Effects of cyclosporin A on the induction of oral tolerance.
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Administration, Oral↗
Biomedical subjects
R B Nussenblatt
Publications and source records attributed to R B Nussenblatt.
Human lymphocyte responses against epitopes of a self antigen: a follow-up at different time points.
This study was aimed at examining the changes that may occur with time in the lymphocyte responses of an individual against peptide determinants of self antigens. Peripheral blood lymphocytes were collected from the same donor at seven different time points during a 10-month period and tested for their proliferative responses against whole human S-antigen and 40 overlapping peptides derived from the sequence of this uveitogenic retinal protein. Lymphocytes collected at different dates varied in their responsiveness to all tested antigens, as well as in the pattern of their response against individual peptides. The latter variability was expressed by differences in the hierarchical order of the most stimulatory peptides for lymphocytes collected at the seven time points. Despite the variability in their stimulatory capacity, six of the peptides exhibited their immunodominance by eliciting proliferation in lymphocytes collected at all time points. Our results thus indicate that data collected from a single sample of blood may be insufficient to accurately assess the level of cellular response to autologous antigens.
Amino Acid Sequence↗
CD8 T-cells are not essential for the induction of "low-dose" oral tolerance.
To examine whether CD8 T-cells are essential for the induction of "low-dose" oral tolerance, we tested animals deficient in CD8 T-cells, i.e., Lewis rats in which CD8 cells were eliminated by injections of specific antibodies and beta 2m(-/-) mice in which the CD8 cells are scarce and poorly functional. Oral tolerance was induced in the rats by repeated feedings with the uveitogenic retinal S-antigen, while in the mice the fed antigen was ovalbumin. Feeding reduced in both species the specific cellular immune response, measured by the lymphocyte proliferation assay. In the rats, this treatment also inhibited the development of the inflammatory eye disease, experimental autoimmune uveoretinitis. In addition, the levels of specific antibodies in the fed animals were moderately lower than those in their controls. Both the CD8-depleted rats and the beta 2m(-/-) mice resembled their normal controls in demonstrating reduced immune responses following feeding with the corresponding antigen. This observation thus indicates that CD8 T-cells are not essential for the induction of low-dose oral tolerance.
Administration, Oral↗
Experimental autoimmune uveitis and its relationship to clinical ocular inflammatory disease.
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Animals↗
Intraocular levels of methotrexate after intravenous administration.
PURPOSE: To determine if adequate intraocular levels of methotrexate are achieved after intravenous administration. METHODS: After intravenous administration, methotrexate levels were determined in the serum, the anterior chamber, and the cerebrospinal fluids of a patient with recurrent ocular lymphoma. A fluorescence polarization immunoassay was used to make the determinations. RESULTS: At seven hours into a 24-hour intravenous infusion, methotrexate was at cytotoxic level in all samples. At 74 hours, cytotoxic levels were present only in the aqueous humor. CONCLUSION: Sustained cytotoxic ocular methotrexate levels are achievable after systemic administration.
Anterior Chamber↗
A randomized, masked, cross-over trial of acetazolamide for cystoid macular edema in patients with uveitis.
PURPOSE: To study the effect of acetazolamide on cystoid macular edema in patients with uveitis. METHODS: Forty patients with chronic intermediate, posterior, or panuveitis associated cystoid macular edema were randomized into a masked, cross-over trial comparing acetazolamide versus placebo. Patients received an initial 4-week course of either acetazolamide or placebo (course A) followed by a 4-week washout period. They then received a 4-week course of the opposite study medication (course B). Primary endpoints included area of cystoid macular edema measured on late-phase views of fluorescein angiography and visual acuity. RESULTS: Thirty-seven patients completed the trial and were available for analysis; 17 (46%) were randomized to receive acetazolamide and 20 (54%) to receive placebo during course A. Acetazolamide resulted in a 0.5-disc area (25%) decrease in cystoid macular edema over that of placebo (P = 0.01; estimated treatment effect = -0.5 disc areas; 95% confidence interval, -0.9 to -0.1). However, there was no statistically significant effect of acetazolamide on visual acuity (P = 0.61; estimated treatment effect = 0.6 letters; 95% confidence interval, -2 to 3). CONCLUSIONS: A 4-week course of acetazolamide therapy results in a statistically significant but small decrease in cystoid macular edema in patients with chronic uveitis, and does not improve visual acuity. In contrast to previous studies in the literature, acetazolamide may have a more limited clinical benefit in patients with long-standing cystoid macular edema associated with chronic uveitis.
