tacrolimus and Uveitis

Human T-cell lymphotropic virus (HTLV) is the first discovered retrovirus causing malignancy in human. HTLV infection affects host's ocular tolerance and causes various diseases in the eye. Here we discuss the manifestations, mechanisms, treatments, and future directions of HTLV-related ocular diseases. RECENT FININGS: Recent serological researches showed that the number of HTLV-1 carriers in metropolitan area was increasing, although seroprevalence of HTLV-1 in general population was decreased after screening serological tests in blood donors started. The most common clinical entity of uveitis was still HTLV-1 uveitis in HTLV-1 highly endemic area, but prevalence of HTLV-1 uveitis varies in different parts of the world. As for treatment of inflammation, tacrolimus and 5-azacytidine were reported to be effective for autoimmune manifestations in HTLV-1-related overlap syndrome (deratomyositis/Sjogren's syndrome) and HTLV-1-related myelodysplastic syndrome. Interleukin-2 receptor targeted therapies improved scleritis in patients with adult T-cell leukemia/lymphoma caused by HTLV-1. Basic researches identified that HTLV-1 tax and HTLV-1 basic leucine zipper factor play critical roles in the HTLV-1-related disease and are now being investigated as targeted therapies.. Development of modern molecular biology makes it possible to reveal deep insights of HTLV-1-related ocular diseases. Although effective therapies based on basic researches have been reported, further endeavor is necessary to establish much more specific treatments of the ocular diseases.

Topics: Azacitidine; Enzyme Inhibitors; Human T-lymphotropic virus 1; Humans; Immunosuppressive Agents; Keratoconjunctivitis Sicca; Leukemia-Lymphoma, Adult T-Cell; Tacrolimus; Uveitis

Experimental autoimmune uveoretinitis (EAU) induced by immunization with retinal antigen (Santigen or interphotoreceptor retinoid-binding protein; IRBP) serves as an animal model of human uveoretinitis. As the first stage, we demonstrated the similarities between EAU and ocular inflammation in Behçet's disease by investigating anti-retinal antibodies, leukocyte migration inhibition by retinal antigen, immunogenic antigens, aberrant functions of neutrophils, and dominant Th1 lymphocyte reaction. From these findings, we verified that EAU, which is not associated with the systemic disorders observed in Behçet's disease, is an appropriate model for translational research targeting ocular inflammation. In the second stage, we set 3 therapeutic strategies for uveitis in Behçet's disease to be conducted in the translational research: (1) intraocular administration of an immunosuppressive drug; (2) inhibition of Th1 lymphocytes; and (3) activation of immunoregulatory cells. In strategy 1, our studies indicated that intravitreal injection of 10 microg of tacrolimus (FK 506) was not harmful to the retina and was predominantly effective in suppressing ongoing EAU in rats. In strategy 2, two approaches were adopted to prevent differentiation of Thl cells. One is anti-cytokine antibody therapy using anti-IL-12 monoclonal antibodies(mAb). The other is blockade of co-stimulatory signals, especially the ICOS-B7RP-1 pathway. Administration of anti-IL-12 mAb at the time of IRBP immunization completely inhibited development of EAU, and antagonistic anti B7RP-1 mAb suppressed the severity of EAU even when administered after development of EAU. In strategy 3, adoptive transfer of antigen presenting cells treated with a neuropeptide (vasoactive intestinal peptide or calcitonin gene-related peptide) or CD 4+ CD 25+ regulatory T cells suppressed EAU. We look forward to the day when therapies that are being developed in our translational research using EAU will become available for treating intraocular inflammation in Behçet's disease.

Topics: Adoptive Transfer; Animals; Antibodies, Monoclonal; Antigens, Differentiation, T-Lymphocyte; Autoimmune Diseases; Behcet Syndrome; CD28 Antigens; CD4-Positive T-Lymphocytes; Disease Models, Animal; Humans; Inducible T-Cell Co-Stimulator Protein; Interleukin-12; Interleukin-2 Receptor alpha Subunit; Neuropeptides; Rats; Retinitis; Tacrolimus; Th1 Cells; Uveitis

Uveitis, inflammation of the eye, is a common occurring disease resulting from a wide variety of traumatic and immunogenic insults and, in most cases, can be treated successfully by corticosteroids. However, corticosteroids have severe side effects. Alternative therapy is using nonsteroidal anti-inflammatory agents like indomethecin, diclofenac and flurbiprofen. The uveitic cases are prominent in the third world countries, and many of the patients are not responsive or become refractory to steroidal or nonsteroidal therapy. Therefore, there is another class of compounds "immunosuppressive drugs" found to be successful in treating uveitis. These include cyclosporin A, tacrolimus, and sirolimus. However, being immunosuppressive they also have side effects. Therefore, the effective therapy with lower side effects is the treatment with combination of these drugs in lower dosages. Cyclosporin A plus sirolimus or tacrolimus in threshold doses alleviate signs of uveitis with lower incidence of side effects.

