|
 |
| CURRENT OPHTHALMOLOGY |
|
| Year : 1999 | Volume
: 47
| Issue : 2 | Page : 65-77 |
|
Immunomodulation in human and experimental uveitis: Recent advances
Vijay Kumar Singh1, Sumita Biswas1, Geeta Rai1, Shyam Swaroop Agarwal2
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
India
 Source of Support: None, Conflict of Interest: None  | Check |
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 |
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 naïve 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 naïve 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) | |  |
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 | | |
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 | | |
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 | | |
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 | | |
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 | | |
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 | | |
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 | | |
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 | | |
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 | | |
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 | | |
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 naïve Fl rats was considerably reduced.[93] In contrast, lymph node cells from diseased rats easily transferred EAU into naïve 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 | | |
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 | | |
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 | | |
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 | | |
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 | | |
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.
| References | | |
| 1. | Wacker WB, Lipton NM. Experimental allergic uveitis. I. Production in the guinea-pig and rabbit by immunization with retina in adjuvant. J Immunol 1968; 101:151-56.  |
| 2. | Wacker WB, Rao NA, Marak GE Jr. Immunopathogenic responses of rabbits to "S" antigen. I. Phlogistic characteristics associated with antigen source and sensitizing dose. Ophthalmic Res 1981; 13:302-11. |
| 3. | Shinohara T, Singh V K, TSuda M, Yamaki K, Abe T, Suzuki S. S-antigen:from gene to autoimmune uveitis Exp Eye Res 1990; 50:751-57. |
| 4. | Suttorp-Schulten MSA, Rothova A. The possible impact of uveitis in blindness: a literature survey. Br J Ophthalmol 1996; 80:844-48. |
| 5. | Bloch-Michel E, Nussenblatt RB. International uveitis study group recommendations for evaluation of intraocular inflammatory diseases. Am J Ophthalmol 1987;103:234-35. [ PUBMED] |
| 6. | Chan C, Nussenblatt RB, Fujikawa LS, Palestine AG, Stevens G Jr, Parver LM, et al. Sympathetic ophthalmia: immunopathological findings. Ophthalmology 1986;93:690-95. |
| 7. | Chan C, Palestine AG, Kuwabara T, Nussenblatt RB. Immunopathologic study of Vogt-Koyanagi-Harada syndrome. Am J Ophthalmol 1988;105:607-11. |
| 8. | Nussenblatt RB. Uveitis in Behcet's disease. Int Rev Immunol 1997;14:67-79. [ PUBMED] |
| 9. | Charteris DG, Champ C, Rosenthal AR, Lightman SL. Behect's disease-activated T lymphocytes in retinal perivasculitis. Br J Ophthalmol 1992;76:499-501. |
| 10. | Dugel PU, Smita RE. Intermediate uveitis (pars planitis). In: Nozik RA, Michelson JB, editors. Ophthalmology Clinics of North Amevica: Uveitis. Philadelphia: WB Saunders Company;1993. Vol.6, p 29-37. |
| 11. | Kaplan HJ, Waldrep JC, Nicholson JK, Gordon D. Immunological analysis of intraocular mononuclear cell infiltrates in uveitis. Arch Ophthalmol 1984;102:572-75. |
| 12. | Arocker-Mettinger E, Steurer-Georgiew L, Steurer M, Huber-Spitzy V, Hoelzl E, Grabner G, et al. Circulating ICAM-1 levels in serum of uveitis patients. Curr Eye Res 1992;11:161-66. |