Acetazolamide↗
Primary retinal vasculitis. Systemic associations and diagnostic evaluation.
BACKGROUND: Inflammation of the retinal vasculature without an infectious etiology, systemic disease association, or concomitant ocular disease is termed primary retinal vasculitis, and can result in severe and permanent vision loss. Patients with primary retinal vasculitis usually are subjected to an extensive but unrewarding diagnostic evaluation. This study was undertaken to determine the value of such a diagnostic workup, and to determine whether systemic diseases develop in these patients during the course of their illness. METHODS: The clinical records of 25 patients seen between 1984 and 1994 with the referring diagnosis of primary retinal vasculitis were reviewed retrospectively. Recorded data included patient age, sex, race, medical history, medications, visual acuity, extent of retinal disease, and the results of their diagnostic evaluations. RESULTS: On presentation, none of the patients had an underlying systemic disease attributable as the cause of their retinal vasculitis. Review of systems was suggestive of an underlying systemic disease in 1 of 25 patients. Diagnostic evaluation in this patient showed a positive antinuclear antibody value and a double-stranded DNA, suggestive of systemic lupus erythematosus. Subsequently, systemic lupus erythematosus was diagnosed based on the development of other diagnostic criteria. The review of systems was not suggestive of an underlying systemic disease in 24 of 25 patients. False-positive diagnostic test results were obtained in 5 (20.8%) of these 24 patients. No underlying systemic disease associated with the patients' retinal vasculitis subsequently developed in any of these five patients (mean follow-up, 4 years). CONCLUSION: Few diagnostic tests should be ordered in patients with retinal vasculitis in the absence of a medical history suggestive of underlying systemic disease.
Adolescent↗
Fluorescein angiography in the progressive outer retinal necrosis syndrome.
PURPOSE: Progressive outer retinal necrosis syndrome is a devastating retinopathy seen primarily in patients with acquired immune deficiency syndrome. To provide additional details of the pathogenesis of this disease, the authors describe the evolution of clinical and fluorescein angiographic changes during the course of progressive outer retinal necrosis syndrome. METHODS: The authors performed serial clinical examinations, fundus photography, and fluorescein angiography in a patient with acquired immune deficiency syndrome with progressive outer retinal necrosis syndrome. Clinical and fluorescein angiographic findings were correlated to provide detailed sequential analysis of the pathologic changes occurring during the course of this disorder. RESULTS: The angiographic changes seen during the various stages of the disease consisted of zonal microvascular alterations, retinal pigment epithelium (RPE) destruction, and choroidal leakage. Retinal damage was correlated closely with regions of choroidal leakage and was clinically evident as outer retinal whitening. Disease reactivation occurred as a prominent brush-fire border of intense leakage involving the retina, RPE, and choroid. Extensive damage to the retinal vasculature and RPE was noted in the wake of clinical infection. CONCLUSIONS: The angiographic findings in our patient demonstrate that the progressive outer retinal necrosis syndrome is a retinochoroiditis that involves the full thickness of retina as well as the RPE and choroid. The inflammatory changes seen throughout the course of this disease correlate with the histopathologic patterns reported to date.
Acquired Immunodeficiency Syndrome↗
Visual prognosis and sympathetic ophthalmia.
Sympathetic ophthalmia is probably the ocular disorder best known to practitioners outside of ophthalmology. It is characterized by a bilateral, nonnecrotizing granulomatous panuveitis that occurs after intentional or unintentional trauma to the exciting eye. So far, the identity of the inciting antigen has not been delineated with certainty. The sequelae from sympathetic ophthalmia have declined markedly in this century as a result of earlier diagnosis, use of corticosteroids, and better management of ocular injuries, in large part due to improved surgical techniques. Cases of sympathetic ophthalmia, however, still occur with their severe sight-threatening complications, which impose on ophthalmologists the importance of prompt diagnosis and aggressive treatment in order to achieve good visual outcome.
Humans↗
Adenovirus-mediated gene transfer of ornithine aminotransferase in cultured human retinal pigment epithelium.
