Detection of molecular changes in primary intraocular lymphoma by microdissection and polymerase chain reaction.
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Adult↗
Biomedical subjects
R B Nussenblatt
Publications and source records attributed to R B Nussenblatt.
Reduction of cyclosporine dosage with ketoconazole in a patient with birdshot retinochoroidopathy.
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Chorioretinitis↗
Retrovirus-mediated gene transfer of ornithine-delta-aminotransferase into keratinocytes from gyrate atrophy patients.
Gyrate atrophy is a progressive blindness associated with deficiency of ornithine aminotransferase (OAT). The strategy of using an autologous keratinocyte graft, modified to express high levels of OAT as an ornithine-catabolizing skin-based enzyme sink, is investigated. Two OAT-containing retroviral vectors were constructed with or without a resistance gene. When packaged in a retroviral vector particle generated with the gibbon ape leukemia (GALV) virus envelope (PG13), these vectors could readily transduce >50% of target keratinocytes. The transduced keratinocytes in culture expressed up to 75-fold more OAT than normal control keratinocytes and these gene-modified cells extracted [14C]ornithine more efficiently than controls. The vector prepared without neo transduced cells more efficiently and led to higher levels of OAT expression than the neo-containing vector. Ornithine catabolism was maintained at high levels when the transduced patient keratinocytes were differentiated in vitro as a multilayered cutaneous organoid.
3T3 Cells↗
Therapeutic effect of combination antiretroviral therapy on cytomegalovirus retinitis.
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AIDS-Related Opportunistic Infections↗
Immunologic mechanisms of uveitis. New targets for immunomodulation.
The uvea consists of the choroid, ciliary body, and iris, and inflammation of the uveal tract is termed uveitis. Nevertheless, uveitis is commonly used to more generally describe intraocular inflammation involving not only the uvea, but also the retina, vitreous, and sclera. Fifty years ago, infectious organisms such as syphilis and tuberculosis were thought to be the cause of most forms of uveitis. Since that time, many causes of uveitis have been described as infectious and noninfectious. Scientists have shown that the immune response plays a critical role in the development of infectious and noninfectious forms of the disease. With a more detailed understanding of the immune mechanisms leading to the development of uveitis, we are now able to develop new therapeutic approaches based on targeting various components of the immune response.
Adjuvants, Immunologic↗
Association of interleukin 10 in the vitreous and cerebrospinal fluid and primary central nervous system lymphoma.
BACKGROUND: Diagnosis of primary central nervous system lymphoma (PCNSL) is usually made by identifying malignant lymphocytes in the brain, cerebrospinal fluid (CSF), or vitreous. However, these cells are few and friable, and misdiagnosis can occur, even in properly prepared specimens. Recent data suggest that levels of interleukin 10 (IL-10) are elevated in the serum and vitreous of patients with non-Hodgkin lymphoma; levels of interleukin 6 (IL-6) are elevated in the vitreous of patients with intraocular inflammation unrelated to a malignant neoplasm. We investigated whether PCNSL involving the vitreous or CSF is associated with elevated ratios of IL-10 to IL-6. PATIENTS: Vitreous specimens were obtained from 5 patients with PCNSL involving the eye and from 13 control patients with intraocular inflammation not related to a malignant neoplasm; CSF specimens were obtained from 11 patients with PCNSL. RESULTS: Levels of IL-10 exceeded those of IL-6 in all 5 patients with intraocular lymphoma but in none of the 13 patients with uveitis (P < .001). In patients with PCNSL, levels of IL-10 exceeded those of IL-6 in 6 of 11 CSF samples with malignant cells compared with 7 of 53 samples without malignant cells (P = .01). The calculated odds ratio (OR) suggests that the risk for malignant involvement of the CSF is about 8 times higher when IL-10 levels exceed IL-6 levels. METHODS: Levels of IL-10 and IL-6 were determined by enzyme-linked immunosorbent assay in both vitreous and CSF specimens. CONCLUSIONS: The occurrence of PCNSL in the eye was strongly associated with elevated vitreous levels of IL-10 relative to levels of IL-6. Moreover, among patients with diagnosed PCNSL, malignant cells were significantly more likely to be present in CSF when levels of IL-10 exceeded those of IL-6.
Central Nervous System Neoplasms↗
Ganciclovir implant exchange. Timing, surgical procedure, and complications.