| 13. | Singh VK, Nagaraju K. Experimental autoimmune uveitis:Molecular mimicry and oral tolerance. Immunol Res 1996;15:323-46. |
| 14. | Faure JP, de Kazak Y, Dorey C, Usui M, Tuyen VV. Experimental autoimmune uveoretinitis: Activity of different antigenic preparations from the retina. Proc Assoc Res Vis Ophthalmol 1975;94. |
| 15. | de Kozak Y, Sakai J, Thillaye B, Faure JP. S-antigen induced experimental autoimmune uveoretinitis in rats. Curr Eye Res 1981;l:327-36. |
| 16. | Gery I, Mochizuki M, Nussenblatt RB. Retinal specific antigens and immunopathogenic processes they provoke. In: Osborne NN, Chader GJ, editors. Progress in Retinal Research. New York: Pergamon Press;1986.Vol.5, p 75-109. |
| 17. | Nussenblatt RB, Kuwabara T, de Monasterio FM, Wacker WB. S-antigen uveitis in primates. A new model for human disease. Arch Ophthalmol 1981;99:1090-92. |
| 18. | Nussenblatt RB, Gery I, Ballintine EJ, Wacker WB. Cellular immune responsiveness of uveitis patients to retinal S-antigen. Am J Ophthalmol 1980;89:173-79. |
| 19. | Hirose S, Donoso LA, Shinohara T, Palestine AG, Nussenblatt RB. Lymphocyte responses to an 18-mer peptide derived from the retinal S-antigen in uveitis patients. Jpn J Ophthalmol 1990;34:298-305. |
| 20. | Nityanand S, Singh VK, Shinohara T, Paul AK, Singh V, Agarwal PK, et al. Cellular immune response of uveitis patients to peptide M, a retinal S-antigen fragment. J Clin Immunol 1993;13:352-58. |
| 21. | Rajasingh J, Singh VK, Singh V, Sharma K, Agarwal SS. Cellular immune response to retinal S-antigen and interphotoreceptor retinoid binding protein fragments in human idiopathic uveitis patients. Indian J Med Res 1996;103:222-26. |
| 22. | de Smet MD, Yamamoto JH, Mochizuki M, Gery I, Singh VK, Shinohara T, et al. Cellular immune response of uveitis patients to retinal antigens and their fragments. Am J Ophthalmol 1990;110:135-42. |
| 23. | Kalsow CM, Wacker WB. Pineal reactivity of anti-retina sera. Invest Ophthalmol Vis Sci 1977;16:181-84. |
| 24. | Kalsow CM, Wacker WB. Pineal gland involvement in retina-induced experimental allergic uveitis. Invest Ophthalmol Vis Sci 1978;17:774-83. |
| 25. | Abe T, Shinohara T. S-antigen from the rat retina and pineal gland have identical sequences. Exp Eye Res 1990;51:lll-12. |
| 26. | Shinohara T, Dietzschold B, Craft CM, Wistow G, Early JJ, Donoso LA, et al. Primary and secondary structure of bovine retinal S-antigen (45 kDa protein). Proc Natl Acad Sci USA 1987;84:6975-79. |
| 27. | Tsuda, M, Syed M, Bugra K, Whealan JP, McGinnis JF, Shinohara T. Structural analysis of mouse S-antigen gene. Gene 1988;73:ll-20. |
| 28. | Tsuda M, Kikuchi T, Yamaki K, Shinohara T. The mouse S-antigen. Comparison with human and Drosophila. Eur J Biochem 1991;200:95-101. |
| 29. | Yamaki K, Tsuda M, Shinohara T. The sequence of human retinal S-antigen reveals similarities with α-transducin. FEBS Lett 1988;234:39-43. |
| 30. | Yamaki K, Tsuda M, Kikuchi T, Chan KH, Huang KP, Shinohara T. The structural organization of the human S-antigen gene. J Biol Chem 1990;265:257-62. |
| 31. | Yamaki K, Takahashi Y, Sakuragi S, Matsubara M. Molecular cloning of S-antigen cDNA from bovine retina. Biochem Biophys Res Commun 1987;142:904-10. |
| 32. | Abe T, Yamaki K, Tsuda M, Singh VK, Suzuki S, McKinnon R, et al. Rat pineal S-antigen:sequence analysis reveals presence of a-transducin homologous sequence. FEBS Lett 1989;247:307-ll. |
| 33. | Shinohara T, Kikuchi T, Tsuda M, Yamaki K. A family of retinal S-antigens (arrestins) and their genes; Comparative analysis of human, mouse, rat, bovine and Drosophila. Comp Biochem Physiol 1992;103B:505-9. |
| 34. | Ngo JT, Klisak I, Sparkes RS, Mohandas T, Yamaki K, Shinohara T, Bateman JB. Assignment of the S-antigen gene (SAG) to chromosome 2q24-37. Genomics 1990;7:84-87. |