PURPOSE: To evaluate the efficacy of adenovirus mediated transfer of ornithine delta-aminotransferase (OAT) into human retinal pigment epithelial (RPE) cells. METHODS: Adenovirus-mediated gene transfer into primary cultures of human RPE was evaluated by measurement of enzyme activity in whole cell extracts and by Western blot analysis. To assess mitochondrial integrity, succinate dehydrogenase activity was measured in transduced RPE cells. Expression of adenovirus early genes was evaluated using reverse transcription-polymerase chain reaction. RESULTS: OAT activity, which was 65 nmol/mg.hour in untransduced cells, could be increased to levels in excess of 20,000 nmol/mg.hour using an adenovirus vector carrying the OAT cDNA. There was, however, a significant reduction in succinate dehydrogenase activity associated with OAT activity greater than 12,000 nmol/mg.hour. Transduced human RPE displayed an altered morphology that appears to be a response to the vector because similar changes could be induced by an adenovirus vector that does not carry the OAT cDNA. Adenovirus early gene expression was detected in transduced RPE. CONCLUSIONS: This study represents a first step in the development of intraocular gene replacement therapy for the treatment of gyrate atrophy. The authors demonstrate that adenovirus is an efficient vehicle for the delivery of OAT into human RPE and that RPE will tolerate greater than a 150-fold increase in OAT-specific activity. Evidence for disruption of mitochondria when OAT activity exceeds 12,000 nmol/mg.hour and vector-induced toxicity indicate that more controlled transgene expression and refinement of the vector systems is needed.
Adenoviruses, Human↗
Periocular inflammation in mice with experimental systemic lupus erythematosus. A new experimental blepharitis and its modulation.
Experimental systemic lupus erythematosus (SLE) can be induced in mice by immunization with a human monoclonal anti-DNA Ab, bearing a major Id 16/6Id. Immunized mice initially produce Abs to 16/6Id, DNA and nuclear Ags, and subsequently develop various clinical manifestations including leukopenia and renal immune complex disease. MHC class I Ags play a critical role in the induction and progression of experimental SLE. The present study reports that ocular changes also occur in mice with experimental SLE. The ocular disease is characterized by bilateral subacute and chronic inflammation of the eyelids (blepharitis) with immune complex IgG deposition and hypertrophic meibomian glands. The severity of ocular changes was strain dependent: most severe in 129 mice, less intense in BALB/c animals and only minimal in C3H.SW mice. No blepharitis developed in mice deficient in MHC class I expression. Further, the disease was strongly inhibited in BALB/c mice treated with methimazole, an agent that has been shown to repress transcription of MHC class I. In these cases, there was no IgG deposition and a decreased infiltration of inflammatory cells in the eyelids. These observations thus suggest that, similar to the observation with experimental SLE, MHC class I is critical in the onset of this experimental autoimmune blepharitis. The new experimental eye disease described here provides an animal model for chronic blepharitis in humans, a common condition for which such a model has been sought.
Animals↗
Synergistic effect of rapamycin and cyclosporin A in the treatment of experimental autoimmune uveoretinitis.
Immunosuppressive drugs currently available for the treatment of autoimmune diseases display a narrow therapeutic window between efficacy and toxic side effects. The use of combinations of drugs that have a synergistic effect may expand this window and reduce the risk of toxicity. We evaluated the combination effect of rapamycin (Rapa) and cyclosporin A (CsA) in an autoimmune disease model of the eye. The dose-effect relationship of Rapa with CsA was measured in vitro on the inhibition of proliferation of retinal S-Ag-primed lymphocytes. A median effect analysis was performed and a combination index (CI) calculated for 50% inhibition of proliferation. Rapa and CsA were markedly synergistic over a wide dose range (lowest CI = 0.31). Calculated dose reduction factors indicated that Rapa could be reduced nine-fold and CsA reduced five-fold when these drugs were used in combination. These reduced doses were tested in vivo for the treatment of experimental autoimmune uveoretinitis (EAU). Twelve of 15 rats treated with CsA, 2 mg/kg/day, developed EAU with a median severity of 2.5. Fourteen of 15 rats treated with Rapa, 0.01 mg/kg/day, developed EAU with a median severity of 3.25. Complete inhibition of EAU was achieved in all 15 animals treated with the combination of Rapa and CsA (combined vs CsA alone, p < 0.0002; combined vs Rapa alone, p < 0.00001). The demonstrated synergistic relationship between Rapa and CsA will allow the use of reduced doses of each drug to achieve a therapeutic effect. The use of lower doses may reduce the toxicity of these drugs for the treatment of autoimmune uveitis.
