Ординатура / Офтальмология / Английские материалы / Ocular Disease Mechanisms and Management_Levin, Albert_2010

18.Fisher SK, Lewis GP. Muller cell and neuronal remodeling in retinal detachment and reattachment and their potential consequences for visual recovery: a review and reconsideration of recent data. Vis Res 2003;43:887–897.

24.Walshe R, Esser P, Wiedemann P, et al. Proliferative retinal diseases:

myofibroblasts cause chronic vitreoretinal

traction. Br J Ophthalmol 1992;76:550– 552.

25.Grisanti S, Guidry C. Transdifferentiation of retinal pigment epithelial cells from epithelial to mesenchymal phenotype. Invest Ophthalmol Vis Sci 1995;36:391– 405.

29.Heidenkummer HP, Kampik A, Petrovski B. Proliferative activity in epiretinal

Key references

membranes. The use of the monoclonal antibody Ki-67 in proliferative vitreoretinal diseases. Retina 1992;12:52– 58.

64.Guidry C. Tractional force generation by porcine Muller cells: development and differential stimulation by growth factors. Invest Ophthalmol Vis Sci 1997;38:456– 468.

S E C T I O N   1 0

Uveitis

C H A P T E R 79

Immunologic mechanisms of uveitis

Overview

A deeper appreciation of the pathogenic mechanisms underlying uveitis, or intraocular inflammation involving the uveal tract (i.e., iris, ciliary body, choroid), has contributed to our abilities to treat these potentially vision-threatening conditions. The spectrum of uveitis ranges from acute, selflimited episodes of anterior uveitis to severe, progressive panuveitis syndromes, which may lead to blindness if not properly managed with immunosuppressive treatment regimens.

This chapter highlights our current knowledge regarding the pathogenic immune mechanisms underlying uveitic conditions. Topics discussed include pathologic features and etiologies of common clinical uveitic conditions, animal models of uveitis, the contribution of immunogenetics to uveitis, the cellular immune response described in patients with uveitic disease, and soluble mediators of inflammation (i.e., cytokines and chemokines). We also discuss the key principle of immune tolerance, which is thought to be compromised in uveitic disease. Specific disease entities are mentioned as related to these central concepts; however, a full discussion of the broad range of uveitic diseases is beyond the scope of this chapter and several excellent reviews regarding specific disease entities are available.1,2

Clinical background

The anatomic classification of uveitis using the Standardization of Uveitis Nomenclature (SUN) Working Group scheme is the preferred method of classifying disease for both patient care and research purposes (Table 79.1). The goals of the SUN classification scheme included improving clinical research across centers, permitting the meta-analyses of data, and improving our understanding of the varied therapeutic responses of patients to different disease processes.3 Ocular inflammatory disease is termed “anterior uveitis” when inflammation involves the iris and ciliary body (Figure 79.1), “intermediate uveitis” with inflammation primarily found in the vitreous cavity (Figure 79.2), and “posterior uveitis” in conditions involving the retina and choroid. The term “panuveitis” refers to inflammation in all three anatomic locations, including the iris/ciliary body, vitreous

cavity, and retina and/or choroid (Figure 79.3). Because the literature differs with respect to uveitis classification prior to implementation of the SUN criteria, some of the literature referenced in this chapter classifies disease by systemic entity (e.g., Behçet’s disease-associated uveitis). In the future, it will be important to understand the pathogenesis of specific disease entities (e.g., sarcoidosis-associated intermediate uveitis) in addition to a more general understanding of disease pathogenesis according to anatomic classification (e.g., acute anterior uveitis).

Pathology

Pathologic examination of ocular specimens has provided valuable information about the cellular mediators (discussed below), tissue injury, and healing mechanisms that are observed in patients with uveitis. Immune cells identified in pathologic specimens have included T- and B-cell lymphocytes, macrophages, and epithelioid cells.

