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Biomedical subjects

R Nussenblatt

Publications and source records attributed to R Nussenblatt.

At least 19 recordsLinked to original sources
PubMed2007

Interferon-beta and adhesion molecules (E-selectin and s-intracellular adhesion molecule-1) are detected in sera from patients with retinal vasculitis and are induced in retinal vascular endothelial cells by Toll-like receptor 3 signalling.

Retinal vasculitis is a major component of ocular inflammation that plays a role in retinal tissue damage in patients with idiopathic uveitis and Behçet's disease. Here we show that type 1 interferons (IFN alpha/beta) were not detected in sera from normal individuals but were identified in up to 46% of the sera from retinal vasculitis patients. The predominant form of IFN observed was IFN-beta, which was detected in 39% of Behçet's disease patients and 47% of idiopathic uveitis patients. Seven patients whose sera contained IFN-beta were monitored prospectively. IFN-beta was shown to be present for 6-12 months in all seven of the sera samples tested. Furthermore, the adhesion molecule profile identified in this study was strikingly different when Behçet's and uveitis patient sera were compared to sera from normal controls. Sera from Behçet's disease patients contained significantly elevated levels of the soluble adhesion molecules, sE-selectin and s-intracellular adhesion molecule-1 (sICAM-1), whereas sera from patients with idiopathic uveitis contained significantly increased sE-selectin. In vitro studies evaluating the cell source of these cytokines revealed that polyriboinosinic polyribocytidylic acid (poly I:C) activated retinal vascular endothelial cells produce sE-selectin, sICAM-1 and IFN-beta. Production of these molecules was inhibited by pretreatment with anti-Toll-like receptor 3 (TLR-3) antibody. In conclusion, IFN-beta, sE-selectin and sICAM-1 are elevated in patients with retinal vasculitis and are induced in retinal vascular endothelial cells in vitro by activating the innate immune system through TLR-3. Further analysis of innate immune signalling may prove to be a novel target for future studies on pathogenic mechanisms and therapeutic approaches in retinal vasculitis.

Acute Disease↗
PubMed1999

Gene therapy in the treatment of ocular inflammation.

Gene therapy may become a powerful therapeutic modality in the treatment of both ocular inflammatory disease and as a means of preventing rejection following tissue transplantation. By directly introducing into ocular cells genes that encode proteins capable of down-regulating the immune response, gene therapy has potential for both therapy and as a method for studying mechanisms of disease. While marked and rapid advances in the study of gene therapy have been realized, technical questions regarding the appropriate vector or the choice of efficacious immunomodulatory protein still remain.

Animals↗
PubMed1998

Chronic uveitis in guinea pigs infected with varicella-zoster virus expressing Escherichia coli beta-galactosidase.

There is no small animal model that replicates chickenpox and herpes zoster, which are caused by varicella-zoster virus (VZV). Therefore, to detect VZV in tissues of infected animals, the Escherichia coli beta-galactosidase gene was inserted into the viral genome. Intravitreal inoculation of guinea pigs with virus-infected cells resulted in a chronic uveitis, with mononuclear cells in the vitreous cavity of the eye of nearly all animals. Staining with X-gal demonstrated the presence of VZV in the ciliary body or iris of approximately 40% of the animals and in retinal pigmented epithelial cells in 4 animals. X-gal staining showed VZV in the eye of 1 animal 140 days after inoculation. These experiments indicate that VZV expressing beta-galactosidase is useful for detecting virus in tissues and that VZV can cause a chronic uveitis in which virus can be detected in some animals for up to 4 months.

Animals↗
PubMed1996

Advances in the management of AIDS-related cytomegalovirus retinitis.

