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   Table of Contents      
Year : 1999  |  Volume : 47  |  Issue : 2  |  Page : 65-77

Immunomodulation in human and experimental uveitis: Recent advances

1 Department of Immunology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow, India
2 Department of Medical Genetics, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow, India

Correspondence Address:
Vijay Kumar Singh
Department of Immunology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow - 226 014
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Source of Support: None, Conflict of Interest: None

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Experimental autoimmune uveitis (EAU) is a T-cell mediated autoimmune disease that targets the neural retina and serves as a model of human uveitis. EAU can be induced against several retinal proteins in rats, mice, and subhuman primates. These include the S-antigen, a major protein in retinal photoreceptor cells; interphotoreceptor retinoid-binding protein (IRBP); and rhodopsin and other antigens of retinal origin. There are many similarities between clinical uveitis and EAU, but the latter differs in being self-limited, and needs adjuvant for disease induction. The experimental disease can be induced only in susceptible animal strains. Use of the EAU model has helped investigators understand the pathophysiology of the disease and to evaluate disease-modifying strategies, which could be applied in the clinic. There has been significant progress in this field during last decade, but much more understanding is needed before the knowledge can be transferred to clinical practice. A deeper understanding of the immune mechanisms involved in the EAU model may lead to the development of new therapeutic approaches targeted at various components of the immune response by immunomodulation to control uveitis. This review summarises the evidence from the EAU model, which could be of relevance to the clinical management of patients with uveitis.

Keywords: Experimental autoimmune uveitis, human uveitis, immunomodulation, retinal antigens

How to cite this article:
Singh VK, Biswas S, Rai G, Agarwal SS. Immunomodulation in human and experimental uveitis: Recent advances. Indian J Ophthalmol 1999;47:65-77

How to cite this URL:
Singh VK, Biswas S, Rai G, Agarwal SS. Immunomodulation in human and experimental uveitis: Recent advances. Indian J Ophthalmol [serial online] 1999 [cited 2023 May 30];47:65-77. Available from: https://journals.lww.com/ijo/pages/default.aspx/text.asp?1999/47/2/65/22796

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The role of ocular antigens in the pathogenesis of inflammatory diseases of the eye has been investigated since early in this century, but it was only in 1965 that Wacker and Lipton demonstrated that homologous guinea pig retina emulsified in complete Freund's adjuvant (CFA) was a highly efficient tissue source for the induction of experimental autoimmune uveitis (EAU).[1] S-antigen, a potent uveitogenic agent, was later partially purified by Wacker from guinea pig retinal extracts.[2] It was then isolated in a highly purified form and was characterized as a 50,000 mol. wt. protein containing a relatively high proportion of non-polar amino acid. During the last 10 years much information has accumulated concerning the structure and function of S-antigen with regard to its role in the pathogenesis of EAU,[3] and in the phototransduction of vision. This S-antigen is recognized by the immune system of the body like any other antigen.

When a nave T-cell recognizes an antigen in association with major histocompatibility complex (MHC) on an appropriate antigen-presenting cell, it gets activated, initiating a primary response. Activation depends on: 1) a signal induced by engagement of the CD3-T-cell receptor (TCR) complex with MHC-peptide complex, and 2) the co-stimulatory signal induced by CD28 - B7 interaction. These signals trigger the entry of T-cell into the G1 phase of the cell cycle, and at the same time, induce transcription of the gene for interleukin (IL-2) and α-chain of high-affinity IL-2 receptor. In addition, the co-stimulatory signal increases the half-life of the IL-2 mRNA. The increase in IL-2 transcription, together with stabilization of IL-2 mRNA. increases IL-2 production 100-fold in the activated cell. Secretion of IL-2 and its subsequent binding to the high-affinity IL-2 receptor induces the activated nave T-cell to proliferate and differentiate. T-cells activated in this way divide repeatedly generating a large clone of progeny cells, which differentiate into memory or effector T-cell populations.

Activation of T and B cells needs to be appropriately regulated. The response of the immune system against the self is termed autoimmunity. Normally, the mechanism of self-tolerance protects an individual from self-reactive lymphocytes. Earlier it was believed that all self-reactive lymphocytes are eliminated during development, and failure to eliminate these lymphocytes leads to autoimmune consequences. Experimental evidence later revealed that not all self-reactive lymphocytes are deleted during maturation. Instead, normal healthy individuals have been shown to produce mature self-reacting lymphocytes. Since the presence of these self-reactive lymphocytes does not inevitably result in autoimmune reaction, their activity must be regulated in normal individuals through clonal anergy or clonal suppression. A breakdown in this regulation leads to activation of self-reactive clones of T and B cells resulting in cellular or humoral autoimmunity.