For example, in sarcoidosis-associated uveitis, CD4+ T cells predominate, although CD8+ T cells and B cells have also been observed.4,5 Granulomas consisting of multinucleated giant cells (macrophage aggregates) and epithelioid cells are also seen; however, granulomas have also been identified in other uveitic processes, including ocular tuberculosis and sympathetic ophthalmia.

Following the infiltration of ocular tissue by inflammatory cells, the release of cytokines (discussed below) and the recruitment of additional leukocytes lead to further tissue injury and resultant scarring and fibrosis. These processes are exemplified by the late phase of Vogt–Koyanagi–Harada’s (VKH) disease, in which subretinal fibrosis and choroidal neovascularization are observed in a significant percentage of patients with chronic VKH disease.6

Etiology

Determining the etiology of a particular uveitic syndrome may be a difficult task because of the wide array of diagnostic considerations. However, correct identification of the predominant anatomic location of a disease entity is helpful in narrowing the differential diagnosis. The SUN Working Group criteria were valuable in describing the four major

Figure 79.1  Keratic precipitates (KP). Multiple inferior KP on corneal endothelium may be observed in anterior uveitis. Numerous granulomatous KP are found on the inferior corneal endothelium.

Table 79.1  The Standardization of Uveitis Nomenclature (SUN) working group anatomic classification of uveitis

*As determined clinically.

Reproduced with permission from Jabs DA, Nussenblatt RB, Rosenbaum JT,

et al. Standardization of uveitis nomenclature for reporting clinical data. Results of the first international workshop. Am J Ophthalmol 2005;140:509–516.

classes of uveitis: (1) anterior uveitis; (2) intermediate uveitis; (3) posterior uveitis; and (4) panuveitis.

Etiologies of anterior uveitis include sarcoidosis, human leukocyte antigen (HLA)-B27-associated uveitis, syphilis, tuberculosis, and Lyme disease. Causes of intermediate uveitis also include sarcoidosis, syphilis, Lyme disease, and tuberculosis. However, entities more commonly associated with intermediate uveitis (cf. anterior uveitis) include multiple sclerosis (MS), human T-cell lymphotrophic virus-1 (HTLV-1), and primary intraocular lymphoma, which may masquerade as a chronic vitritis in an elderly patient (i.e., masquerade syndrome). Posterior uveitis may be caused by systemic conditions, including sarcoidosis, syphilis, tuberculosis, and Lyme disease. Some causes of posterior uveitis

Figure 79.2  Intermediate uveitis. Diffuse vitritis in an elderly patient. Primary intraocular lymphoma may masquerade as an intermediate uveitis and should be considered in the differential diagnosis in elderly patients.

isolated to the eye include serpiginous choroidopathy, birdshot retinochoroidopathy, and multiple evanescent whitedot syndrome (Box 79.1). Panuveitis, which includes anterior-chamber, vitreous, retina, and choroidal inflammation, may be observed in sarcoidosis, syphilis, tuberculosis, VKH disease, and sympathetic ophthalmia. Endophthalmitis may also manifest as a panuveitis, and infectious etiologies of ocular inflammation (e.g., bacterial, fungal, viral) should also be considered in certain clinical situations. For example, in immunosuppressed patients (e.g., cancer patients on chemotherapy, patients with indwelling catheters and lines), fungal and bacterial endophthalmitis should be considered in cases of panuveitis. In other clinical settings (e.g., AfricanAmerican patients with hilar adenopathy) other considerations such as sarcoidosis should be higher on the differential diagnosis of panuveitis.

Pathophysiology

Animal models of uveitis

Experimental models of uveitis have contributed greatly to our understanding of uveitis. Each of these models involves the activation of the immune system against specific retinal or uveal tract antigens (Box 79.2).7 During induction of experimental autoimmune uveitis or uveoretinitis (EAU), animals are sensitized to known retinal antigens such as retinal S-antigen, RPE65,8 or interphotoreceptor-binding protein (IRBP),9,10 which are emulsified in complete Freund’s adjuvant to augment the immune response. A second agent such as pertussis toxin is also used to activate the immune response further. Using this technique, inflammation of the iris, ciliary body, retina, and choroid is consistently observed. With this reproducible technique, it is possible to study the cellular components, soluble mediators and their receptors, therapies, and drug delivery systems targeted against the inflammatory response.11