Animals↗
32 cases of sympathetic ophthalmia. A retrospective study at the National Eye Institute, Bethesda, Md., from 1982 to 1992.
OBJECTIVE: To examine the relationship between visual outcome and the clinical management of patients with sympathetic ophthalmia. METHODS: Thirty-two patients with sympathetic ophthalmia who were seen at the National Eye Institute, Bethesda, Md, between 1982 and 1992, were retrospectively reviewed. RESULTS: There were equal numbers of males and females. Sympathetic ophthalmia occurred after trauma in 23 patients and surgery in nine patients. Sixteen of the 32 patients had a final visual acuity of 20/40 or better; 10 patients had a visual acuity worse than 20/200. Good visual outcome was associated with early and aggressive treatment with corticosteroids, sometimes in combination with other immunosuppressive agents. Poor visual acuity was associated with glaucoma, chorioretinal scars in the macula, and persistent uncontrolled inflammation. CONCLUSION: Prompt and aggressive use of antiinflammatory therapy can improve the visual outcome of patients with sympathetic ophthalmia.
Adolescent↗
Interleukin-10 in the vitreous of patients with primary intraocular lymphoma.
PURPOSE: To find an accurate and simple method to diagnose primary intraocular lymphoma. METHODS: We prospectively analyzed concentrations of interleukin-10, interleukin-1, interleukin-2, interleukin-4, and interleukin-6 in vitrectomy specimens from three patients with primary intraocular lymphoma and five patients with uveitis by enzyme-linked immunosorbent assay. RESULTS: Interleukin-10 in the vitreous was detected in patients with primary intraocular lymphoma. Interleukin-10 levels correlated with clinical activity and the number of malignant cells. CONCLUSION: Concentrations of interleukin-10 in the vitreous may be a helpful clue to both clinicians and pathologists in diagnosing primary intraocular lymphoma.
Enzyme-Linked Immunosorbent Assay↗
Monoclonal antibodies against CD54 (ICAM-1) and CD11a (LFA-1) prevent and inhibit endotoxin-induced uveitis.
We studied the effect of monoclonal antibodies (mAbs) against CD54 (intercellular adhesion molecule-1; ICAM-1) and CD11a (lymphocyte function-associated antigen-1; LFA-1) on the prevention and treatment of endotoxin-induced uveitis (EIU). When treated at the time of endotoxin injection the mean number of inflammatory cells infiltrating the eye +/- S.E.M. on histologic sections was 469.2 +/- 51.9 for controls, 13.8 +/- 2.6 for rats receiving anti-ICAM-1 mAb (P < 0.0001), and 195.8 +/- 48.8 for rats receiving anti-LFA-1 mAb (P = 0.0003). When treated after the start of inflammatory disease, the mean number of infiltrating inflammatory cells +/- S.E.M. was 273.0 +/- 30.7 for controls, 6.4 +/- 1.7 for rats receiving anti-ICAM-1 mAb (P < 0.0001), and 54.2 +/- 7.6 for rats receiving anti-LFA-1 mAb (P < 0.0001). The mean number of cells per milliliter of aqueous humor +/- S.E.M. was 1867.6 +/- 321.8 for controls, 21.7 +/- 5.3 for rats receiving anti-ICAM-1 mAb (P < 0.0001), and 295.1 +/- 71.2 for rats receiving anti-LFA-1 mAb (P < 0.0001). MAbs against ICAM-1 and LFA-1 significantly inhibited the development of EIU and were effective in treating clinically evident ocular inflammatory disease.
Animals↗
Inhibition of experimental autoimmune uveoretinitis by mycophenolate mofetil, an inhibitor of purine metabolism.
