are materially blunted. Some examples of the perils that result from maintenance of immune privilege are that innate and/or adaptive-immune elimination of intraocular tumors may not be possible; acute retinal necrosis secondary to new or recurrent herpes virus infection of the anterior segment is a serious risk, as virus-specic ACAID is induced transiently, rendering the retina vulnerable to direct viral toxicity; and tumors that develop within the eye may never activate a destructive immune response and thereby cannot be eliminated.

RESPONSES OF T CELLS EXPOSED IN VITRO TO ANTIGEN-PULSED, TGF- -TREATED APCs THAT INDUCE ACAID
One way to explore the ACAID-inducing properties of TGF2-treated APCs is to examine the extent to which antigenspecic T cells respond in vitro after the APCs have been pulsed with antigen [56, 57]. OVA-specic T cells exposed in vitro to TGF- -treated APCs are activated to proliferate and secrete small amounts of IL-2, just as are T cells exposed to untreated, OVA-pulsed APCs. In specic, CD4 T cells (DO11.10) exposed to OVA-pulsed, TGF- 2-treated APCs secrete IL-4 and TGF- but not IFN- , and the resultant T cells have been found to suppress activation of bystander T cells in vitro and to inhibit induction and expression of DH in vivo. CD8 T cells (OT-1) similarly exposed to ACAID-inducing APCs in vitro secrete TGF- , lose their capacity to lyse target cells, and suppress expression of DH in vivo. It is anticipated

The eyes dim view of ocular immunity and inammation

The dim view that the eye takes of immunity and inammation leads to the following outcomes: Activation of effector T cells (Th1, Th2) and innate-immune effectors (natural killer cells, macrophages, polymorphonuclear neutrophils) that generate amplied, nonspecic inammation is avoided, and a microenvironment rich in antagonists of inammatory mediators is created; and the risk of overwhelming ocular infection is reduced by infusing the ocular microenvironment with / defensins, lysozyme, lactoferrins, and other molecules that can eliminate pathogens before proinammatory innate and adaptive immunity intervenes. This spectrum of outcomes is apparStreilein Ocular immune privilege 183

ently based on the evolutionary gamble that few pathogens that reach the eye require Th1/Th2 immunity and complementxing antibodies for elimination.

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The eyes practical view of ocular immunity and inammation

The practical view that the eye takes of immunity and inammation leads to the following outcomes: Activation and expression of adaptive- and innate-immune effectors that eliminate pathogens and infected cells with elegance and specicity, such as cytotoxic T cells and noncomplement-xing antibodies, are permitted; and even as these elegant, specic effectors run the risk of elimination of critical, nonreplicating cells (such as the corneal endothelium and retinal neurons), expression of MHC class Ia and class II molecules on key ocular parenchymal cells is reduced or eliminated so that the cells are virtually invisible to effector T cells that have been primed elsewhere (extraocularly). This spectrum of outcomes is apparently based on the evolutionary hope that most pathogens can be eliminated before infection of ocular parenchymal cells by encounters outside the eye.

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ACKNOWLEDGMENTS
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Some of the research reported here was supported by U.S. Public Health Service Grants EY 05678 and EY 10987. I greatly appreciate the collaborators and contributors to the recent experimental work presented in this review: Drs. Sharmila Masli, Jack Lawler, Masaru Takeuchi, Michele Kosiewicz, Takeshi Kezuka, Joan Stein-Streilein, Koh-Hei Sonoda, and Douglas Faunce.

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