Endotoxin-induced uveitis (EIU) has also been a useful animal model of uveitis. In this animal model, lipopolysaccharide (endotoxin) is administered to the animal, leading

Box 79.1  Anatomic classification of uveitis and

disease considerations

to an acute inflammatory response in the uveal tract that occurs 6 hours after endotoxin injection and peaks within 24 hours. Iris hyperemia, miosis, increased aqueous humor protein, and infiltration of the anterior chamber and uvea by inflammatory cells are observed following EIU induction.12

A model of experimental autoimmune anterior uveitis (EAAU) has also been described previously. EAAU is induced in animal models via injection of a number of peptides, including myelin basic protein,13 melanin-bound antigens of the retinal pigment epithelium,14 or melanin-associated antigen.15 Experimental models have also been described for specific uveitic syndromes, including VKH disease in dogs16 and rats,17 ocular histoplasmosis,18 and ocular toxoplasmosis.19 Because much of our knowledge stems from studies in animal models, some of these studies are referenced in the discussion of clinical uveitis throughout this chapter. Table

620

Box 79.2  Cellular and soluble mediators of

inflammation in uveitis

79.2 highlights various details of the animal models used in the study of uveitis.

Immunogenetics and uveitis

The relationship between immunogenetics and the clinical manifestation of ocular inflammatory disease has been the subject of several recent reviews.20,21 Genes may influence individual susceptibility to an inflammatory disease; however, the mechanisms leading from a specific genetic profile to the disease phenotype may also involve environ-

Anterior-chamber infiltrates, vitreous infiltrates, choroidal and retinal inflammation, exudative retinal detachments

mental triggers, loss of regulatory elements preventing ocular autoimmunity, and other yet undefined mechanisms.

The HLA genes, which are located on chromosome 6, are responsible for expression of major histocompatibility complex (MHC) class I and II antigens. MHC class I antigens are found on almost all cells in the human body, whereas MHC class II antigens are located primarily on cells involved in antigen presentation, such as lymphocytes and dendritic cells (tissue macrophages). Both HLA class I MHC and class II MHC associations with uveitis have been reported in a number of uveitic syndromes. Specifically, the association of HLA-B27 with acute anterior uveitis and a variety of associated systemic diseases, including the seronegative spondyloarthropathies, has been observed.22 A class I MHC association with uveitis has been observed in the posterior uveitic syndrome birdshot retinochoroidopathy; greater than 90% of individuals diagnosed with this syndrome carry a copy of the HLA-A29 allele.23,24 Behçet’s disease, which may present with panuveitis, retinal vasculitis, or acute anterior uveitis, has been associated previously with HLA-B51.25,26 Class II MHC associations have been identified in patients with VKH disease27 (HLA-DR1 and -DR4) and in pars planitis28 (HLA-DR2). Table 79.3 summarizes the known HLAassociations of various uveitic syndromes.

Single-nucleotide polymorphisms (SNPs) that may predispose individuals to a certain disease phenotype have also been studied recently. El-Shabrawi et al reported an association of specific SNPs within the tumor necrosis factor-α (TNF-α) promoter that may increase the susceptibility of HLA-B27-positive individuals towards the development of intraocular inflammation.29 A correlation of clinical phenotype in patients with anterior uveitis and SNPs within the cytokine genes interleukin (IL)-1R, IL-6, IL-10, and TNF has also been reported.30,31

Besides examining single-nucleotide changes in DNA, other investigators have examined the role of differential gene expression in producing various ocular inflammatory phenotypes. In a recent study by Li et al, gene expression profiling using cDNA microarray analysis of peripheral

Table 79.3  Selected ocular diseases and their human leukocyte antigen (HLA) associations

AA, African-American; M; mixed ethnic study; O, oriental; W, white.

