[Recurrent uveitis of unknown origin in childhood]. / Kindliche rezidivierende Uveitis unklarer Genese.

This report describes a 12-year-old girl with diffuse infiltrating retinoblastoma. This inflammatory condition belongs to the uveitis masquerade syndromes, which comprise a group of various ocular diseases such as chronic intraocular inflammation and ocular tumors.

[Topical and systemic corticosteroid therapy for uveitis in childhood]. / Topische und systemische Kortikosteroidtherapie bei Uveitis im Kindesalter.

Systemic and topical corticosteroids constitute an important part in the treatment of children with uveitis, because of their rapid therapeutic onset. Patients with anterior uveitis receive eye drops initially every 30 minutes or every hour. Children will experience the same side effects as adults but, in addition, there will be a growth retardation. Therefore, if treatment is required for extended periods of time it is important to avoid steroid quantities above the Cushing level and to initiate an additional systemic immunosuppressive treatment regimen early.

[Cystoid macular edema in uveitis]. / Zystoides Makulaödem bei Uveitis.

Cystoid macular edema (CME) is the most frequent cause of visual deterioration in uveitis patients. Intraocular inflammation disturbs the blood-retina barrier and leads to retinal edema. The basis of successful treatment is the anti-inflammatory and immunosuppressive therapy of uveitis. Restoration of the blood-retina barrier is mediated by corticosteroids and nonsteroidal anti-inflammatory agents. Resorption of extracellular fluid is improved by systemic carboanhydrase inhibitors. Despite aggressive therapy loss of visual acuity is frequent. Therefore, early diagnosis of CME and initiation of treatment, even if visual acuity is not yet impeded, is mandatory.

Immunopathology of recurrent uveitis in spontaneously diseased horses.

Equine recurrent uveitis (ERU) is the most serious eye disease in horses worldwide. Despite the fact that ERU is generally considered to be immune mediated, a detailed description of the histopathology of the posterior part of ERU eyes is lacking. Here, we examined sections of paraffin-embedded eyes using histological and immunhistological methods. Twenty seven eyes of 20 horses with ERU and 30 eyes of 15 healthy control horses were included in this study. We could consistently demonstrate an involvement of the retina and the choroid in all examined eyes of horses with spontaneous ERU. In eyes with minimal histopathological changes, the infiltrates consisted almost exclusively of T-cells. Histopathological changes start with the destruction of the photoreceptor outer segments, which often leads to focal retinal detachment. In more severely affected eyes, there is additional disintegration of the ganglion cell layer and the inner nuclear layer. In almost all examined eyes, lymphoid follicle formation could be demonstrated. Typical localizations of these follicles were the iris stroma and the choroid underneath the transition zone of the retina without photoreceptor cells to the region containing photoreceptor cells. These follicles consist of a T-cell rich periphery with a small center of CD3-negative lymphocytes. In cases with extreme histopathological changes, the retinal architecture is widely disintegrated with massive infiltration of the retina, the choroid, and the ciliary body by several types of inflammatory cells. Necrotic remnants of the retina are end-stage findings and there is only a minor inflammatory infiltration left. This study provides clear evidence that the retina is involved in all stages of ERU. Inflammation is mainly driven by T-cells as T-cells were demonstrated in mild stages of the disease and are also the predominating cell type in all other stages of ERU.

Immune responses to retinal autoantigens and peptides in equine recurrent uveitis.