| 35. | Danciger M, Kozak CA, Tsuda M, Shinohara T, Farber DM. The gene for retinal S-antigen (48 kDa protein) maps to the centromeric portion of mouse chromosome 1 near IDH-1. Genomics 1989;5:378-81. |
| 36. | Donoso LA, Merryman CF, Shinohara T, Sery TH, Smith A. Experimental autoimmune uveitis following immunization with small synthetic peptide. Arch Ophthalmol 1987;105:838-40. |
| 37. | Singh VK, Yamaki K, Donoso LA, Shinohara T. S-antigen: Experimental autoimmune uveitis induced in guinea pigs with two synthetic peptides. Curr Eye Res 1988;7:87-92. |
| 38. | Singh VK, Nussenblatt RB, Donoso LA, Yamaki K, Chan CC, Shinohara T. Identification of a uveitopathogenic and lymphocyte proliferation site in bovine S-antigen. Cell Immunol 1988;115:413-19. |
| 39. | Gregerson DS, Merryman CF, Obritsch WE, Donoso LA. Identification of a potent new pathogenic site in human retinal S-antigen which induces experimental autoimmune uveoretinitis in LEW rats. Cell Immunol 1990;128:209-19. |
| 40. | de Smet MD, Bitar G, Roberge FG, Gery I, Nussenblatt RB. Human S-antigen: Presence of multiple immunogenic and immunopathogenic sites in the Lewis rat. J Autoimmun 1993;6:587-99. |
| 41. | Redmond TM, Wiggert B, Robey FA, Chader GJ. Interspecies conservation of structure of interphotoreceptor retinoid binding protein. Similarities and differences as adjudged by peptide mapping and N-terminal sequencing. Biochem J 1986;240:19-26. |
| 42. | Borst DE, Redmond TM, Elser JE, Gonda MA, Wiggert B, Chader GJ, et al.. Interphotoreceptor retinoid binding protein. Gene characterization, protein repeat structure, and its evolution. J Biol Chem 1989;264:1115-23. |
| 43. | Sanui H, Redmond TM, Kotake S, Wiggert B, Hu LH, Margalit H, et al. Identification of an immunodominant and highly immunopathogenic determinant in the retinal interphotoreceptor retinoid binding protein (IRBP). J Exp Med 1989;169:1947-60. |
| 44. | Inoue H, Takeuchi M, Tanaka T, Usui M, Taguchi O. Analysis of the uveitopathogenic determinant in repeat structure of retinal interphotoreceptor retinoid-binding protein (IRBP). Clin Exp Immunol 1994;97:219-25. |
| 45. | Silver PB, Rizzo LV, Chan CC, Donoso LA, Wiggert B, Caspi RR. Identification of a major pathogenic epitope in human IRBP molecule recognized by mice of the H-2r haplotype. Invest Ophthalmol Vis Sci 1995;36:946-54. |
| 46. | Gelderman MP, Fernandez FG, Baer CA, Wiggert B, Chan CC, Vistica BP, et al. Uveitogenic and immunogenic properties of Xenopus IRBP in rats. Invest Ophthal Vis Sci 1998;39:S777. |
| 47. | Singh VK, Kalra HK, Yamaki K, Donoso LA, Abe T, Shinohara T. Molecular mimicry between the uveitopathogenic site of retinal S-antigen and viral peptides: Induction of experimental autoimmune uveitis in Lewis rats. J Immunol 1990;144:1282-87. |
| 48. | Singh VK, Yamaki K, Abe T, Shinohara T. Molecular mimicry between uveitopathogenic site of retinal S-antigen and Escherichia coli protein: Induction of experimental autoimmune uveitis and lymphocyte cross-reaction. Cell Immunol 1989;122:262-73. |
| 49. | Singh VK, Yamaki K, Donoso LA, Shinohara T. Molecular mimicry: Yeast histone H3 induced experimental autoimmune uveitis. J Immunol 1989;142:1512-17. |
| 50. | Singh VK, Usukura J, Shinohara T. Molecular mimicry: Uveitis induced in Macaca fasicularis by microbial protein having sequence homology with retinal S-antigen. jpn J Ophthalmol 1992;36:108-16. |
| 51. | Singh VK, Yamaki K, Donoso LA, Shinohara T. Sequence homology between Yeast histone H3 and uveitopathogenic site of S-antigen: Lymphocyte cross-reaction and adoptive transfer of the disease. Cell Immunol 1989;119:211-21. |
| 52. | Wildner G, Thurau SR. Cross-reactivity between an HLA-B27-derived peptide and a retinal autoantigen peptide:a clue to major histocompatibility complex associated with autoimmune disease. Eur J Immunol 1994;24:2579-85. |