Modified from Nussenblatt RB. Elements of the immune system and concepts of intraocular inflammatory disease pathogenesis. In: Nussenblatt R (ed.) Uveitis: Fundamentals and Clinical Practice. Philadelphia, PA: Mosby, 2004.

blood samples in patients with noninfectious uveitis revealed increased expression of several cytokine, chemokine, and chemokine receptor genes when compared to normal controls.32 The examination of local gene expression in EAU demonstrated a local upregulation of inflammatory cytokines and chemokines with a bias towards a T-helper cell type 1 (Th1)-immune response (see below); specifically, upregulation of interferon-γ (IFN-γ), RANTES/CCL5, and MIG/CXCL9 with low levels of the T-helper cell type 2 (Th2) cytokines IL-4 and IL-5 was observed.33 Further analysis of differential gene expression may help to identify inflammatory mediators responsible for specific disease phenotypes in the future.

In 2001, a single gene mutation in the nucleotide oligomerization domain (NOD2) gene was identified as a cause of the familial form of uveitis known as familial juvenile systemic granulomatosis (Blau syndrome or Jabs disease).34 Blau syndrome consists of a triad of uveitis, arthritis, and skin inflammation. The uveitis has been previously characterized in 16 patients from eight families. In this series, 15 of 16 patients presented with multifocal choroiditis and panuveitis whereas only one patient presented with anterior uveitis.35 The NOD2 gene mutation causes structural changes in an intracellular protein named CARD15, which is thought to be involved in the recognition of intracellular bacteria via recognition peptide motifs in microbial cell walls. The precise pathways that result in uveitis clinically are under investigation.

Cellular mediators of uveitis

Immune cellular mediators of uveitis have been studied extensively in animal models of uveitis, as well as from the peripheral blood, aqueous, and vitreous samples from patients with uveitis.

Macrophages play a significant role in the ocular immune response, serving at least three major functions. These include the direct killing of foreign pathogens and clearing of diseased tissue, the activation of the immune system via antigen presentation, and the secretion of potent inflammatory cytokines IFN-γ, TNF-α, and IL-1 that augment the immune response.36

The T-cell response is thought to be the arm of the immune system primarily responsible for the majority of uveitic syndromes, with CD4+ T-helper (Th) cells being the subset of immune cells most commonly implicated.37 The successful use of a humanized monoclonal blocking antibody against T-cell growth factor IL-2 receptor (CD25) in treating uveitis further supported the critical role of T cells in the pathogenesis of human uveitis.38 T-cell receptors recognize specific antigen epitopes presented in the context of MHC by antigen-presenting cells (e.g., macrophages, dendritic cells). CD8+ T cells recognize antigen presented in the context of class I MHC molecules, whereas CD4+ T cells recognize antigen presented by class II MHC molecules. A second signal, or costimulatory signal, via the interaction of CD28 (T-cell surface antigen) and B7 antigen (antigenpresenting cell), is required for T-cell activation. Ophthalmic inflammatory diseases thought to be CD4+ T-helper cell-mediated include sarcoidosis,39 VKH disease,40,41 and intermediate uveitis.42 Pathologic evidence from patients with sarcoidosis has demonstrated a predominantly CD4+ T-cell population.5 However, other disease entities such as Behçet’s disease have been associated with a cytotoxic CD8+ T-cell population.43

The Th cell response is divided into Th1, Th2, and recently described Th17 subtypes, all of which are associated with specific cytokine profiles and cellular responses. The Th1 cellular response is thought to be proinflammatory and is most commonly associated with proinflammatory cytokines, including IFN-γ, IL-12, IL-1, IL-6, and TNF-α. The Th2 cellular response is more commonly associated with atopic disease, and often an anti-inflammatory response. Its associated cytokines include IL-4, IL-5, and IL-10. Recently, Th17 cells, associated with IL-17 and the IL-23 family of cytokines,

have been implicated in the pathogenesis of uveitis and scleritis.44 One report described an elevation of IL-23p19 mRNA, IL-23 levels, and increased IL-17 by stimulated peripheral blood mononuclear cells and CD4+ T cells in patients with VKH disease.45 Recent evidence has also suggested that the presence of Th17 cells in inflamed tissue may contribute to chronicity of ocular inflammation; further studies are underway to characterize this pathway better.