Cytomegalovirus (CMV) retinitis, a common complication of the acquired immunodeficiency syndrome (AIDS), is increasing in frequency as patients infected with the human immunodeficiency virus (HIV) live longer. In recent years, the lifetime risk for CMV disease in HIV-infected persons has increased from 24.9% to 44.9%. Cytomegalovirus retinitis is usually diagnosed clinically: Almost all patients are CMV seropositive and have CD4+ counts less than 50 cells/mm3. Specific diagnostic tests that use antigen detection or quantitation of circulating nucleic acid to detect CMV are being developed, but they have not been validated for routine clinical use. Such tests would help predict disease, diagnose acute retinitis, and monitor therapy. Therapy with systemic agents, including intravenous ganciclovir, intravenous foscarnet, and intravenous cidofovir, is effective. However, it is cumbersome, costly, and associated with considerable toxicity, therapy encouraging investigation of other therapeutic approaches. Intravitreous injections with antiviral agents are effective, but the short half-life of available agents makes these injections inconvenient. Intraocular implants that slowly release ganciclovir have been effective for both acute therapy and long-term maintenance, but they need to be directly compared with intravenous and oral regimens to determine which regimen will optimally maximize convenience, preserve vision, and improve survival. Cytomegalovirus retinitis could be prevented by improved antiretroviral therapies or by immune-based therapies that would prolong the time during which patients remain immunocompetent. Once patients become immunologically susceptible to CMV end-organ disease (when their CD4+ counts decrease to < 50 cells/ mm3), specific chemotherapy with oral ganciclovir is promising, but the cost, inconvenience, toxicity, and conflicting reports of efficacy associated with this strategy mean that it needs careful assessment before it can be considered standard treatment. Management of CMV retinitis is on the verge of major changes. In the next few years, improvements in diagnostic, therapeutic, and preventive tools should reduce morbidity and mortality from this disease.

AIDS-Related Opportunistic Infections↗
PubMed1992

The expanding use of immunosuppression in the treatment of non-infectious ocular disease.

Cyclosporin has been used for an increasing number of ocular indications. This review attempts to put into perspective the present scope of cyclosporin use in the treatment of ophthalmic disorders. This includes a review of randomized masked trials performed to date and work done to minimize and characterize cyclosporin induced renal toxicity. In addition, the ocular surface is an ideal target for topical cyclosporin therapy, and the status of this therapeutic approach is reviewed.

Bromocriptine↗
PubMed1992

Hydrated clearance of gadolinium-DTPA as a measurement of glomerular filtration rate.

Technetium (99mTc)-diethylene triamine pentaacetic acid (DTPA) hydrated clearance studies are accurate for determining GFR but require special facilities for handling and measuring samples. We investigated the potential of a non-radioactive paramagnetic analog, Gadolinium (Gd)-diethylene triamine pentaacetic acid (DTPA), an approved NMR contrast agent, as a glomerular filtration marker. Instead of relying on the radioactivity of technetium, this test is based on the fact that gadolinium induces alterations in the NMR T1 relaxation times in blood and urine samples. Ninety patients underwent simultaneous determinations of GFR using 1 mCi of Tc-DTPA and 0.05 mmol/kg Gd-DTPA (Berlex Labs) IV. The patients were hydrated with oral and intravenous fluid. Following a one hour equilibrium period, three or four consecutive urine collections were obtained; plasma samples were acquired at the beginning and end of each approximately 20-minute interval. 99mTc-DTPA radioactivity was determined with a scintillation counter. T1 relaxation times were measured on a 10 MHz NMR spectrometer. These were converted to Gd-DTPA concentration by comparison with standard solutions. The Gd-DTPA derived GFR closely approximated the 99mTc-DTPA derived GFR which ranged from 15 to 147 ml/min. The equation and correlation coefficient of the regression line is y = 1.04 x -2.2, r = 0.94. Thus, Gd-DTPA is a safe, non-radioactive indicator of GFR that may provide an alternative renal clearance method for clinical studies of progressive renal disease and nephrotoxicity.

Contrast Media↗
PubMed1991

Ocular complications of Stevens-Johnson syndrome and toxic epidermal necrolysis in patients with AIDS.