Autoimmune diseases in humans can be divided into two broad categories: 1) systemic and 2) organ specific. In systemic autoimmune disease, the response is directed towards a broad range of target antigens and involves a number of organs and tissues. These diseases reflect a generalized defect in immune regulation that results in hyperactive T and B cells. Tissue damage is widespread both from cell-mediated immune responses and from direct cellular damage caused by autoantibodies or by accumulation of immune complexes. In organ-specific autoimmune disease, the immune response is directed towards a target antigen unique to a specific organ or gland so that the manifestations are largely limited to that organ. The target organs may be subjected to direct cellular damage by humoral or cell-mediated mechanisms. Alternatively, the function of a target organ may be stimulated or blocked by autoantibodies. Uveitis is a well-known example of organ-specific autoimmune disease that has been investigated in depth to understand different aspects of the immunoinflammatory response.

The inflammation of the uvea, or uveitis, causes sight-threatening damage to the eye. Infection, autoimmune disease, trauma, and malignancy are known to induce uveitis. The aetiological factor in about 30% of all uveitis cases remains unknown.[4] It is recommended that different forms of uveitis be classified according to their anatomical localization, that is, anterior uveitis, intermediate uveitis, posterior uveitis, and panuveitis.[5]

Uveitis manifests in various forms, such as sympathetic ophthalmia, Vogt-Koyanagi Harada (VKH) syndrome, Behcet's disease and pars planitis. Sympathetic ophthalmia is a bilateral inflammation of the entire uveal tract, usually following perforating injury to one eye.[6] Clinically, there is bilateral panuveitis with choroidal thickening and optic nerve head swelling. The disease usually follows a relapsing course and treatment is aimed at immunosuppression. In VKH syndrome the ocular involvement is usually bilateral, and is associated with panuveitis, optic nerve head swelling, detachment of the retina, and infiltration of both the choroid and retinal pigment epithelium.[7] In patients of both VKH syndrome and sympathetic ophthalmia, T-lymphocyte infiltration was seen in the uvea and retina. There is increase in CD4+ T-cells in the early stages of the disease and an increase in CD8+ T-cells at a later stage.[6],[7]

Behcet's disease is characterized by an occlusive vasculitis and can affect different organ systems.[8] The disease occurs in several forms, which can overlap. This ocular disease is characterized by panuveitis and occlusive retinal vasculitis, classically with hypopyon, and oral ulcers. Complexes of IgG and components C3 and C5 have been found in the aqueous humour. Circulating immune complexes and altered levels of C3 may be found in serum of patients with Behcet's disease. Immunopathologic study of an eye removed from a patient with active Behcet's disease showed intramural and perivascular infiltration of cells which stained positive for CD4 and IL-2 receptor surface marker. Cell-mediated immunity plays an important role in the pathogenesis of this disease.[9]

Pars planitis is a chronic ocular inflammatory disorder.[10] There is often optic nerve head swelling and macular edema with patchy leakage from the retinal veins demonstrable on fluorescein angiography. There is detachment and collapse of the vitreous body with fibrous organization of the vitreous base. The disease is characterized by "snow banks" overlying the pars plana occurring particularly in children and young adults. Kaplan et.al[11] observed a relatively greater number of B-cells than T-cells in the aqueous and vitreous samples of patients with pars planitis. They concluded that normal T-cell regulation of B-cell function is deranged in this condition. Increased antibody to retinal S-antigen has been found in the serum of these patients. Raised intracellular adhesion molecules (ICAM-1) have been demonstrated by Arocker-Mettinger et al.[12]

The uvea plays an important role in ocular immunological defense mechanisms. Immunologically the eye has a privileged position because of blood-retina barrier, absence of lymphatic drainage, and a special feature called anterior chamber associated immune deviation (ACAID). These special defense mechanisms contribute to preservation of vision.[4]

  Experimental Autoimmune Uveitis (EAU) Top

The ocular disease developing in susceptible animals immunized with S-antigen or other retinal or uveal antigens has been termed EAU.[13] The capacity of S-antigen to induce EAU depends on the inclusion of adjuvants; no disease is induced in animals injected with S-antigen alone.[14],[15] The clinical as well as histopathological features of EAU in animals closely resemble certain uveitic conditions in humans and are considered a model for posterior uveitis.[16],[17] The possible role of S-antigen in the aetiopathogenesis of a subset of human uveitis is supported by the observation that many patients with uveitis show lymphoproliferative response to the human and bovine S-antigen sequences.[18-22] The EAU is not only a valuable model for human inflammatory eye disease, it is also a useful system for studying many aspects of immunobiology and immunomodulation.