The role of a population of regulatory T cells has been characterized in EAU but regulatory T cells have been difficult to isolate and characterize in patients with uveitis. In EAU mice immunized with IRBP, adoptively transferred CD4+CD25+ regulatory T cells (obtained from naïve mice) resulted in decreased clinical severity and histopathologic scores. In addition, EAU mice that received CD4+CD25+ cells demonstrated reduced proliferation of uveitogenic T cells isolated from their cervical lymph nodes and spleens.46 In another study by Silver et al, vaccination of naked DNA encoding IRBP protected mice from the development of EAU following immunization with IRBP at least 10 weeks after vaccination. In addition, IRBP-specific CD4+CD25(high) T cells derived from vaccinated mice conferred protection to EAU-challenged recipients and were found in vitro to be FoxP3-positive and antigen-specific.47

While T cells are thought to be the immune cell most intimately associated with the pathogenesis of the majority of uveitic syndromes, B cells may also play a limited role in some forms of uveitis. For example, in the subretinal fibrosis and uveitis syndrome, histopathologic investigation has revealed a markedly inflamed choroid with a predominance of plasma cells and B cells.48 The deposition of complement and IgG within Bruch’s membrane was reported in this syndrome; another report of this syndrome implicated the involvement of T cells, as similar proportions of T and B cells were found in areas of choroid with infiltrating immune cells.49 Several other ocular inflammatory diseases in which B cells have been identified in limited numbers in pathologic specimens include VKH,50 ocular sarcoidosis,5 and sympathetic ophthalmia51,52; however, these conditions are thought to be primarily T-cell-mediated conditions.

Recent interest in the precise role of natural killer (NK) cells in patients with autoimmune disease has arisen from several studies suggesting that a distinct population of immunoregulatory NK cells arises during the treatment of active uveitis or MS with humanized monoclonal antibody (mAb) against IL-2 receptor (daclizumab, Zenapax).53,54 In both MS and in active uveitis, the administration of daclizumab was associated with an increase in a population of CD56bright NK cells. In MS patients, daclizumab therapy was associated with a decrease in T-cell populations and an increase in CD56bright NK cells, which correlated with clinical treatment response. Furthermore, in vitro studies demonstrated that NK cells inhibited T-cell survival via a contactdependent mechanism.53 In patients with active uveitis, a smaller population of CD56bright cells was observed when compared to patients with inactive uveitis following treatment with daclizumab. Additionally, CD56bright cells were able to secrete IL-10 in large amounts, whereas CD56dim cells were unable to do so, suggesting a possible mechanism by which CD56bright cells could potentially serve an immunoregulatory function.54

Soluble mediators of uveitis and cell adhesion molecules

Cytokines

The most well-characterized group of soluble mediators of inflammation in uveitis are cytokines, chemical mediators involved in the recruitment of ocular immune cells, augmentation of the immune response, and tissue damage in some cases. A number of soluble inflammatory mediators of uveitis have been characterized in both peripheral blood serum samples and ocular fluids (i.e., aqueous and vitreous), as well as in experimental models of uveitis.

In EAU, the Th1-mediated cellular immune response and its associated cytokines predominate. Foxman et al observed

an elevation of Th1-associated cytokines and chemokines, including IL-1α, IL-1ß, IL-1R antagonist, IL-6, TNF-α, and IFN-γ in the EAU model.55 IL-1 and TNF-α receptor-deficient mice show decreased inflammation in an immune complex model of uveitis, suggesting a role for these cytokines in this animal model of uveitis56 (Figure 79.4). Antagonists of cytokines and chemokines associated with Th1-mediated ocular inflammation have demonstrated some efficacy in the treatment of uveitis (see below), and further exploration of therapeutic agents targeting these soluble mediators of inflammation is warranted.