| 53. | Brochuyse RM, Kuhlman ED, Winkers HJ. Experimental autoimmune anterior uveitis (EAAU), a new form of experimental uveitis. Induction by a detergent-insoluble intrinsic protein fraction of the retinal pigment epithelium. Exp Eye Res 1991;52:465-74. |
| 54. | Brochuyse RM, Kuhlman ED, Winkens HJ. Experimental autoimmune uveitis (EAAU), a new form of uveitis. Dose dependent induction and adoptive transfer using a melanin bound antigen of the retinal pigment epithelium. Exp Eye Res 1992;55:401-11. |
| 55. | Kim MC, Kabeer NH, Tandhasetti MT, Kaplan HJ, Bora NS. Immunohistochemical studies on melanin associated antigen (MAA) induced experimental autoimmune anterior uveitis (EAAU). Curr Eye Res 1995;14:703-10. |
| 56. | Wacker WB, Donoso LA, Kalsow CM, Yankeelov JA Jr, Organisciak DT. Experimental allergic uveitis. Isolation, characterization, and localization of a soluble uveitopathogenic antigen from bovine retina. J Immunol 1977;119:1949-58. |
| 57. | Salinas-Carmona MC, Nussenblatt RB, Gery I. Experimental autoimmune uveitis in the athymic nude rats. Eur J Immunol 1982;12:481-84. |
| 58. | Caspi RR, Roberge FG, Chan CC, Wiggert B, Chader GJ, Rozenszajn LA, et al. A new modej for autoimmune disease. Experimental autoimmune uveoretinitis induced in mice with two different retinal antigens. J Immunol 1988;140:1490-95. |
| 59. | Iwase K, Fuji Y, Nakashima I, Kato N, Fujino Y, Kawashima H, Mochizuki M. New method for induction of experimental autoimmune uveoretinitis (EAU) in mice. Curr Eye Res 1990;9:207-16. |
| 60. | Shinohara T, Donoso LA, Tsuda M, Yamaki K, Singh VK. S-antigen: Structure, function and autoimmune uveitis (EAU). In: Osborne NN, Chader GJ, editors. Progress in Retinal Research. New York: Pergamon Press;1988. Vol 8, p 51-66. |
| 61. | de Kozak Y, Mirshahi M, Boucheix C, Faure JP. Inhibition of experimental autoimmune uveoretinitis in rats by S-antigen-specific monoclonal antibodies. Eur J Immunol 1985;15:1107-ll. |
| 62. | Nussenblatt RB, Rodrigues MM, Wacker WB, Cevario SJ, Salinas-Carmona MC, Gery I. Cyclosporin A: Inhibition of experimental autoimmune uveitis in Lewis rats. J clin Invest 1981;67:1228-31. |
| 63. | Mochizuki M, Kuwabara T, McAllister C, Nussenblatt RB, Gery I. Adoptive transfer of experimental autoimmune uveoretinitis in rats: Immunopathogenic mechanisms and histological features. Invest Ophthalmol Vis Sci 1985;26:l-9. |
| 64. | Dick AD, Cheng YF, Liversidge J, Forrester JV. Immunomodulation of experimental autoimmune uveoretinitis: A model of tolerance induction with retinal antigens. Eye 1994;8:52-59. |
| 65. | Dua HS, Sewell H, Forrester JV. The effect of retinal S-Ag specific monoclonal antibody therapy on experimental autoimmune uveoretinitis and experimental autoimmune pinealitis. Clin Exp Immunol 1989;75:100-105. |
| 66. | DeKozak Y, Mirshahi M, Boucheix C, Faure JP, Letts LG, Rothlein R. Prevention of experimental autoimmune uveoretinitis by active immunisation with auto antigen-specific monoclonal antibodies. Eur J Immunol 1990;17:541-47. |
| 67. | Dua HS, Abrams M, Barret JA, Gregerson DS, Forrester JV, Donoso LA. Epitopes and idiotypes in experimental autoimmune uveoretinitis: A review. Curr Eye Res 1992;ll:59-66. |
| 68. | Wetzig R, Hooks JJ, Percopo CM; Nussenblatt R, Chan CC, Detrick B. Anti-la antibody diminishes ocular inflammation in experimental autoimmune uveoretinitis. Curr Eye Res 1988;7:809-18. |
| 69. | Atalla L, Linker-Israeli M, Steinman L, Rao NA. Inhibition of autoimmune uveitis by anti CD4 antibody. Invest Ophthamol Vis Sci 1990;31:7-11 |
| 70. | Saoudi A, Hurez V, de Kozak Y, Kuhn J, Kaveri SV, Kazatchkine MD, et al. Human immunoglobulin preparations for intravenous use prevent experimental autoimmune uveoretinitis. Int Immunol 1993;5:1559-67. |