  Retinal S-antigen Top

S-antigen, a 45-kDa protein, is the most potent retinal antigen that initiates autoimmune inflammatory reactions in the eye. It is specifically localized in visual tissues and is remarkably conserved through phylogenetic development of visual organs. The unique relationship between S-antigen and vision is supported by the presence of this antigen in the pineal gland.[23] It is of interest to note that the pineal gland is often affected in the inflammatory processes which develop in animals immunized with S-antigen. The inflammatory effect of S-antigen immunization on the pineal gland is termed as experimental autoimmune pinealitis (EAP).[24]

The complete amino acid sequence of human, bovine, rat and mouse retinal S-antigen as well as rat pineal gland S-antigen has been determined.[25][26][27][28][29][30][31][32][33] Comparison of amino acid sequences indicates a high degree of sequence homology among different species.[32] The S-antigen gene is assigned to chromosome 2q[25-38] in the human and to the centromeric portion of chromosome 1 near the IDH-1 locus in the mouse.[33],[34]

  Uveitopathogenic Sites of Retinal Antigens Top

The knowledge of S-antigen amino acid sequences allowed investigators to identify the uveitopathogenic sites in S-antigen. Three sites of bovine and human S-antigen were identified to be immunopathogenic in Lewis rats, namely, peptide 303-320 (peptide M), and 286-297 (peptide N) which are non-dominant, and 343-362 (peptide G) which has immunodominant characteristics.[36][37][38][39] Later, de Smet and co-workers showned that there are several uveitopathogenic determinants within S-antigen, suggesting the same may be true in uveitis patients.[40] The existence of multiple determinants would place considerable restrictions on the feasibility of immunotherapy in patients. Immunotherapy directed against a single determinant is unlikely to be effective in humans. Only immunomodulatory approaches like oral tolerance that can induce non-specific suppression, even if limited to a specific inflammatory site, are likely to be effective.

The other major retinal antigen capable of inducing EAU and EAP is IRBP. It is a 140 kDa evolutionarily conserved glycoprotein found to be an equally potent uveitopathogenic molecule as S-antigen, producing EAU at very low doses.[41],[42] Experimental studies have shown that there are several uveitopathogenic epitopes in bovine IRBP, of which peptide 1169-1191 has been shown to be immunodominant.[43],[44] Recently Silver et al[45] reported an additional uveitopathogenic epitope (161-180) in human IRBP for B10.RIII mice. A recent study suggests that Xenopus IRBP is also uveitopathogenic in Lewis rats.[46]

The phenomenon by which the host responds to exogenous antigens that cross-react with self by sharing linear or conformational epitopes common to microbial antigens and host structures is known as molecular mimicry and it may provide a mechanism for triggering autoimmune diseases and tolerance.[13] The question of how autoimmune diseases such as endogenous posterior uveitis are initiated remains to be fully answered. Circumstantial evidence suggests a link between autoimmune diseases and triggering events such as a recent viral or bacterial infection. This has led to the hypothesis that circulating autoreactive T-cells that are present in all healthy individuals recognize epitopes on a processed foreign antigen, which possess extensive amino-acid sequence homology to host autoantigens.

The knowledge of the uveitopathogenic sites of S-antigen enabled us to look for similar sequences in foreign antigens. We compared amino acid sequences of various uveitopathogenic peptides of S-antigens with a variety of proteins in the National Biomedical Research Foundation database for sequence homology. We found 4-6 amino acids sequence homology between one of the uveitopathogenic peptides of S-antigen (peptide M) and various microbial proteins. The amino acid sequences of microbial proteins were used to synthesize oligopeptides of 12-20 amino acids. Lewis rats were immunized intradermally with various peptides emulsified in CFA followed by intravenous injection with Bordetella pertussis. Interestingly, our results showed induction of EAU with peptides derived from DNA polymerase of hepatitis-B virus, gag-pol polyprotein of AKV murine leukemia virus, gag-pol polyprotein of Baboon endogenous virus,[47] Escherichia coli hypothetical protein E-116,[48] and yeast histone H3.[49] Yeast histone H3 peptide also induced EAU in monkey.[50],[51]

A sequence of HLA-B27 antigen which shares homology with an S-antigen derived peptide was found to be capable of inducing uveitis. The in-vitro lymphocyte cross-reactivity was also shown in uveitis patients.[52]