Topics: Animals; Cyclosporine; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Sirolimus; Tacrolimus; Uveitis

Topics: Administration, Oral; Administration, Topical; Animals; Arrestin; Azathioprine; Chlorambucil; Cyclophosphamide; Cyclosporine; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Immunotherapy; Methotrexate; Rats; Steroids; Tacrolimus; Uveitis

Behçet's disease is an inflammatory disorder affecting many organs including the eye and one of the most common sight-threatening causes in countries around the Mediterranean basin and in the Asia including Japan, Korea and China. A number of clinical and laboratory findings suggest the significant involvement of the immune alterations in the pathophysiology and the pathogenic mechanisms of Behçet's disease. The immune alterations demonstrated in the disease include the alteration of the T cell circuitry and abnormal functions of the leukocyte. Because immunologic processes are believed to be in the chain of events in the manifestation of Behçet's disease, various agents capable of modulating the immune responses have been used to treat the disease. These drugs include corticosteroids, colchicine, cytotoxic agents, and immunophilin ligands (cyclosporine and FK506). This paper reviews the experimental and clinical investigations to analyze the immunopharmacological activities of these immunosuppressive agents in animal models and in patients with Behçet's disease.

Topics: Adrenal Cortex Hormones; Animals; Antineoplastic Agents; Behcet Syndrome; Colchicine; Cyclosporine; Humans; Immunosuppressive Agents; Immunotherapy; Ligands; Tacrolimus; Uveitis

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.

Topics: Adrenal Cortex Hormones; Anterior Eye Segment; Behcet Syndrome; Cataract; Colchicine; Cyclosporine; Humans; Tacrolimus; Uveitis; Vitreous Body

To compare tacrolimus monotherapy with tacrolimus and prednisone therapy for the maintenance of disease remission in subjects with noninfectious posterior segment intraocular inflammation (PSII).. Randomized, controlled, phase 2b, open-label, dual-center noninferiority trial.. Fifty-eight patients with sight-threatening PSII.. Patients requiring a second-line systemic immunosuppressive agent to control their PSII were treated with therapeutic doses of oral tacrolimus. Those subjects who subsequently were able to taper their prednisone dose to 10 mg daily without disease reactivation were assigned randomly either to stop prednisone or to continue 7.5 to 10 mg prednisone daily for 9 months.. Change in logarithm of the minimum angle of resolution (logMAR) visual acuity (VA) and rate of patient withdrawal resulting from treatment inefficacy or intolerance.. Thirty-five patients successfully tapered their prednisone to 10 mg daily. Of these, 16 were allocated randomly to receive tacrolimus monotherapy and 19 to continue taking prednisone and tacrolimus dual therapy. The difference in the mean change in VA for monotherapy compared with the dual therapy group was less than 1 logMAR letter (logMAR, -0.008; 95% confidence interval, -0.108 to 0.092; P = 0.870). The proportion of patients who tolerated treatment and maintained disease remission for 9 months after randomization also was similar in both groups (monotherapy, 62.5%; dual therapy, 68.4%; P = 0.694). All monotherapy treatment failures were the result of disease reactivation, whereas 50% of dual-therapy failures were the result of drug intolerance.. This study provides preliminary evidence that corticosteroids can be withdrawn in tacrolimus-treated patients who are able to achieve control of PSII with 10 mg prednisone daily, and any advantage of dual therapy in the prevention of disease reactivation was offset by its greater treatment intolerance. These findings support the further evaluation of corticosteroid-free treatment in future phase 3 trials (International Standard Randomised Controlled Trial Number Register identification, ISRCTN46576063).. Proprietary or commercial disclosure may be found after the references.

Topics: Administration, Oral; Adult; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Maintenance Chemotherapy; Male; Prednisone; Remission Induction; Tacrolimus; Treatment Outcome; Uveitis; Visual Acuity

A multicenter open study was conducted to investigate optimum dose schedule of FK506 on refractory uveitis associated with Behçet's disease and allied conditions. Fifty-three patients (41 with Behçet's and 12 with allied conditions) were enrolled in this study. A daily oral dose of FK506 was initially 0.05, 0.1, 0.15 or 0.2 mg/kg, but adjusted in more than half patients during the study based on clinical conditions of patients and/or adverse effects of FK506. The improvement rate of initial daily dose as well as final improvement rate were evaluated in the study. The improvement rate of initial daily dose was increased dose-dependently; 37.5% with 0.05 mg/kg initial daily dose group, 60.0% with 0.1 mg/kg, 91.7% with 0.15 mg/kg and 78.6% with 0.2 mg/kg. The final improvement rate was 76.5%. In patients with Behçet's disease, ocular symptoms improved in 30 (75.0%) of 40 patients evaluable for efficacy and the frequency of ocular attacks was significantly reduced. In eight (66.7%) of 12 patients with Behçet's disease in whom cyclosporin treatment had been failed, their ocular symptoms improved by FK506. Main adverse reactions of FK506 were renal impairment (28.3%), neurologic symptoms (22.6%), gastrointestinal symptoms (20.8%), hypomagnesemia (28.3%), hyperkalemia (13.2%), and hyperglycemia (13.2%. Most of the adverse effects disappeared or ameliorated after FK506 dose reduction or withdrawal from FK506 therapy. It seems that the incidence of the adverse effects depends on the dosage of FK506. The lower dosage (0.05 and 0.1 mg/kg) caused a relatively small number of adverse effects, and the higher dosage (0.15 and 0.2 mg/kg) caused them more frequently. Through level is recommended to maintain between 15-25 ng/ml during early days of treatment based on the safety and efficacy. It is also recommended that a initial daily dose is 0.15 mg/kg on the basis of the efficacy and safety results, and then adjusted based on symptoms of patients and whole blood through level of FK506.