Mycophenolate mofetil (MM), an inhibitor of purine metabolism, was found to effectively inhibit the development of experimental autoimmune uveoretinitis (EAU) induced by S-antigen (SAg) in Lewis rats. MM completely inhibited EAU development in the majority of rats when administered daily, on days 0-13, at a dose of 30 mg kg-1 day-1. The drug was less effective, however, when given on days 7-20: minimal disease inhibition was achieved with the drug at 30 mg kg-1 day-1, although at 60 mg kg-1 day-1 the drug inhibited EAU development in most treated rats during the period of its administration. MM also completely inhibited in most treated rats the development of EAU adoptively transferred by SAg-sensitized lymphocytes, thus depicting its capacity to inhibit the efferent limb of the immune response. Treatment with MM also suppressed the cellular and humoral immune responses against SAg, with a good correlation being observed between the inhibition of these responses and suppression of EAU in the different groups of rats. MM is currently being examined for its immunosuppressive effects in humans and the data recorded here thus suggest this compound may be useful in treatment of immune-mediated uveitic conditions.
Animals↗
Combined intravenous ganciclovir and foscarnet for children with recurrent cytomegalovirus retinitis.
PURPOSE: Children with the acquired immune deficiency syndrome (AIDS) and cytomegalovirus (CMV) retinitis may not complain of symptoms despite the presence of advanced sight-threatening disease. Although little data exist regarding CMV retinitis in this population, the treatment of this disease may be difficult because of frequent, extensive recurrences after reduction of drug dose from induction to maintenance levels. The authors reported the results of the use of combined ganciclovir and foscarnet for treatment of recurrent CMV retinitis in three children with AIDS. METHODS: Three children with recurrent CMV retinitis were treated with combined ganciclovir and foscarnet administered intravenously. All patients initially received induction dosages of ganciclovir followed by maintenance therapy, at which time they experienced reactivation of their disease. The dosing regimen for induction with the combined therapy was foscarnet (60 mg/kg every 8 hours) and ganciclovir (5 mg/kg daily for 3 weeks). Maintenance with combined therapy consisted of foscarnet (90 mg/ kg daily) and ganciclovir (5 mg/kg daily). RESULTS: All patients showed complete healing of the retinitis during the first 3 weeks of combined therapy. Median survival after initiation of combined therapy was 15 weeks (range, 12-33 weeks). None of the children experienced reactivation of CMV retinitis during combined therapy with ganciclovir and foscarnet. Combined therapy was well tolerated in all patients without major side effects. No patient required discontinuation or interruption of either drug during combined therapy. CONCLUSION: Children with recurrent CMV retinitis may not report visual symptoms, which can delay therapeutic intervention. Therefore, recurrent disease in children should be treated aggressively to avoid potentially devastating visual loss. A combination of ganciclovir and foscarnet appears to be a safe and effective therapeutic option for treatment of recurrent CMV retinitis in children with AIDS. This approach causes no additional toxic reactions and may provide improved long-term control of recurrent CMV retinitis in children.
AIDS-Related Opportunistic Infections↗
Effects of topical FK506 on endotoxin-induced uveitis (EIU) in the Lewis rat.
FK506 is a macrolide antibiotic and a potent immunosuppressant. To investigate the effect of topical FK506 on acute ocular inflammation, we evaluated its action on the development of endotoxin-induced uveitis (EIU). At two different concentrations of 0.05% and 0.3%, topical FK506 was applied to Lewis rats with EIU. In aqueous, the mean number of inflammatory cells per microliter +/- SEM was 2,389 +/- 1,277, 1,571 +/- 1,562, 898 +/- 882, and 69 +/- 152 for rats treated with vehicle alone, 0.05%, 0.3% FK506, and 1% prednisolone acetate. The median of histological grades was 2, 1.5, 0.8, and 0.5 for animals treated with these 4 different regimens respectively. Analysis of aqueous protein showed a small reduction in FK506-treated animals. Mean blood levels of FK506 were low in rats treated with topical FK506 (0.05%, 0.84 ng/ml; 0.3%, 2.0 ng/ml) suggesting that its therapeutic effect was not secondary to the systemic absorption of the drug. Although FK506 is not as effective as prednisolone, 0.3% FK506 produced significant decreases in the mean aqueous inflammatory cell number and histological inflammatory score as compared to control vehicle alone. We conclude that topical FK506 can suppress EIU in a dose-dependent fashion and may be an alternative medication for patients with anterior uveitis and contra-indication to topical steroid.
Administration, Topical↗