  Experimental autoimmune anterior uveitis (EAAU) as a model for human anterior uveitis Top

EAAU is an organ-specific autoimmune disease and has been shown to be induced in Lewis rat by bovine melanin-associated antigen (MAA) derived from the iris and ciliarly body.[53] Like EAU and S-antigen, MAA is used to induce EAAU in animals along with two adjuvants CFA and purified pertussis toxin. It closely resembles human acute anterior uveitis. The immunopathogenesis of EAAU appears to be linked to the presence of the CD4+ T-cells.[54] A recent study suggests that EAAU can be induced in Lewis rat without addition of an adjuvant and future studies concerning the pathogenesis of EAAU can be performed without an adjuvant.[55] This review mainly discusses EAU and posterior uveitis.

  EAU and Human Posterior Uveitis Top

EAU has been reproducibly induced in a variety of animals, including primates,[17] rabbits,[2] guinea pigs,[56] rats,[57] and mice.[58],[59] The clinical and histopathological appearance of uveitis occurring in these animal models closely resembles certain uveitic conditions in man.[13], [16],[17],[60] changes in primates with EAU are of particular interest, because of their possible similarity with sympathetic ophthalmia. Although humoral responses have been noted in animals with EAU,[61] it is well documented that cell-mediated responses play a dominant role in the pathogenesis of EAU. [57, 62, 63]

  Immunomodulation in EAU Top

Attempts to minimise the inflammatory response in EAU may be targeted at various stages of the immune response [Table - 1] after initial immunization with retinal antigen.[64] Prevention of antigen presentation can be achieved with monoclonal antibodies directed against components of TCR/peptide/MHC complex or against accessory molecules such as intercellular adhesion molecule-1. Monoclonal antibodies to S-antigen have also been used successfully, probably via generation of anti-idiotype, which inhibits induction of the disease.[65][66][67] Approaches preventing antigen presentation in EAU, including antibodies directed against MHC class II antigens[68] or CD4 antigen[69] have been successful.

Various immunomodulatory approaches have been tried with EAU in different laboratories, in order to gain some clue to develop a therapy for human uveitis. Infusion of IV Ig, starting on the same day as S-antigen immunization, protected (Lewis x Brown-Norway) F1 rats against EAU.[70] Recently, Whitcup et al[71] reported that early treatment with anti-CD40L monoclonal antibody completely inhibits the development of EAU. This suggests that early co-stimulation through CD40L may be required for pathogenesis of EAU.

  Oral Tolerance Top

The primary mechanisms by which orally administered antigen induce immunologic tolerance are via the generation of active suppression or clonal anergy. Several studies have demonstrated the effectiveness of orally administered antigen. It was shown that EAU could be prevented by oral administration of native bovine S-antigen or its peptides prior to immunization.[72][73][74][75] Recently, we have shown that feeding of recombinant E. coli expressing retinal S-antigen to Lewis rats prior to uveitopathogenic challenge with S-antigen resulted in significant suppression of EAU.[75] The exact mechanism by which protection is conferred is not well understood.[77] It has been shown that three feedings of 0.2 mg IRBP every other day before immunization did not protect against EAU, whereas a similar regimen of five doses was protective.[78] This effect was due to increased production of anti-inflammatory cytokines TGF-β (transforming growth factor-β), IL-4 and IL-10 induced by IL-2 administration, and tolerance induced by five feeding regimen was due to anergy. Using knockout models of IL-4 and IL-10, same investigators demonstrated that these cytokines have a role in the induction of low-dose tolerance, because these mice were successfully protected with a high-dose feeding regimen.[79] Furthermore, it has been suggested that CD8+ T-cells are not essential for the induction of low-dose oral tolerance.[80]

Effectiveness and mechanisms of oral tolerance in EAU have mainly been studied in the acute, monophasic model in Lewis rats. Recently, Thurau and coworkers[81] investigated the effect of oral tolerance induction in the acute as well as the chronic-relapsing models in the B10.A mice. In the chronic-relapsing EAU, antigen feeding was started only after the animals had recovered from their first attack of uveitis. Under these experimental conditions the subsequent relapse was largely prevented suggesting that oral tolerance may have practical clinical implications in human uveitis, which is predominantly a chronic-relapsing condition in humans.

  Intranasal Tolerance Top

Additional studies showed that tolerance to retinal antigen could be induced via the upper respiratory tract, preventing subsequent induction of EAU.[82] The mechanism of tolerance induction appears to be antigen specific since tolerization to S-antigen did not protect against EAU induced by the other uveitogenic proteins present in the retinal extract. Results show that tolerance induction impairs the onset and severity of EAU by inhibiting the delayed type hypersensitivity (DTH) response to retinal antigens.[83] These authors also speculate that the inhalation tolerance may be better than oral tolerance due to small amounts of antigen used to induce the tolerance.