PURPOSE: To test the hypothesis that autoimmune mechanisms are involved in horses in which equine recurrent uveitis (ERU) develops spontaneously. METHODS: Material obtained from horses treated for spontaneous disease by therapeutic routine vitrectomy was analyzed for total IgG content and IgG specific for S-Antigen (S-Ag) and interphotoreceptor retinoid-binding protein (IRBP). The cellular infiltrate of the vitreous was analyzed by differential counts of cytospin preparations and flow cytometry using equine lymphocyte-specific antibodies. Antigen-specific proliferation assays were performed comparing peripheral blood lymphocytes (PBLs) with vitreal lymphocytes by stimulation with S-Ag and several S-Ag- and IRBP-derived peptides. RESULTS: The total IgG content of specimens from horses with ERU was very high with great variability among the investigated samples (11.5 +/- 8.0 mg). Autoantibodies to S-Ag or IRBP or both were found in 72% of vitreous specimens from horses with uveitis. The leukocyte infiltrates (up to 2 x 10(8) cells per sample) were dominated by lymphocytes (>90%) in most cases (22/32). Flow cytometry showed that more than 50% of these cells were CD4(+) T cells. In vitro stimulation of vitreal lymphocytes, but not of PBL, showed a strong proliferative response to peptides derived from S-Ag or IRBP in 9 of 12 patients. CONCLUSIONS: In the eyes of horses with ERU, IgG antibodies and autoreactive T cells specific for retinal antigens were detected. These results strongly support the hypothesis that ERU is an autoimmune-mediated disease and is highly similar to recurrent uveitis in humans in both clinical and immunologic parameters.

Oral tolerance with an HLA-peptide mimicking retinal autoantigen as a treatment of autoimmune uveitis.

Endogenous uveitis is a T cell mediated autoimmune disease leading to impairment of visual acuity. The association of different uveitis entities with HLA-class I antigens and the discovery of antigenic mimicry between a peptide of uveitis-associated HLA-class I antigens and a peptide of retinal autoantigen led to a new hypothesis for the pathogenesis of uveitis. On the basis of this mechanism an open trial of oral tolerance induction with the HLA-peptide B27PD was initiated for nine patients with long lasting, therapy-refractive uveitis. Within 6 weeks of oral peptide treatment all patients responded with a marked decrease of intraocular inflammation, which allowed a reduction of systemic corticosteroids in seven patients. One patient, who suffered from an acute relapse, responded within 2 weeks, followed by an increase of visual acuity. In addition, two patients discontinued azathioprine immediately prior to oral tolerance induction without the occurrence of relapses. Visual acuity remained unchanged or increased in 14 of 16 eyes. One patient did not finish oral peptide treatment. None of these patients experienced any adverse events. It was concluded that the oral application of highly tolerogenic peptides might be a potent approach for the treatment of autoimmune diseases.

Oral tolerance in a murine model of relapsing experimental autoimmune uveoretinitis (EAU): induction of protective tolerance in primed animals.

Oral administration of uveitogenic retinal antigens suppresses the expression of EAU induced by a subsequent immunization with these antigens. Effectiveness and mechanisms of oral tolerance in EAU have mainly been studied in the acute, monophasic model in Lewis rats by feeding antigen prior to induction of disease. In this study we investigated the effect of oral tolerance induction in the acute as well as the chronic-relapsing models in the B10.A mouse. In acute murine EAU we could effectively suppress disease by induction of oral tolerance prior to immunization. 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. These experiments demonstrate that oral tolerance may have practical clinical implications in uveitis, which is predominantly a chronic-relapsing condition in humans.

Molecular mimicry as a therapeutic approach for an autoimmune disease: oral treatment of uveitis-patients with an MHC-peptide crossreactive with autoantigen--first results.

In the rat model of experimental autoimmune uveitis (EAU) we have demonstrated that a peptide from the sequence of human disease-associated MHC-class I antigens can induce uveitis upon immunization. Moreover, oral administration of this MHC-peptide tolerized Lewis rats to the disease induced with two different retinal autoantigens, retinal S-antigen (S-Ag) and IRBP. In uveitis patients T cells responding to S-Ag peptide also respond to the MHC-peptide, which shows crossreactivity with the major epitope from S-Ag due to some shared discontinuous amino acid homologies. The 14-mer peptide B27PD is derived from the sequence of all HLA-B antigens that are statistically associated with uveitis (including HLA-B27). Patients with long-lasting endogenous uveitis, suffering from side effects of conventional immuno-suppressive therapy or being therapy-refractive, were orally tolerized with peptide B27PD in this first open therapeutic trial. Patients received peptide three times a week over a 12 weeks period, while only low dose steroids were allowed as concomitant medication. The aims were (1) to investigate whether immunosuppressive therapy could be discontinued and steroids reduced while relapses of ocular inflammation reside and (2) to search for side effects. The Helsinki Declaration was strictly observed and the study design approved by the local ethical committee. The first patients orally tolerized with the HLA-peptide (two had stopped azathioprine immediately prior to onset of oral peptide treatment) could discontinue their 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-antigens and crossreactive with the organ-specific autoantigen seems to be a potent therapeutic approach.