Recent reports suggest that acquired immunodeficiency syndrome (AIDS) patients are at higher risk of developing mucocutaneous reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome (SJS). Resultant dry eye may be further exacerbated by human immunodeficiency virus (HIV) related lacrimal gland dysfunction and lead to a chronic keratoconjunctivitis. We report one patient with AIDS and toxic epidermal necrolysis and two patients with AIDS and SJS who developed severe dry eye misdiagnosed as infectious keratoconjunctivitis. Cicatrizing mucocutaneous reactions should be suspected in AIDS patients and the dry eye treated to control symptoms and prevent complications.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Liver injury from cyclosporine A.

To assess the incidence of cyclosporine A-induced hepatotoxicity, we retrospectively analyzed liver biochemical test results in 59 patients with endogenous uveitis who received cyclosporine A. All patients had normal liver tests before treatment and had at least six determinations during a 6- to 36-month course of therapy with cyclosporine A at a dose of 2-10 mg/kg/day. Thirty-four (58%) patients developed at least one abnormality of liver tests, and 19 (32%) had a prolonged pattern of abnormalities. The usual abnormalities consisted of a mild, transient increase in alkaline phosphatase levels occasionally accompanied by slight elevations in serum bilirubin and aminotransferase activities. Peak alkaline phosphatase levels ranged from 125 to 243 units/liter and persisted for seven days to 48 months. Thus, biochemical evidence of mild cholestatic liver injury was common in patients receiving cyclosporine A. These abnormalities are usually self-limited and asymptomatic but may cause diagnostic difficulty if a preexisting liver disease is present.

Adolescent↗
PubMed1990

Down-regulation of autoantibody levels of cyclosporine and bromocriptine treatment in patients with uveitis.

The administration of cyclosporine A, cyclosporine A plus bromocriptine, or bromocriptine results in down-regulation of antinuclear autoantibody levels in the sera of patients with uveitis. Decreased levels of autoantibodies against DNA, histones, cardiolipin, RNP, Sm, Ro (SS-A), and La (SS-B) were detected in the sera of patients with uveitis receiving cyclosporine A or cyclosporine A plus bromocriptine following 3 months of treatment. In contrast to the decreased antibody titers obtained following the treatment, the total immunoglobulin levels remained within the normal range. The results indicate that cyclosporine may affect B cell function, thereby yielding the observed decrease in autoantibody levels. This phenomenon might have clinical importance as a serological indicator of the efficiency of the patients to respond to the drug.

Autoantibodies↗
PubMed1989

ELISA HIV testing and viral culture in the screening of corneal tissue for transplant from medical examiner cases.

The spread of AIDS and its association with a retrovirus, commonly called T-lymphotropic virus type III (HIV) has produced great concern among those involved in transplantation about the possibility for transmission of this disease through tissue and organ transplant. Isolation of the virus from conjunctiva and tears further heightened this concern for corneal transplants. This review of medical examiner (ME) cases, a population in which high numbers of transplant corneas are retrieved, has revealed positive serologic tests for HIV in serum from 5 cases in 205 screens. These represent potential donors based on other standard medical criteria available at the time of collection. This tissue was also submitted for viral culture, and virus was recovered from the corneal tissue in McCarey-Kaufman (MK) media. These findings and case reviews are discussed.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Anti-Ia antibody diminishes ocular inflammation in experimental autoimmune uveitis.

An experimental model of inflammatory eye disease, experimental autoimmune uveitis (EAU), was established by injecting rats in the footpad with S-antigen in complete Freund's adjuvant. This model system was used to evaluate the role of major histocompatibility complex (MHC) class II antigens (Ia) in the pathogenesis of this T cell mediated disease. One day prior to S-antigen priming, rats were injected with either anti-Ia antibodies or with mouse ascites. Clinical and histopathological analysis of eyes from rats treated with anti-Ia antibody showed less ocular inflammation as well as a delay in onset of EAU when compared to controls (p = 0.01). Furthermore, immunocytochemical evaluation demonstrated that tissue obtained from animals receiving anti-Ia therapy also expressed less Ia antigen, as well as a diminution in the number of infiltrating macrophages and lymphocytes. These data show that anti-Ia treatment significantly modifies the course of EAU in the rat. In addition, this study suggests that MHC class II antigen expression may be involved in the initiation and continuation of immune responses that results in ocular inflammatory diseases.