  T-Cell Receptors Top

T-cell receptors (TCR) are present on the surface of T-cells and serve to bind the antigen in association with MHC. Structurally, the T-cell receptor is a heterodimer composed of either α and β, or γ and δ chains. Recent studies have investigated the role of γδ TCR+ in induction and suppression of EAU.[84] Depletion of α/β TCR completely abrogated disease, whereas treatment with anti-γδ antibodies had no influence on onset or intensity of uveitis. Anti α/β TCR monoclonal antibody treatment has in one instance been reported to reduce the induction of EAU in rat.[85] Uveitis induced by a peptide derived from S-antigen was suppressed by γ/δ+T-cells from rats orally tolerized with the same peptide as well as HLA peptide homologous to S-antigen. This is the first demonstration of a direct immunological link between HLA class I antigens and an organ-specific autoantigen, where the class I antigen itself is presented as a peptide and, thereby, as cross-reactive with the respective peptide from the ocular antigen.

  Bystander Suppression Top

It has been speculated that feeding with one retinal antigen could suppress induction of uveitis with the other retinal protein by means of bystander suppression.[86] Both uveitopathogenic effector and suppressor cells should find their antigens within the retina, where the suppressor cells would be expected to act on the effector cells. However, reciprocal combinations of antigens (IRBP and S-antigen) used for induction and suppression of uveitis failed to prevent onset of diseases, demonstrating that bystander suppression obviously does not occur in the eye.

  Th1 and Th2 Cytokines Top

CD4+ effector T-cells form two subpopulations characterized by the panel of cytokines they secrete. Secretion of IL-2, interferon-γ (IFN-γ) and tumor necrosis factor-β (TNF-β) distinguishes one population, called the Th1 subset from Th2 subset which secrete IL-4, IL-5, IL-6 and IL-10. The Th1 subset is responsible for classical cell-mediated functions, such as DTH and activation of cytotoxic T lymphocytes. Most cases of organ-specific autoimmune disease develop as a consequence of self-reactive CD4+ T cells. Analysis of these CD4+ T-cells has revealed that the Th1/Th2 balance has an impact on the development of autoimmunity.[87] Th1 cells have been implicated in the development of autoimmunity, whereas Th2 cells not only protect against the induction of disease but also against the progression of established disease. Study of response patterns in mice confirmed that high Th1 responders were susceptible, whereas low Th1 responders and Th2 responders were resistant to EAU. Susceptibility of EAU is connected with a Th1 dominant response.[88]

It has been suggested that genetic susceptibility to ocular autoimmunity in the rat model may be connected to an elevated Th1 response.[89] Jones et al[90] have suggested that IFN-α is not required to prime pathogenic T-cells or to effect the retinal damage and photoreceptor loss typical of EAU. Saoudi et al [91,92] have shown that mercuric chloride (HgCl2) injections protected (LEW x BN) Fl rats against EAU induced by immunization with retinal S-antigen and induction of Th2 response. In contrast, HgCl2-injected Fl rats develop EAU following transfer of lymph node cells from rats immunized with S-antigen alone. The ability of lymph node cells from rats protected against EAU to transfer the disease into nave Fl rats was considerably reduced.[93] In contrast, lymph node cells from diseased rats easily transferred EAU into nave Fl rats, produced significant IL-2 and IFN-γ levels but barely exhibited mRNA for IL-4.[94] Treatment of Lewis rats with IL-4 exacerbated EAU, as was evident from both clinical and histological criteria.[95] Simultaneous treatment with neutralizing anti-IL-4 antibodies attenuated this increase in the severity of the disease.

Furthermore, in a subsequent study six strains were immunized with IRBP.[96] Three strains were susceptible (B10.A, C57BL/10, and BALB/k), one was minimally susceptible (A/J), and two were resistant (AKR and BALB/c) to induction of EAU. The three susceptible strains showed a dominant Th1-like response profile characterized by high IFN-γ and IL-12 p40 (but not IL-4) responses, and a predominance of IgG2a antibody. The minimally susceptible strain had an IFN-γ response detectable only at the mRNA level, but produced predominantly IgG2a antibody. Xu et al[97] investigated the nature of the pathogenic effector T-cell in EAU and the effect of different cytokines on these cells in vitro. Their results suggest that the uveitogenic effector T-cell has Th1-like phenotype.