Orally induced, peptide-specific gamma/delta TCR+ cells suppress experimental autoimmune uveitis.

We investigated the role of gamma/delta TCR+ T cells in induction and suppression of the T cell-mediated disease experimental autoimmune uveitis. Disease induction was studied in Lewis rats perinatally depleted of alpha/beta or gamma/delta TCR+ subpopulations. Depletion of alpha/beta TCR+ cells completely abrogated disease, whereas treatment with anti-gamma/delta antibodies had no influence on onset or intensity of uveitis. However, adoptively transferred gamma/delta+ cells from orally tolerized rats could mediate suppression of uveitis in an antigen-specific fashion. Uveitis induced by a peptide derived from the uveitogenic retinal soluble antigen (S-Ag) was suppressed by gamma/delta+ cells from rats orally tolerized with the same peptide as well as HLA peptide B27PD. This disease ameliorating effect could also be observed when rats were fed with the HLA peptide before immunization with S-Ag peptide. Transfer of alpha/beta+ T cells from the same donors as well as gamma/delta+ or alpha/beta+ cells from animals fed with control peptide had no ameliorating effect.

Orally induced bystander suppression in experimental autoimmune uveoretinitis occurs only in the periphery and not in the eye.

Oral administration of retinal soluble antigen (S-Ag) suppresses the induction of S-Ag-mediated experimental autoimmune uveitis (EAU) in Lewis rats. EAU induced with interphotoreceptor retinoid-binding protein (IRBP), another retinal autoantigen, can also be suppressed by oral administration of IRBP. It has been speculated that feeding with one retinal autoantigen could suppress induction of uveitis with the other retinal protein by means of bystander suppression. Both uveitogenic 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 used for induction and suppression of uveitis failed to prevent onset of disease, demonstrating that bystander suppression obviously does not occur in the eye. To investigate further the localization of suppressor mechanisms, we fed Lewis rats either with retinal S-Ag or with ovalbumin (OVA) and then immunized the animals either with a mixture of S-Ag and OVA or with each antigen separately, injected into contralateral hind legs. Feeding of S-Ag prior to immunization led to suppression of uveitis, whereas feeding of OVA had no tolerizing effect when S-Ag and OVA were injected into different legs. Nevertheless, immunizing rats with a mixture of S-Ag and OVA after OVA feeding suppressed uveitis to a high degree. These findings suggest that orally induced bystander suppression might not occur in the target organ, but rather peripherally at the site of induction of the autoimmune T cells.

Treatment of endogenous uveitis with anti-CD4 monoclonal antibody: first report.

A patient with endogenous uveitis was treated with a chimeric monoclonal anti-CD4 antibody. This patient with long-standing therapy-refractive uveitis did not benefit immediately from antibody infusions, although the frequency of uveitis relapses was sharply reduced after this therapy. After treatment with the monoclonal antibody, this patient's response to conventional immunosuppression improved. The patient had very low CD4+ T-cell counts before the beginning of antibody therapy. In this case, peripheral T-cell counts slowly increased. Antigen-specific T-cell responses to retinal S-antigen in this patient were significantly elevated only just prior to a clinical relapse. The initially high level of spontaneous T-cell proliferation normalized after antibody infusions.