Animals↗
PubMed1988

Ocular complications of the acquired immunodeficiency syndrome.

The acquired immunodeficiency syndrome (AIDS) affects the ocular structures in several ways. Kaposi's sarcoma has been observed on the bulbar conjunctiva of the globe. Retinal complications, however, are of major concern. Cotton-wool spots are commonly seen in AIDS patients and are usually of no consequence, except that they must be distinguished from the early stages of cytomegalovirus (CMV) retinitis, seen in 20-40% of these patients. CMV causes a necrotic-type retinitis potentially leading to blindness. 9-[2-Hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine (DHPG) has been found effective in the short-term treatment of this disorder. It is planned to use AS101 in the regimen to see if a long-term cure from this disease can be affected. Care must be taken in handling ocular tissue of AIDS patients or the re-use of ophthalmic instruments touching the eye of AIDS patients since the human immunodeficiency virus has been found in these structures.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Immunohistopathology of experimental uveitis induced by a non-ocular antigen.

Inflammation was induced in the eye by active and passive Arthus reactions using a non-ocular antigen and was examined by histologic and immunopathologic techniques. T cells were seen to infiltrate the eye when the inflammation occurred in the active Arthus reaction and were not seen after passive immunization. The findings were compared to those of experimental autoimmune uveoretinitis.

Animals↗
PubMed1986

Effect of 9-(1,3-dihydroxy-2-propoxymethyl) guanine on serious cytomegalovirus disease in eight immunosuppressed homosexual men.

Eight immunosuppressed homosexual men with cytomegalovirus viremia--seven with serious bilateral retinitis, one with colitis in addition to retinitis, and one with pneumonitis only--were treated with a new acyclovir derivative, 9-(1,3-dihydroxy-2-propoxymethyl) guanine, which has excellent in-vitro activity against cytomegalovirus. All patients had virologic and clinical improvement, but substantial leukopenia developed in three patients. Both clinical relapses and viral relapses occurred frequently, usually within 30 days after cessation of treatment. 9-(1,3-Dihydroxy-2-propoxymethyl) guanine represents the first clinically and virologically effective agent for the treatment of cytomegalovirus disease, but more effective and less toxic therapeutic regimens for both acute and chronic use must be developed.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Lymphocyte migration in the adoptive transfer of EAU.

Experimental autoimmune uveoretinitis (EAU) was transferred into naive male Lewis rats using 1 X 10(8) indium-111 labeled lymphocytes from syngeneic donors immunized with S-antigen. The migration of the lymphocytes was monitored by gamma camera imaging and by determining the accumulation of radioactivity in selected organs. The majority of the cells leave the peritoneal cavity within 24 hr and migrate to the liver, spleen, and thymus. Only a small fraction of the labeled cells reach the eye. However, there were significantly more labeled cells present in eyes that developed EAU as compared with controls using lymphocytes sensitized against bovine serum albumin. These results indicate the adoptive transfer of EAU is a complex process in which only a small number of transferred cells actually reach the eye to induce uveoretinitis.

Animals↗
PubMed1984

Unilateral cytomegalovirus retinochoroiditis and bilateral cytoid bodies in a bisexual man with the acquired immunodeficiency syndrome.

A 42-year-old bisexual man with the acquired immunodeficiency syndrome, cryptococcal meningitis, disseminated Mycobacterium avium-intracellulare with mycobacteremia, and oropharyngeal candidiasis developed unilateral retinitis and bilateral cotton wool patches. Histopathologic examination revealed unilateral necrotizing retinochoroiditis with virions in retinal and choroidal tissues. Postmortem cultures of retina and choroid were positive for cytomegalovirus.

Acquired Immunodeficiency Syndrome↗