IL-12 plays a critical role in Th1 differentiation. Caspi et al[98] investigated whether IL-12 is required for development of EAU. Primed cells of IL-12 deficient mice produced a more Th2 like, cytokine profile. Anti-IL-12 treatment not only prevented the development of pathogenic Th1 cells, but also induced suppressive Th2 cells that protect the animals from further challenge the same antigens.[99]

  Other Methods of Immunomodulation Top

Studies in rats immunized with the retinal S-antigen showed cyclosporin to be therapeutically successful.[62] In addition, a large number of immunotherapeutic agents have been tested in this model, and FK506, with a mode of action idential to cyclosporin, was noted to be effective in EAU.[99] Other agents that positively altered the expression of EAU in rats include rapamycin, mycophenylate mofetil, and leflunomide.[101-103] Anti-adhesion molecules did appear to either abolish the expression of EAU or make it less severe in those rats treated with anti-intercellular adhesion molecule and anti-leukocyte function associated antigen antibodies.[104],[105] Recently, antibodies against the IL-2 receptor have been used in the treatment of EAU induced in non-human primates, with diminution of the severity of disease.[106] Another approach was the use of a construct made of IL-2 and Pseudomonas exotoxin. It was highly successful in preventing the expression of EAU induced by S-antigen.[107] Other methods have attempted to induce ACAID with IRBP, which resulted in the protection from EAU.[108] T-cell immunization using autoaggressive T-cell lines specific against uveitopathogenic peptides proved to be of limited success.[109] T-cell receptor immunization, using the fragment that conferred protection to animals with experimental autoimmune encephalomyelitis, did not prove successful.[110]

TNF-α has an important pro-inflammatory function in EAU and possibly in human uveitis. The treatment with rabbit anti-TNF-α serum significantly reduced the disease when given during the afferent stage but had no effect when given during the efferent stage of EAU in B10.A mice.[111] The effect on DTH, lymphocyte proliferation, and abundance of antigen-reactive cells roughly paralleled the effect on disease.[112] Neutralization of systemic TNF ameliororated the disease. Administration of human p55-TNF receptor IgG fusion protein significantly reduces tissue damage in B10.R11 mice in both afferent and efferent stages of EAU.[113]

The majority of antigenic peptides exhibit restricted interaction with the MHC molecules on APC of different haplotypes. Certain peptides, however, are permissive, that is, they bind strongly to different MHC molecules and are selected as the immunodominant epitopes by animals using these MHC gene products. Four regions of human S-antigen show high levels of permissiveness.[114] Each of these peptides was found to be immunodominant in at least 1 of 4 inbred rat strains and five cynomolgus monkeys immunized with whole S-antigen. Using IRBP peptides, it was recently shown that peptide affinity can be enhanced by single amino acid substitution. Enhancement of peptide affinity for MHC molecules increased both immunogenicity and uveitopathogenecity.[115] Recently, Prasad and Gregerson[116] suggested a novel mechanism-low-affinity occupancy of the autoantigen-specific TCR by self-antigen that may act in concert with the well-known mechanisms to maintain tolerance to S-antigen in the Lewis rat. Koevary and Capsi,[117] demonstrated that intrathymic injection of S-antigen (25-100 mg) reduced the incidence of EAU in animals subsequently immunized with S-antigen (100 mg) and B. pertussis and prevented it entirely in rats immunized in the absence of B. pertussis.

Sueda et al[118] investigated the role of apoptosis in immunopathogenic mechanisms of EAU and suggested that apoptosis regulates the inflammatory process in the eye with EAU. Shimizu et al[119] in a recent study suggested that retinal S-antigen and IRBP induce nitric oxide synthetase lead to nitric oxide production, which may accelerate photoreceptor degeneration in uveitis.

  Immune response of uveitis patients to retinal antigens Top

As is evident from the animal model, there does not appear to be a clear role of antibodies in the induction of uveitis. Antibodies to S-antigen have been found in patients with uveitis,[120],[121] but others have reported no difference between controls and uveitis patients.[122-125]