In patients with noninfectious intermediate and posterior uveitis, serum levels of IL-2 receptor and soluble TNF-α receptor were elevated compared to normal controls.57 Besides TNF-α receptor levels, aqueous and serum levels of

mRNA level (normalized units x 10-2)

TNF-α have also been elevated in uveitis patients.58 Lacomba et al reported an elevation in IL-2 and IFN-γ in both the aqueous and sera of patients with uveitis when compared to controls.59

Cytokine profiles likely differ between specific disease entities, and this has been studied in several reports. For example, levels of TNF-α were observed to be elevated in the aqueous humor in HLA-B27 patients with uveitis.60 This may explain, in part, the disease-specific efficacy reported on infliximab for the use of HLA-B27-associated uveitis.61 In one patient with uveitis associated with the chronic infantile neurological cutaneous articular (CINCA) syndrome, which is thought to be an IL-1-mediated inflammatory process, the successful use of the IL-1 receptor antagonist anakinra has been reported.62 In patients with active Behçet’s disease, elevated levels of serum TNF-α receptor have been identified, as well as an increase in IL-10 and IL-1263; studies in Behçet’s disease-associated uveitis treated with the TNF-α antagonist infliximab have demonstrated an ability to reduce the number of uveitis relapses,64,65 a reduction in daily immunosuppressive requirement,63,64 and improved visual acuity in some cases.66

Chemokines, growth factors, and other   mediators of inflammation

Patterns of chemokines, or chemoattractant cytokines, have also been identified in both patients and in animal models of uveitis. In one report of patients with acute idiopathic anterior uveitis, levels of the chemokines IL-8, interferoninducible protein-10 (IP-10), MCP-1, RANTES and macrophage inflammatory protein-1β (MIP-1β) were increased and correlated with disease severity.67 In another study examining aqueous humor samples in patients with active uveitis, IL-6, IL-10, IFN-γ, soluble vascular cell adhesion molecule (sVCAM), regulated on activation, normal T cell was expressed and secreted (RANTES), and IP-10 was elevated when compared to uveitis patients with quiescent disease. In studies in EAU, elevations of Th1-associated chemokine receptors (CCR5, CXCR3,) have been described.55 An elevation in fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) has also been described in EAAU.68 Abu ElAsrar et al reported an increased level of the chemoattractant IP-10, gelatinase A, and gelatinase B in the aqueous humor of patients with active uveitis.69

The role of vascular permeability in the pathogenesis of uveitis and uveitis-associated cystoid macular edema (CME) has received some attention in the literature that warrants further investigation. Fine et al observed a significant increase in levels of vascular endothelial growth factor (VEGF) in aqueous specimens from uveitis patients with CME when compared to those patients without CME.70 A recent retrospective review evaluated the efficacy of the anti-VEGF agent bevacizumab for uveitic CME. In this study, 6 of 13 patients treated with bevacizumab experienced a significant reduction in foveal thickness over a median follow-up period of 91 days; however, the logMAR visual acuity change over the follow-up period was not significant.71 It is possible that, while VEGF may play a role in the pathogenesis of uveitic CME, the blockade of underlying, persistent inflammation also needs to be addressed to prevent the cycle of inflammation and subsequent breakdown of retinal vascular permeability.

Cellular adhesion molecules

Cellular adhesion molecules expressed in the eye direct leukocyte trafficking during episodes of ocular inflammation. In pathologic specimens of enucleated eyes from uveitis patients, intercellular adhesion molecule-1 (ICAM-1) was observed on endothelial cells of retinal and choroidal blood vessels. Lymphocyte function-associated antigen-1 (LFA-1) has also been identified on lymphocytes infiltrating ocular tissues.72 In a murine model of EAU, ICAM-1 (CD54) and LFA-1 (CD11a/CD18) have been observed on endothelial cells and lymphocytes; in this study, ICAM-1 appeared before histological evidence of inflammation. Treatment with monoclonal antibody to both molecules reduced ocular inflammation clinically and histologically.73 Efalizumab, humanized IgG1 anti-CD11a has been utilized for the treatment of psoriasis74 and more recently has been used in a phase I/II trial for renal transplantation,75 but further clinical studies are needed in uveitis before implementation into clinical practice.