BACKGROUND: The ganciclovir implant is effective for the treatment of cytomegalovirus (CMV) retinitis. The device eventually runs out of drug, however, and must be replaced. We report our experience with exchanging ganciclovir implants during the course of a randomized clinical trial. METHODS: During our study, patients with newly diagnosed peripheral CMV retinitis were treated with a ganciclovir implant. The implant was scheduled for exchange at 32 weeks. It was exchanged earlier if progression of CMV retinitis occurred. Patient examinations and standard fundus photography were performed at 2-week intervals after the exchange procedure. RESULTS: Twenty-six exchange procedures were performed. Twenty-two eyes in 15 patients received a second implant and 4 eyes in 4 patients later received a third implant. Cytomegalovirus retinitis was rendered or maintained inactive in 22 of 23 cases with more than 1 month of follow-up after the second or third implants. Complications after the second implant procedure included transient vitreous hemorrhage in 5 eyes, postoperative inflammation in 1 eye, and retinal detachment in 1 eye. Median visual acuity returned to 20/25 by 28 days and to 20/20 by 42 days. Complications after the third implant procedure included dense vitreous hemorrhage in 3 of 4 eyes. Median survival time after a second implant procedure was 89 days. CONCLUSIONS: The initial ganciclovir implant exchange procedure is well tolerated with continued long-term control of CMV retinitis. Multiple reentries through the same wound may be associated with an increased risk for vitreous hemorrhage.
Antiviral Agents↗
Apoptosis in patients with posterior uveitis.
BACKGROUND: Apoptosis plays a part in the pathogenesis of autoimmune diseases. OBJECTIVE: To investigate the expression of apoptotic markers in the eyes of patients with uveitis. METHODS: With the use of immunohistochemical and in situ apoptotic detection techniques, apoptotic molecules (Fas or Fas ligand [FasL]) and nuclear DNA fragmentation were examined in 8 enucleated eyes with Behçet's disease (1), sarcoidosis (1), subretinal fibrosis and uveitis (1), sympathetic ophthalmia (4), and the Vogt-Koyanagi-Harada syndrome (1); in 5 chorioretinal biopsy specimens with acute retinal necrosis (2), multifocal choroiditis (1), sarcoidosis (1), and subretinal fibrosis and uveitis (1); and in 3 normal control eyes. RESULTS: Fas and FasL were constitutively expressed in the normal human retina, but they were expressed much less in the choroid. Increased expression of Fas and FasL was found in the retina, chorioretinal scar, and choroidal granulomas in uveitic eyes. However, Fas and FasL expression was absent in the biopsy specimens with acute retinal necrosis, and little Fas or FasL was noted on infiltrating lymphocytes. DNA fragmentation was also identified in eyes with chorioretinal scar and gliosis. CONCLUSIONS: Apoptosis occurs in uveitic eyes and may play a regulatory role in limiting ocular inflammation. In uveitic eyes, a dysregulation of the Fas-FasL apoptotic pathway may lead to gliosis and fibrosis.
Adolescent↗
Elevation of laser flare photometry in patients with cytomegalovirus retinitis and AIDS.
PURPOSE: To investigate an alteration of the blood-ocular barriers by laser flare photometry in patients with acquired immunodeficiency syndrome (AIDS) diagnosed with cytomegalovirus retinitis. METHODS: Serial laser flare photometry measurements from 31 eyes of 31 patients with AIDS and newly diagnosed cytomegalovirus retinitis were compared with measurements from 31 control patients with AIDS but without documented eye disease. Location and extent of retinitis, presence of visual symptoms, and CD4 lymphocyte counts were also compared with laser flare photometry readings. RESULTS: Laser flare readings (mean +/- SE) were significantly higher in eyes with (13.0 +/- 1.5 photon counts per msec) than without cytomegalovirus retinitis (4.9 +/- 0.3 photon counts per msec) (P < .001). Lesions within the arcade vessels resulted in significantly higher laser flare photometry readings (17.3 +/- 2.5 photon counts per msec) compared with peripheral retinitis (9.8 +/- 1.5 photon counts per msec) (P = .01). A significant correlation was found between area of involvement of peripheral retinitis and laser flare photometry readings (P = .008). Readings in patients without cytomegalovirus retinitis increased significantly 10 months after the first measurement (9.5 +/- 1.9 photon counts per msec) (P = .04). Readings in patients with cytomegalovirus remained elevated 3 months after successful treatment of retinitis (12.3 +/- 2.3 photon counts per msec) (P = .6). CONCLUSIONS: Laser flare photometry readings are significantly elevated in eyes with cytomegalovirus retinitis, suggesting a breakdown of the blood-ocular barriers. Increasing laser flare photometry readings over time in patients without known ocular disease suggests that HIV infection may cause progressive breakdown of the blood-ocular barrier.
Acquired Immunodeficiency Syndrome↗
Treatment of uveitis by oral administration of retinal antigens: results of a phase I/II randomized masked trial.