Lymphocytes isolated from peripheral blood of patients with uveitis have manifested proliferative response to retinal S-antigen, its synthetic peptides, IRBP and its fragments in-vitro.[118],[19],[22],[121] While lymphocytes from control may show occasional proliferative responses, the patients' proliferative response is generally much higher. In one study, out of 82 patients with posterior uveitis from the U.S.A. and Japan, 24 had Behcet's disease, 19 had VKH syndrome, 18 sarcoidosis, 9 Birdshot retinochoroidopathy, 6 pars planitis, and 6 sympathetic ophthalmia.[22] Of 47 U.S.A. patients, 13 showed a positive response to S-antigen, 17 to peptide M and 9 to peptide N of S-antigen, 9 to IRBP, 15 to IRBP fragment R4, and 12 to R14 peptide. Of the remaining 35 Japanese patients, 5 showed a positive response to native S-antigen, 6 to peptide M and 18 to peptide N, 7 to IRBP and 7 to R14 of IRBP. Other studies have shown in-vitro T-cell proliferative response of uveitis patients to S-antigen fragment.[126] In one study, 21 patients from the U.S.A. were evaluated for T-cell proliferative responses to various retinal antigens in-vitro. Four had anterior, 2 intermediate, and 15 posterior or panuveitis. One of two intermediate uveitis patients responded to both antigens. Five of 15 posterior or panuveitis patients showed a positive response to S-antigen, with 3 of them also responding to peptide M. In short, patients with Behcet's disease showed the most positive response. A significant response to IRBP was found in patients with Birdshot retinochoroidopathy. The ability of some patients to respond to both retinal antigens in culture is a unique finding, which may help elucidate certain aspects of the mechanisms involved in chronic uveitis.

Recently, we have demonstrated proliferative response of peripheral blood lymphocytes of uveitis patients to native S-antigen and its various fragments.[20],[21] In our preliminary report from India, we have demonstrated that 12 of 39 uveitis patients showed positive in-vitro T-cell proliferative response to peptide M.[21] Subsequently, we have shown positive in-vitro T-cell proliferative response in 7 out of 38 additional uveitis patients against native bovine S-antigen, its fragments, and IRBP peptide.[21] These studies suggest that retinal antigens may play a role in the aetiopathogenesis of a subset of idiopathic human uveitis. These responses may encourage the development of treatment strategies using these molecules.

Recently Soylu et al[127] identified S-antigen peptide determinants that are recognized by lymphocyte lines derived from uveitis patients, with specificity towards whole S-antigen. They found that several peptides are recognized by multiple cell lines against S-antigen.

  Immunomodulation in uveitis patients Top

The understanding gained from the EAU model has provided an insight into potential mechanisms of action of ocular inflammatory disease as well as sites for interventional therapy. The use of animal models has helped us understand the basic mechanisms of intraocular inflammatory diseases and has helped craft better ways to provide more effective means of immunosuppression.[128] Initial attempts began with the use of immunosuppressive agents and the first such agent was cyclosporin-A [Table - 2]. Cyclosporin has been shown to block genes involved in T-cell activation by interfering with IL-2 production. Based on information obtained with EAU,[62] cyclosporin-A was administered to patients with uveitis resistant to corticosteroids. Results from clinical trials have demonstrated beneficial effects both in improvement of visual acuity and reduction of inflammation in patients with sight-treatening uveitis following cyclosporin-A therapy.[129][130][131] FK506 and combination of cyclosporin-A with steroids has also been used in patients with refractory uveitis with positive therapeutic results.[132],[133]

Methotrexate is a safe and effective second-line therapy in treatment of various autoimmune disorders. Zamiri et al[133] have reported low-dose methotrexate as a second line adjunctive therapy in treatment of non-infective refractory uveitis.

Corticosteroids are also used in immunosuppressive therapy. They are the first choice for therapy of noninfectious, bilateral uveitis that has been refractory to topical and periocular steroid injections. But the efficacy of oral corticosteroids varies considerably from patient to patient.

Cyclophosphamide is an another immunosuppressive agent that acts by killing activated lymphocytes and also causes bone marrow depression.[135] Cyclophosphamide treatment markedly decreases both circulating B-and T-lymphocytes in the order of 30% to 50% as early as two weeks after onset of therapy.

Azathioprine, another immunosuppressive drug exerts its maximal immunosuppressive effect when administered immediately after antigenic challenge. Azathioprine possesses a selective toxicity to T-helper inducer cells.[136]

A patient with endogenous uveitis was treated with a chimeric monoclonal anti-CD4 antibody.[137] This patient with long-standing refractory uveitis did not benefit immediately from antibody infusions, although the frequency of relapses was sharply reduced after this therapy. Antigen-specific T-cell response to retinal S-antigen was significantly elevated prior to clinical relapse. The high level of spontaneous T-cell proliferation normalized after antibody infusions.