| 71. | Whitcup SM, Chan CC, Grey I, Kalled SL, Wiggert B, Magone MT. Anti-CD40 ligand (CD40L) antibody inhibits experimental autoimmune uveitis (EAU). Invest Ophthal Vis Sci 1998;39:S867. |
| 72. | Singh VK, Kalra HK, Yamaki K, Shinohara T. Suppression of experimental autoimmune uveitis in rats by the oral administration of the uveitopathogenic S-antigen fragment or a cross-reactive homologous peptide. Cell Immunol 1992;139:81-90. |
| 73. | Nussenblatt RB, Caspi RR, Mahdi R, Chan CC, Roberge F, Lider O, Weiner HL. Inhibition of S-antigen induced experimental autoimmune uveoretinitis by oral induction of tolerance with S-antigen. J Immunol 1990;144:1689-95. |
| 74. | Vrabec TR, Gregerson DS, Dua HS, Donoso LA. Inhibition of experimental autoimmune uveoretinitis by oral administration of S-antigen and synthetic peptides. Autoimmunity 1992;12:175-84. |
| 75. | Thurau SR, Chan CC, Suh E, Nussenblatt RB. Induction of oral tolerance to S-antigen induced experimental autoimmune uveitis by a uveitogenic 20 mer peptide. J Autoimmun 1991;4:507-16. |
| 76. | Singh VK, Anand R, Sharma K, Agarwal SS. Suppression of experimental autoimmune uveitis in Lewis rats by oral administration of recombinant Escherichia coli expressing retinal S-antigen. Cell Immunol 1996;172:158-62. |
| 77. | Gregerson DS, Obritsch WF, Donoso LA. Oral tolerance in experimental autoimmune uveoretinitis. Distinct mechanisms of resistance are induced by low vs high dose feeding protocols. J Immunol 1993;151:5751-61. |
| 78. | Rizzo LV, Miller-Rivero NE, Chan CC, Wiggert B, Nussenblatt RB, Caspi RR. Interleukin-2 treatment potentiates induction of oral tolerance in a murine model of autoimmunity. J Clin Invest 1994;94:1668-72. |
| 79. | Caspi RR, Stiff LR, Morawetz R, Miller-Rivero NE, Chan CC, Wiggert B, et al. Cytokine modulation of oral tolerance in a murine model of autoimmune uveitis. Ann NY Acad Sci 1996;778:315-24. |
| 80. | Vistica BP, Chanaud NP 3rd, Felix N, Caspi RR, Rizzo LV, Nussenblatt RB, et al. CD8 T-cells are not essential for the induction of low-dose oral tolerance. Clin Immunol Immunopathol 1996;78:196-202. |
| 81. | Thurau SR, Chan CC, Nussenblatt RB, Caspi RR. Oral tolerance in a murine model of relapsing experimental autoimmune uveoretinitis (EAU):Induction of protective tolerance in primed animals. Clin Exp Immunol 1997;109:370-76. |
| 82. | Dick AD, Cheng YF, McKinnon A, Liversidge J, Forrester JV. Nasal administration of retinal antigens suppresses the inflammatory response in experimental allergic uveoretinitis. A preliminary report of intranasal induction of tolerance with retinal antigens. Br J Ophthalmol 1993;77:71-75. |
| 83. | Dick AD, Cheng YF, Liversidge J, Forrester JV. Intranasal administration of retinal antigens suppresses retinal antigen-induced experimental autoimmune uveoretinitis. Immunology 1994;82:625-31. |
| 84. | Wildner G, Hung Y, Thurau SR. Orally induced, peptide-specific γ/δ TCR + cells suppress experimental autoimmune uveitis. Eur J Immunol 1996;26:2140-48. |
| 85. | Ohkawa T, Yamagami S, Sakai R, Kaku M, Kawashima H. Effects of anti αβ T cell receptor monoclonal antibody R73 on the induction' of experimental autoimmune uveoretinitis in rats. Invest Ophthal Vis Sci 1998;39:S780. |
| 86. | Wildner G, Thurau SR. Orally induced bystander suppression in experimental autoimmune uveoretinitis occurs only in the periphery and not in the eye. Eur J Immunol 1995;25:1292-97. |
| 87. | Romagnani S. The Thl/Th2 paradigm. Immunol Today 1997;18:263-66. |
| 88. | Caspi RR, Sun B, Agarwal RK, Silver PB, Rizzo LV, Chan CC. T-cell mechanisms in experimental autoimmune uveoretinitis: Susceptibility is a function of the cytokine response profile. Eye 1997;11:209-12. |