Cross-reactivity between an HLA-B27-derived peptide and a retinal autoantigen peptide: a clue to major histocompatibility complex association with autoimmune disease.

Statistical correlations between the expression of various HLA antigens and certain autoimmune diseases have been observed for both HLA class I and II antigens. Autoimmune diseases like spondyloarthropathies and anterior uveitis are associated with HLA-B27, but uveitis in Behçet's disease with HLA-B51. We describe a peptide from disease-associated HLA class I antigens sharing sequence homologies with a highly uveitogenic epitope from the retinal autoantigen S-antigen. S-antigen induces autoimmune uveitis in the animal model and is a major autoantigen in human disease. The HLA peptide induced uveitis in the Lewis rat and, moreover, suppressed S-antigen-induced disease when administered orally. Patients' PBL cross-reacted with the HLA- and corresponding retinal peptide, explaining the organ specificity of the disease.

[Does combined pancreas-kidney transplantation modify diabetic retinopathy in type-1 diabetic patients?]. / Beeinflusst die kombinierte Pankreas-Nieren-Transplantation die diabetische Retinopathie bei Typ-1-Diabetikern?

The study group consisted of 30 patients with a functioning pancreas graft of at least 12 months. Fifty-seven eyes were examined; 26 eyes from 15 patients with a non-functioning pancreas graft made up the control group. Three patients were in both groups because their graft was rejected after a 12-month period. The mean age in the study group was 37 years, the mean observation time 38 months. The mean duration of diabetes before transplantation was 24 years and all patients were on kidney dialysis. Retinal coagulation for diabetic retinopathy had previously been performed in 80.7% of the patients. The mean age (38 years), observation time (36 months), duration of diabetes before transplantation (24 years), and incidence of retinal coagulation (84.6%) were comparable in the control group. All patients had regular ophthalmological examinations every 6 to 12 months. This included best-corrected visual acuity, applanation tonometry, slit-lamp examination and dilated binocular funduscopy. Seven 30 degrees fundus pictures of the posterior pole were taken: The images were graded by comparing them with the ETDRS (Early Treatment Diabetic Retinopathy Study) Group standard photographs. The original Airlie House grading scale was changed because we did not take stereoscopic pictures. Evaluation and grading were done independently by two examiners. The retinopathy score was graded from 0 (no retinopathy) to 11 (no evaluation possible due to opaque media). Visual acuity remained stable in both the study and control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Cells of the immune system and their cytokines in epiretinal membranes and in the vitreous of patients with proliferative diabetic retinopathy.

In the present study, we specifically investigated the presence of the main immune cells, namely T helper/inducer lymphocytes, T suppressor/cytotoxic lymphocytes, B lymphocytes and macrophages, for HLA-DR antigen expression and the cytokines IL-1 alpha and IL-2 in epiretinal membranes of proliferative diabetic retinopathy (PDR) using immunohistochemical staining. The levels of the two cytokines (IL-1 alpha and IL-2) in the vitreous were measured by ELISA. The results show that 18 out of the 32 epiretinal specimens reacted positively with monoclonal anti-CD4 (marker for T helper/inducer cell subset) antibody (56%), 21 reacted with monoclonal anti-CD8 (marker for T suppressor/cytotoxic subset) antibody (66%), 15 reacted with monoclonal anti-CD22 (marker for B lymphocytes) antibody (47%), and 25 (78%) were positive for monoclonal anti-macrophage and anti-HLA-DR antibodies. IL-1 alpha and IL-2 were detected in the epiretinal membranes in 8 out of 13 tested cases (62%). However, in the vitreous, IL-1 alpha was detected in only 3 out of 13 cases (70, 75 and 80 pg/ml, respectively), while IL-2 was not detected in any of the vitreous samples. The results clearly demonstrate that immune cells and their cytokines were found in about half of the epiretinal membrane specimens. The invasion of the immunocompetent cells in the membranes seems to be a secondary event. They would not participate in the pathogenesis of PDR, but probably induce unspecific reactions and thus complicate the disease.