To evaluate the efficacy and safety of oral administration of retinal antigens as a treatment of uveitis, a pilot trial of S-antigen and a mixture of S-antigen was recently completed.[138],[139] In the preliminary study two patients, one with pars planitis and another with Behcet's disease, were fed with the retinal S-antigen; this resulted in decrease and/ or stoppage of immunosuppressive medication used by the patients.[138] Based on the success of this study, the same investigators performed a phase I/ II randomized masked clinical trial to evaluate the potential safety and efficacy of oral retinal antigen therapy for patients requiring immunosuppressive therapy for endogenous uveitis.[139] Patients were randomly assigned to receive retinal S-antigen alone (10 patients), retinal S-antigen and a mixture of soluble retinal antigens (10 patients), a mixture of soluble retinal antigens alone (10 patients), or placebo (15 patients). An attempt was made to taper patients completely off their standard immunosuppressive therapy. The group receiving the purified S-antigen alone appeared to be tapered off their immunosuppressive medication more successfully compared with patients given placebo (p = 0.08), whereas the other two groups appeared to perform worse than those receiving placebo. No toxic effects were observed. In brief, a positive trend was seen with oral bovine S-antigen but not with the retinal mixture. This phase I/ II study is the first to test the use of orally administered S-antigen in the treatment of uveitis.

As discussed above, a peptide from the sequence of disease-associated HLA-B-molecule, which shares discontinuous ammo acid homologies with a retinal autoantigen peptide could induce uveitis in Lewis rat.[140] Uveitis patients with T-cell responses to retinal S-antigen or its peptide showed T-cell proliferation to the HLA peptide.[140] A therapeutic trial with oral application of the HLA-peptide was carried out for a group of patients with long-lasting and therapy-refractory uveitis with the aim to reduce conventional immunosuppressive therapy, relapses and intraocular inflammation.[141] Patients received peptide three times a week over a 12-week period with low-dose steroid, the only concomittant medication allowed. Of five patients included in this study, the first patient orally tolerized with the HLA peptide could discontinue her steroids because of reduced intraocular inflammation. No side effects of therapy were observed. Oral tolerance induction with a peptide derived from the patients' own HLA-antigen and cross-reactive with the organ-specific autoantigen may prove to be a potent therapeutic approach.

Apoptosis plays a role in the pathogenesis of autoimmune diseases with chorioretinal scar and gliosis. It is apparent that apoptosis occurs in uveitic eyes and may play a regulatory role in limiting ocular inflammation.[142] Behcet's disease is characterized by cellular infiltration consisting of polymorphonuclear leukocytes and monocytes. Recently it has been suggested that IL-8 production may play an important role in this disease.[143]

  Future Directions Top

EAU is a reasonably good model for human uveitis.[144],[145] It is apparent that important, clinically applicable lessons can be learned from the detailed investigation of animal models. At the same time the leads generated require to be translated into clinical action. The set of events that lead to clinical disease in EAU seems to be well documented, at least as to manifestations within the eye. However, there is a lack of understanding of the systemic initiating events. The exact mechanism of retinal cell death is not yet known. It may be direct killing by the cytotoxic T-cells, or toxic effects of elaborated cytokines, or the induction of apoptosis. The mechanism by which local recruitment of autoaggressive cells occrs is also not clear.[146]

Clinical trials with oral administration of S-antigen in uveitis patients have not been very encouraging but clinical trials with HLA antigen in uveitis patients needs particular attention. Anti-TNF therapy has a suppressive effect on EAU, and this effect is caused by the inhibition of priming IRBP-specific lymphocytes rather than by the suppression of effector mechanisms. Because chronic uveitis is thought to involve continuous recruitment and priming of antigen-specific cells, systemic neutralization of TNF could be useful as a clinical approach to treatment of uveitis, either by itself or as an adjunct to existing therapies.

Gene therapy may become a powerful therapeutic strategy. However, the application of this method in the treatment of ocular disease presents interesting and unique questions. Gene therapy for ocular inflammatory disease has potential in therapeutic interventions and as a method to study disease mechanism.[147] Major technical questions remain, including the use of the appropriate vector, the best methodology for the stable insertion of the genome, and the duration and intensity of expression of the transgene. Various transgene studies encoding a wide variety of proteins can be envisaged for the insertion of genes. Future studies will need to focus on the use of better methods for gene insertion and homologous recombination techniques for the development of animal models and later as a strategy for gene therapy.

  Acknowledgements Top

Financial assistance from the Uttar Pradesh Council of Science and Technology, Lucknow, and Indian Council of Medical Research to VKS is gratefully acknowledged. The laboratory infrastructure was provided by a JICA grant-in-aid to the SGPGI projects.

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Retinal S-antigen
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