The role of tolerance in uveitis

Self-tolerance, the ability to distinguish self from foreign antigens, is critical to the prevention of ocular autoimmunity.76 Central tolerance involves the elimination of self-reactive T-cell clones during thymic maturation of lymphocytes, whereas peripheral tolerance involves regulatory elements that prevent the expression of autoimmunity once immunoreactivity against self-antigen has been established. During thymic T-cell maturation, the positive selection of T cells capable of reacting against foreign antigen presented by antigen-presenting cells first occurs; in negative selection, T cells reactive against self-antigen are clonally deleted to mediate central tolerance. Animal studies by Egwuagu et al demonstrated that thymic expression of retinal antigens was correlated to resistance to EAU. In their study, murine, rat, and primate strains in which thymic expression of the retinal antigen IRBP was not observed were susceptible to the development of EAU when immunized with IRBP.77 In contrast, animal species with thymic expression of S-antigen and IRBP were less susceptible to EAU induction. Negative selection appears to be disrupted in the monogenic disease autoimmune polyendocrinopathy– candidiasis–ectodermal dystrophy (APECED), which features autoimmunity involving multiple organs, including ophthalmic structures. Disease features are caused by a mutation in the autoimmune regulatory gene (Aire) whose gene product plays a role in the thymic expression of peripheral self-antigens.78 In a murine model of APECED, Airedeficient mice demonstrated reduced thymic transcription of peripheral antigens resulting in widespread systemic and retinal autoimmunity.79 Interestingly, loss of thymic expression of a single retinal antigen IRBP has been demonstrated to cause spontaneous retinal autoimmunity, even in the presence of functional AIRE gene.80

The two major mechanisms implicated in peripheral tolerance to self-antigens are active suppression and immune ignorance (Figure 79.5). CD4+ T-lymphocyte subsets thought to play a role in active suppression are composed of natural T-regulatory cells and adaptive T-regulatory cells. Natural T-regulatory cells are believed to be antigen-specific and

exhibit in vitro suppression of target immune cells.81 Other CD4+ T-lymphocyte populations, termed adaptive Tr1 and Th3 cells, are generated against self and foreign antigens, and appear to mediate immunosuppression via the immunoregulatory cytokines IL-10 and TGF-ß.82 The proinflammatory cytokines IL-1 and IL-6 may disrupt natural T-regulatory cellmediated immunosuppression and monoclonal antibodies targeting these cytokines may mediate immunosuppressive effects via restoration of natural T-regulatory cell function.82 Immune ignorance involves the failure of effector T cells to recognize peripheral antigen, and consequently, failure of T-cell activation.

Attempts to induce peripheral tolerance have been made with a number of both experimental and clinical protocols. The induction of peripheral tolerance via the oral administration of retinal antigen was initially characterized in EAU. When Lewis rats were fed with retinal S-antigen, the clinical expression of EAU via retinal S-antigen immunization was markedly suppressed. Splenocytes harvested from mice who exhibited this form of tolerance were able to suppress the activation of CD4+ S-antigen-specific T-cell culture line when exposed to S-antigen. Interestingly, this antigenspecific in vitro suppression was blocked by administration of anti-CD8 antibody, indicating that the suppression mechanism was a CD8+ T-cell-dependent process.83 In a phase I/ II randomized masked trial of the oral administration of a mixture of retinal antigens, retinal S antigen alone or placebo was given orally to patients to induce peripheral tolerance. Patients who were fed purified S antigen appeared more likely to be tapered off immunosuppressive medications than patients receiving placebo, with a trend towards statisti-

cal significance.84 Further studies to understand and potentially utilize this mechanism of immunosuppression are warranted.