| 89. | Caspi RR, Silver PB, Chan CC, Sun B, Agarwal RK, Wells J, Oddo S, Fujino Y, Najafian F, Wilder RL. Genetic susceptibility to experimental autoimmune uveoretinitis in rat is associated with an elevated Th1 response. J Immunol 1996;157:2668-75. |
| 90. | Jones LS, Rizzo LV, Agarwal RK, Tarrant TK, Chan CC, Wiggert B, Caspi RR. IFN-γ deficient mice develop experimental autoimmune uveitis in the context of a deviant effector response. J Immunol 1997;158:5997-6005. |
| 91. | Saoudi A, Bellon B, de Kozak Y, Vial MC, Thillaye B, Duret P. Inhibition of experimental autoimmune uveoretinitis by mercuric chloride injections in (Lewis x Brown-Norway) Fl rats. Curt Eye Res 1990;9S:135-38. |
| 92. | Saoudi A, Bellon B, de Kozak Y, Kuhn J, Vial MC, Thillaye B, et al. Prevention of exerimental autoimmune uveoretinitis and experimental autoimmune pinealitis in Lewis x Brown-Norway) Fl rats by HgCl 2. Immunology 1991;74:348-54. |
| 93. | Saoudi A, Bellon B, de Kozak Y, Vial MC, Duret P. Adoptive transfer of experimental autoimmune uveoretinitis in HgCl 2 injected rats. Curr Eye Res 1992;11S:101-105. |
| 94. | Saoudi A, Kuhn J, Huygen K, de Kozak, Velu T., Goldman M, et al. Activated TH2 cells prevent from experimental autoimmune uveoretinitis, a TH1 dependent autoimmune disease. Eur J Immunol 1993;23:3096-103. |
| 95. | Ramanathan S, de Kozak Y, Saoudi A, Goureau O, Van Der Meide P, Duret P, Bellon B. Recombinant IL-4 aggravate experimental autoimmune uveoretinitis in rats. J Immunol 1996;157:2209-15. |
| 96. | Sun B, Rizzo LV, Sun SH, Chan CC, Wiggert B, Wilder RL, et al. Genetic susceptibility to experimental uveitis involves more than a predisposition to generate a T-helper-1-like or a T helper-2-like response. J Immunol 1997;159:1004-11. |
| 97. | Xu-H, Rizzo LV, Silver PB, Caspi RR. Uveitogenicity is associated with a Th1-like lymphokine profile: Cytokine dependent modulation of early and committed effector T cells in experimental autoimmune uveitis. Cell Immunol 1997;178:69-78. |
| 98. | Caspi RR, Silver PB, Rizzo LV, Chan CC, Wiggert B, Magram J, et al. Endogenous IL-2 is required for induction and expression of experimental autoimmune uveitis (EAU). Invest Ophthal Vis Sci 1998;39:S867. |
| 99. | Yokoi H, Tsukahara R, Kezuka T, Sakai J, Usui M, Yagita H, et al. Prevention of experimental autoimmune uveoretinitis by monoclonal antibody to interleukin 12. Invest Ophthal Vis Sci 1998;39:S780. |
| 100. | Fujino Y, Mochizuki M, Chan CC, Raber J, Kotake S, Gery I, et al. FK506 treatment of S-antigen induced uveitis in primates. Curr Eye Res 1991;10:679-90. |
| 101. | Roberge FG, Xu D, Chan CC, de Smet MD, Nussenblatt RB, Chen H. Treatment of autoimmune uveoretinitis in the rat with rapamycin, an inhibitor of lymphocyte growth factor signal transduction. Curr Eye Res 1993;12:197-203. |
| 102. | Chanaud NP III, Vistica BP, Fugui E, Nussenblatt RB, Allison AC, Gery I. Inhibition of experimental autoimmune uveoretinitis by mycophenolate mofetil, an inhibitor of purine metabolism. Exp Eye Res 1995;61:429-34. |
| 103. | Robertson SM, Lang LS. Leflunomide: inhibition of S-antigen induced autoimmune uveitis in Lewis rats. Agents Actions 1994;42:167-72. |
| 104. | Whitcup SM, DeBarge R, Rosen H, Nussenblatt RB, Chan CC. Monoclonal antibody against CDllb/CD18 inhibits endotoxin-induced uveitis. Invest Ophthalmol Vis Sci 1993;34:673-81. |
| 105. | Whitcup SM, DeBarge LR, Caspi RR, Harning R, Nussenblatt RB, Chan CC. Monoclonal antibodies against ICAM-1(CD54) and LFA-1 (CD11/CD18) inhibit experimental autoimmune uveitis. Clin Immunol Immunopathol 1993;67:143-50. |
| 106. | Guex-Crosier Y, Raber J, Hakimi J, Guex-Crosier Y, Raer J. Humanized anti-IL-2 and anti-IL-15 receptor antibodies in the treatment of uveoretinitis in a monkey model. Invest Ophthalmol Vis Sci 1996;37:S896. |