PURPOSE: To evaluate the effect and safety of the oral administration of retinal antigens as a treatment of ocular inflammation. METHODS: In a phase I/II randomized masked trial, patients with endogenous uveitis who were dependent on immunosuppressive agents were randomly assigned to receive either 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 then made to taper patients completely off their standard immunosuppressive therapy over an 8 week period. The primary study endpoint was time to ocular inflammatory attack. The secondary study endpoint was the ability to taper patients completely off their immunosuppressive or cytotoxic medication within 8 weeks. RESULTS: Time to development of the main study endpoint was not statistically significantly different for any of the four treatment groups. However, the group receiving the purified S antigen alone appeared to be tapered off their immunosuppressive medication more successfully compared with patients given placebo (P = .08), whereas all the other groups appeared to do worse than did those receiving placebo. No toxic effects attributable to any treatment were observed. CONCLUSIONS: This phase I/II study is the first to test the use of orally administered S antigen in the treatment of uveitis. Although not statistically significant, patients given S antigen were more likely to be tapered off their chronically administered systemic immunosuppressive therapy than were the other groups tested.
Administration, Oral↗
Long-term follow-up of patients with chronic uveitis affecting the posterior pole treated with combination cyclosporine and ketoconazole.
PURPOSE: Combined treatment with cyclosporine (CsA) and ketoconazole in autoimmune diseases has received little attention. This article reports the outcome of a pilot study in patients receiving combination therapy for chronic uveitis affecting the posterior pole. METHODS: Six patients initially treated with CsA and oral prednisone were observed prospectively on a combination of CsA, prednisone, and ketoconazole. Data were analyzed for visual acuity, number of flare-ups, and signs of systemic toxicity. RESULTS: Patients were treated with CsA for a mean of 13 months and CsA-ketoconazole for a mean of 33 months. Although patients had a number of flare-ups before combination therapy, only two flare-ups in two patients were noted during combined therapy (P = 0.055). Three patients showed signs of renal toxicity on CsA, and two continued to show signs of toxicity on CsA-ketoconazone. One patient stabilized and maintained normal renal parameters. Using CsA, three of six patients showed elevations of systolic and diastolic pressure. After switching to CsA-ketoconazole, the patient's systolic pressure remained unchanged, and the diastolic pressure returned to normal in all patients (P = 0.03). No toxicity related to ketoconazole alone was observed. CONCLUSION: A combination of CsA and ketoconazole is effective in the treatment of chronic uveitis affecting the posterior pole. It appears to be more effective in preventing recurrences than does CsA alone and does not lead to an increased risk of renal toxicity.
Adult↗
Perspectives on gene therapy in the treatment of ocular inflammation.
Gene therapy may become a powerful therapeutic strategy. However, the application of this method in the treatment of ocular disease presents us with interesting and unique questions. Gene therapy for ocular inflammatory disease has the potential for both therapeutic interventions and a method for studying mechanism of disease. An evolving philosophy on this subject would support the use of somatic gene therapy for ocular inflammatory disease, even if not life threatening. Major technical questions remain, including the use of the appropriate vector, the best methodology for the stable insertion into the genome, and the duration and intensity of expression of the transgene. Various transgenes encoding a wide variety of proteins can be envisaged for the insertion of genes. The study of gyrate atrophy, an hereditary ocular disorder and an excellent candidate for gene therapy, has given us enormous information in the development of practical therapeutic strategies, as have in vitro studies of gene insertion. Future concerns will need to concentrate 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. The use of gene therapy as a drug delivery system must also be considered. In addition, the elucidation of the various events controlling transcription for the expression of transgenes in various resident ocular cells is necessary.
Apoptosis↗
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.
Acute Disease↗
Permissive recognition of immunodominant determinants of the retinal S-antigen in different rat strains, primates and humans.
The majority of antigenic peptides exhibit restriction in their interaction with the MHC molecules on antigen-presenting cells of different haplotypes. Certain peptides, however, are "permissive': they bind strongly to different MHC molecules and are selected as the immunodominant epitopes by animals using these MHC gene products. Here we show for the first time that several peptides from four regions of the sequence of human S-antigen (H-SAg), a retinal-specific protein, demonstrate high levels of permissiveness. Each of these peptides was found to be immunodominant in at least some of four inbred rat strains and five cynomolgus monkeys, immunized with whole H-SAg. Moreover, some of these peptides were recognized by lymphocytes from four normal controls and four patients with uveitis who responded against the H-SAg molecule. On the other hand, the permissive peptides stimulated marginal or no response in cultures of Lewis rats injected with adjuvant alone, or rat and human cell lines specific to other antigens, thus demonstrating that these peptides do not carry any non-specific mitogenic activity. One peptide, 29, which was found immunodominant in the monkeys, the uveitis patients and Lewis rats, is highly immunopathogenic in this rat strain. No good correlation between immunodominance and immunopathogenicity was found with other H-SAg peptides. The finding of cross-species permissiveness among peptides of H-SAg and similar observations with myelin proteins suggest that permissiveness could be quite prevalent among peptides of immunopathogenic antigens.