Therapeutic advances in uveitis

Although corticosteroids are effective in the management of acute uveitic conditions, their numerous side-effects (e.g., hypertension, osteoporosis, weight gain, hyperglycemia, cushingoid body habitus) warrant consideration of other corticosteroid-sparing agents including the antimetabolites (methotrexate, azathioprine, mycophenolate mofetil), T-cell calcineurin inhibitors (ciclosporin, tacrolimus), and alkylating agents (cyclophosphamide, chlorambucil).85,86 The majority of these medications target T-cell processes to curb ocular and systemic inflammation. Specifically, the antimetabolites affect immune cell production while calcineurin inhibitors modulate T-cell function. The alkylating agents, which cross-link DNA and prevent cell replication, have been successful in the treatment of severe, refractory ocular inflammatory diseases such as Wegener’s granuloma- tosis-associated scleritis, but they are associated with significant side-effects, including secondary malignancies (e.g., bladder carcinoma in patients on cyclophosphamide) and opportunistic infections.

Recently, more specific biologic agents targeting soluble cytokine mediators and their receptors have been used to target specific arms of the immune response (e.g., TNF-α antagonists, anti-IL-2 receptor daclizumab) (Box 79.3). Currently, three available TNF-α antagonists are infliximab,

Box 79.3  Immunosuppressive therapy for uveitis

adalimumab, and etanercept. Infliximab has demonstrated efficacy in the treatment of a number of uveitic conditions including Behçet’s disease,87,88 HLA-B27-associated uveitis,89 juvenile idiopathic arthritis-associated uveitis,90 and other forms of pediatric uveitis.91 Adalimumab has similarly demonstrated efficacy in the treatment of pediatric uveitis and Behçet’s disease.92,93 Etanercept, however, has shown limited efficacy in the treatment of uveitis when compared with infliximab94 and has reportedly been associated with uveitis exacerbations in some cases.95

Daclizumab, a humanized monoclonal antibody targeting the IL-2 receptor found on activated T cells, has been previously used for the successful prevention of renal allograft rejection96 and for the treatment of subsets of T-cell leukemia/lymphoma, which express high levels of IL-2 receptor.97 Several prospective studies98,99 and retrospective reviews100,101 have also reported the efficacy of daclizumab as a corticosteroid-sparing agent in patients with intermediate, posterior, and panuveitis. In one prospective study,

daclizumab was able to prevent the expression of sightthreatening inflammatory disease in 8 of 10 patients treated over 1 year.98 The etiologies of uveitis treated in this study included a number of Th1-mediated conditions, including sarcoidosis, VKH, idiopathic intermediate uveitis, and multifocal choroiditis.

While these biologic therapies have demonstrated efficacy for a variety of uveitic conditions, our increasing understanding of the pathogenic immunologic pathways mediating ocular inflammation will likely result in more targeted therapies against specific uveitic disease processes.

Conclusion

As we continue to reach a better understanding of the pathogenic mechanisms underlying uveitis, the number of therapeutic alternatives will likely continue to expand for the benefit of our patients. While immunogenetics may predispose certain individuals to the development of ocular inflammatory disease, a myriad of posttranscriptional factors are undoubtedly at play. Experimental models of uveitis including EAU have played an important role in our understanding of uveitis; other disease-specific models of uveitis will likely aid in the development of therapy for known targets. Knowledge of immune cell interactions, including Th1/Th2, Th17, regulatory T cells, NK cells, cytokines, chemokines, growth factors, and cellular adhesion molecules, will allow us to design therapies to disrupt pathogenic inter­ actions in the future. In addition, we have learned that disruption of central or peripheral tolerance may lead to autoimmune consequences; the re-establishment of peripheral tolerance to self-reactive T-cell clones is a therapeutic avenue that requires further study. A number of biologic agents targeting cytokines, cytokine receptors, and other soluble mediators of inflammation (e.g., daclizumab, infliximab, adalimumab, anakinra) have been utilized for the successful treatment of uveitis. Their efficacy in specific inflammatory diseases and their long-term side-effect profiles surely warrant further investigation, but this class of medications appears to be promising for the treatment of ocular inflammatory disease.

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