| 107. | Roberge FG, Lorberbaum-Galski H, LeHoang P, de Smet M, Chan CC, Fitzerald D, et al. Selective immunosuppression of activated T-cells with the chimeric toxin IL-2-PE40:Inhibition of experimental autoimmune uveoretinitis. J Immunol 1989;143:3498-502. |
| 108. | Hara Y, Caspi RR, Wiggert B, Chan CC, Wilbanks GA, Streilein JW. Suppression of experimental autoimmune uveitis in mice by induction of anterior chamber associated immune deviation with interphotoreceptor retinoid binding protein. J Immunol 1992;148:1685-92. |
| 109. | Beraud E, Kotake S, Caspi RR, Oddo SM, Chan CC, Gery I, et al. Control of experimental autoimmune uveoretinitis by low dose T-cell vaccination. Cell Immunol 1992;140:112-22. |
| 110. | Kuwano YI, Sasamoto Y, Kotake S, Thurau SR, Wiggert B, Gery I. Trials of vaccination against experimental autoimmune uveoretinitis with a T-cell receptor peptide. Curr Eye Res 1991;10:789-95. |
| 111. | Sartani G, Silver PB, Rizzo LV, Chan CC, Wggert B, Mastorakos G, et al. Anti-tumor necrosis factor-a therapy suppresses the induction of experimental autoimmune uveoretinitis in mice by inhibiting antigen priming. Invest Ophthalmol Vis Sci 1996;37:2211-18. |
| 112. | Chan CC, Mochizuki M, Nussenblatt RB, Palestine AG, McAllister C, Gery I, et al. T-lymphocyte subsets in experimental autoimmune uveitis. Clin Immunol Immunopath 1985;35:103-10. |
| 113. | Hankey DJR, Lightman S, Greenwood J, Baker D. Administration of p55 TNFR-Ig fusion protein minimizes target organ damage in EAU despite retinal inflammation. Invest Ophthal Vis Sci 1998;39:S781. |
| 114. | Fukushima A, Lai JC, Chanaud NP III, Shiloach J, Whitcup SM, Nussenblatt RB, et al. Permissive recognition of immunodominant determinants of the retinal S-antigen in different rat strains, primates and humans. Int Immunol 1997;9:169-77. |
| 115. | Kozhich AT, Caspi RR, Berzofsky JA, Gery I. Immunogenicity and immunopathogenicity of an autoimmune epitope are potentiated by increasing MHC binding through residue substitution. J Immunol 1997;157:4145-51. |
| 116. | Prasad SA, Gregerson DS. Antigen presentation in uveitis. Eye 1997;11:176-82. |
| 117. | Koevary SB, Caspi RR. Prevention of experimental autoimmune uveoretinitis by intrathymic S-antigen injection. Ocul Immunol Inflamm 1997;5:165-72. |
| 118. | Sueda J, Fukushi K, Sugita S, Ikeda E, Hikita N, Mochizuki M, et al. Kinetics of apoptotic cells in experimental autoimmune uveoretinitis. Invest Ophthal Vis Sci 1998;39:S779. |
| 119. | Shimizu K, Zhang J, Riono WP, Wu GS, Rao NA. Retinal S-antigen and IRBP induce nitric oxide production in macrophages. Invest Ophthal Vis Sci 1998;39:S778. |
| 120. | Gregerson DS, Abrahams IW, Thirkill CE. Serum antibody levels of uveitis patients to bovine retinal antigens. Invest Ophthalmol-Vis Sci 1981;21:669-80. |
| 121. | Doekes G, van der Gaag R, Rothova A, Van Kooyk Y, Boersma L, Zaal MJ, Dijkman G, Fortuin ME, Baarsma GS, Kijlstra A. Humoral and cellular immuneresponsiveness to human S-antigen in uveitis. Curr Eye Res 1987;6:909-19. |
| 122. | Nussenblatt RB, Whitcup SM, Palestine AG. Uveitis: Fundamentals and clinical practice. St Louis: Mosby; 2nd ed; 1996. |
| 123. | Nussenblatt RB, Tabbara KF. Autoimmune diseases. In: Tabbara KF, Nussenblatt RB, editors. Posterior Uveitis: Diagnosis and Management. Boston: Butterworth-Heinenann, 1994:85-114. |
| 124. | Abrahams IW, Gregerson DS. Longitudinal study of serum antibody responses to bovine retinal S-antigen in endogenous granulomatous uveitis. Br J Ophthalmol 1983;67:681-84. |
| 125. | Chan CC, Palestine AG, Nussenblatt RB, Roberge FG, BenEzra D. Anti-retinal autoantibodies in Vogt-Koyanagi-Harada's syndrome, Behcet's disease and sympathetic ophthalmia. Ophthalmology 1985;92:1025-28. |