Adult↗
Uveitis in Behçet's disease.
The ocular complications of Behçet's disease are considered one of the major criteria upon which the diagnosis is based. Its complications are frequently sight threatening and require constant attention. The ocular disease is characterized by repeated, explosive ocular inflammatory attacks which get better by themselves, so that in-between attacks there is little or no evidence of inflammatory disease in the eye. The anterior segment can be involved alone, most frequently presenting as a severe anterior uveitis, frequently with hypopyon. This is not associated with a poor visual outcome, and usually treated with topical medication to make the patient more comfortable. However, the anterior segment disease is usually accompanied by recurrent retinal vaso-occlusive disease which is sight threatening if repeated attacks occur. Treatment is with systemic medications, including corticosteroids, cyclosporine, FK506, anti-metabolites, and cytotoxic agents. Complications of the inflammation can include retinal and optic atrophy, vitreous hemorrhage, neovascular glaucoma, and retinal detachment.
Adrenal Cortex Hormones↗
Use of topical FK506 in a corneal graft rejection model in Lewis rats.
PURPOSE: To evaluate the immunosuppressive effect of topical FK506 on allograft corneal rejection in rats. METHODS: Lewis rats were used as recipients and Fisher rats as corneal graft donors. In Experiment 1, all rats received intraperitoneally FK506 (0.3 mg/kg per day) for 7 days to ensure equal baseline parameters. The rats then were assigned randomly to treatment with topical 0.3% FK506 or vehicle alone. In another set of experiments, rats were treated only with topical treatment. The grafts were inspected by clinical evaluation. Corneas obtained at the time of maximum rejection were used for histology and immunohistochemistry. RESULTS: The selected combination of rat strains caused 100% graft rejection in untreated animals within 2 weeks after the penetrating keratoplasty. In the treated animals, rejection was delayed until the end of topical therapy. One third of corneal grafts remained clear until day 30. Histologic and immunohistochemical studies confirmed the clinical evaluations. Untreated rat corneas had a large number of infiltrating helper-inducer T cells, macrophages, interleukin-2 receptor-expressing cells, and Ia-antigen-expressing cells. At the same timepoint, topically treated corneas showed a limited inflammatory response characterized by a 2/3 reduction in the number of infiltrating helper and cytotoxic cells, and a five-fold decrease in the expression of class I and class II major histocompatibility antigens. CONCLUSIONS: Topical FK506 treatment is an effective way of preventing corneal graft rejection in the Lewis rat corneal graft model. It shows promise as a drug to prevent corneal graft rejection in humans.
Administration, Topical↗
Cytokine-dependent modulation of oral tolerance in a murine model of autoimmune uveitis.
In summary, our data suggest that oral tolerance in the mouse EAU model may occur by anergy/deletion or by suppression, depending on the feeding regimen. Tolerance involving putative regulatory cells appears to require the ability to produce both IL-4 and IL-10, whereas induction of tolerance involving anergy may not require the presence of Il-4 and IL-10. We propose that regulatory cells induced by three feedings of IRBP can be selectively enhanced through the use of cytokines. From the point of view of clinical therapy, it would be worthwhile to explore postimmunization feeding regimens involving administration of IL-4 and IL-10.
Administration, Oral↗
Intraocular inflammatory disease (uveitis) and the use of oral tolerance: a status report.
Intraocular inflammatory disease, or uveitis, is a disorder that mostly affects children and young adults. It is the cause of about 10% of the severe visual handicap in the United States. Many of the severe, sight-threatening uveitic conditions are thought to be driven by putative autoimmune mechanisms, often with high-dose oral prednisone use as treatment, along with cytotoxic agents, antimetabolites, and cyclosporine adjunctively. The feeding of the uveitogenic retinal S-Ag to rats immunized with the same antigen resulted in clinical protection. A pilot study in which two patients, one with pars planitis and the other with Behcet's disease, were fed with the retinal S-Ag resulted in these patients' immunosuppressive medication being decreased and/or stopped. The trial also provided us with information concerning dosage and expected immune responses. A randomized, masked study looking at the effect of feeding retinal antigens to uveitis patients is ongoing.
Administration, Oral↗