| 126. | Ren P, Yan X, Wang S. Lymphocyte proliferative response to S-antigen in patients with uveitis and optic neuritis. Yen Ko Hsueh Pao 1995;11:120-23. |
| 127. | Soylu M, Grey I, Whitcup SM, Nussenblatt RB, Rizzo LV. Identification of S-antigen peptide determinants recognized by S-antigen specific lymphocyte lines from uveitis patients. Invest Ophthal Vis Sci 1998;39:S361. |
| 128. | Nussenblatt RB. Current research in immunomodulation of uveitis. Invest Ophthal Vis Sci 1998;39:S215. |
| 129. | Nussenblatt RB, Palestine AG, Chan CC. Cyclosporine therapy in the treatment of intraocular inflammatory disease resistant to systemic corticosteroids or cytotoxic agents. Am J Ophthalmol 1983;96:275-82. |
| 130. | Masuda K, Nakajima A, Urayama A, Nakae K, Kogure M, Inaba G. Double masked trial of cyclosporine versus colchicine and long term open study of cyclosporine in Behcet's disease. Lancet 1989;1:1093-96. |
| 131. | de Smet MD, Nussenblatt RB. Clinical use of cyclosporin in ocular disease. Int Ophthalmol Clin 1993:33:32-45. |
| 132. | Mochizuki M, Masuda K, Sakane T, Ito K, Kogure M, Sugino N, et al. A clinical trial of FK506 in refractory uveitis. Am J Ophthalmol 1993;115:763-9. |
| 133. | Whitcup SM, Salvo EC Jr, Nussenblatt RB. Combined cyclosporine and corticosteroid therapy for sight-threatening uveitis in Behcet's disease. Am J Ophthalmol 1994;118:39-45. |
| 134. | Zamiri P, Muhaya M, Lightman S. Effectiveness of methotrexate as second line therapy in management of refractory uveitis. Invest Ophthal Vis Sci 1998;39:S611. |
| 135. | Rosenbaum JT. Immunosuppressive therapy of uveitis. In: Nozik RA, Michelson JB, editors. Ophthalmology Clinics of North Amevica Uveitis. Philadelphia: WB Saunders Company; 1993. Vol 6, p 167-75. |
| 136. | Ramadan AM, Nussenblatt RB. Cytotoxic agents in ocular inflammation. In: Singh K, Zimmerman TJ, editors. Ophthalmology Clinics of North America: Advances in ocular Pharmacology. Philadelphia: W.B. Saunders Company; 1997. Vol.10, p 377-87. |
| 137. | Thurau SR, Wildner G, Reiter C, Reiethmuller G, Lund OE. Treatment of endogenous uveitis with anti-CD4 monoclonal antibody: First report. Ger J Ophthalmol 1994;3:409-13. |
| 138. | Nussenblatt RB, Whitcup SM, de Smet MD, Caspi RR, Kozhich AT, Weiner HL, et al. Intraocular inflammatory disease (uveitis) and the use of oral tolerance: A status report. Ann NY Acad Sci 1996;778:325-37. |
| 139. | Nussenblatt RB, Gery I, Weiner HL, Ferris FL, Shiloach J, Remaley N, et al. Treatment of uveitis by oral administration of retinal antigens: Results of a phase I/II randomized masked trial. Am J Ophthalmol 1997;123:583-92. |
| 140. | Wildner G, Thurau SR. Database screening for molecular mimicry. Immunol Today 1997;25:252. |
| 141. | Thurau SR, Diedrich-Mohring M, Fricke H, Arbogast S, Wildner G. Molecular mimicry as a therapeutic approach for an autoimmune disease: oral treatment of uveitis-patients with an MHC-peptide cross-reactive with autoantigens-first results. Immunol Lett 1997;57:193-201. |
| 142. | Chan CC, Matteson DM, Li Q, Whitcup SM, Nussenblatt RB. Apoptosis in patients with posterior uveitis. Arch Ophthalmol 1997;115:1559-67. |
| 143. | Chen J, Kaburaki T, Merino G, Fujino Y. Interleukin8 production in Behcet,s disease. Invest Ophthal Vis Sci 1998;39:S363. |
| 144. | Faure JP. Autoimmunity and the retina. Curr Top Eye Res 1980;2:215-302. |
| 145. | Singh VK, Biswas S, Anand R, Agarwal SS. Experimental autoimmune uveitis as animal model for human posterior uveitis. Ind J med Res 1998;107:53-67. |
| 146. | Whitcup SM, Nussenblatt RB. Immunologic mechanisms of uveitis. New targets for immunomodulation. Arch Ophthalmol 1997;115:520-5. |
| 147. | Nussenblatt RB, Csaky K. Perspectives on gene therapy in the treatment of ocular inflammation. Eye 1997;11:217-21. |
[Table - 1], [Table - 2]
|
.png "Santen")
Search Pubmed for