Topics: Administration, Oral; Adolescent; Adult; Aged; Behcet Syndrome; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Tacrolimus; Uveitis

We studied the clinical effects of the immunosuppressive agent FK506 in patients with noninfectious uveitis.. This study was designed as a multicenter open clinical trial in Japan. Sixteen patients with noninfectious uveitis who had visited the Uveitis Survey Clinic of the Yokohama City University Hospital were given FK506. Eight had Behçet's disease; five, Vogt-Koyanagi-Harada syndrome; one, sympathetic ophthalmia; one, retinal vasculitis; and one, sarcoidosis. In patients with Behçet's disease, ocular attack score before and after therapy was compared to judge clinical status. For the other diseases, the ocular inflammatory symptoms were observed after the initiation of FK506 treatment. All patients underwent blood and urine examinations, electrocardiography, and chest x-rays before and after FK506 treatment.. Of the patients with Behçet's disease, five improved, one remained unchanged, one deteriorated, and the status of one could not be determined. Of the patients with Vogt-Koyanagi-Harada syndrome, four improved, and one remained unchanged. The patient with sympathetic ophthalmia improved, the patient with retinal vasculitis remained unchanged, and the status of the patient with sarcoidosis could not be determined. Major adverse effects were sensations of warmth, hypomagnesemia, renal dysfunction, glucose intolerance, nausea, vomiting, and disorders of the central nervous system. All adverse effects disappeared or improved when FK506 was stopped or when the dosage was decreased. Renal dysfunction and glucose intolerance appeared when the blood level of FK506 was high.. FK506 was effective in patients with uveitis, but it is important to monitor the occurrence of adverse effects.

Topics: Adult; Aged; Behcet Syndrome; Endophthalmitis; Female; Humans; Male; Middle Aged; Retinitis; Tacrolimus; Uveitis; Uveomeningoencephalitic Syndrome; Vasculitis

We performed a clinical open trial to evaluate the efficacy and the adverse side effects of a single therapy with FK506 in refractory uveitis as a multicenter study in Japan. Fifty-three patients (41 patients with Bechçet's disease, five with Vogt-Koyanagi-Harada disease, four with idiopathic retinal vasculitis, and three with other forms of uveitis) were enrolled in the study. FK506 was given orally for 12 weeks. Treatment with FK506 exhibited therapeutic effects in a dosage-dependent manner: the effectiveness was 38% in patients treated with an initial dosage of 0.05 mg/kg of body weight per day, 60% with 0.10 mg/kg of body weight per day, 83% with 0.15 mg/kg of body weight per day, and 79% with 0.20 mg/kg of body weight per day. Overall efficacy with dosage adjustment when needed was 76.5% at the conclusion of the study at the end of the 12th week. The FK506 therapy induced a variety of adverse side effects, the incidence of which depended on the dosage. The major side effects were renal impairment (28.3%, 15 of 53 patients), neurologic symptoms (20.8%, 11 of 53 patients), gastrointestinal symptoms (18.9%, ten of 53 patients), and hyperglycemia (13.2%, seven of 53 patients). The trough level of FK506 in the whole blood correlated with both the efficacy of the therapy and with the incidence of adverse effects. It is recommended to maintain the trough level between 15 and 25 ng/ml. On the basis of these results, a daily dosage of 0.10 to 0.15 mg/kg of body weight per day was suggested as an appropriate therapeutic dosage for refractory uveitis.

Topics: Administration, Oral; Adult; Aged; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Japan; Male; Middle Aged; Tacrolimus; Uveitis; Visual Acuity

Efficacy of a new immunosuppressive agent, FK506, in refractory uveitis was studied in 8 patients: 5 with Behcet's disease and 3 with idiopathic retinal vasculitis. The agent was given by oral administration every 12 hours. The previous therapy with systemic corticosteroids or immunosuppressive agents including cyclosporine failed to subside uveitis in these cases. During the observation period of 21.6 +/- 7.8 weeks (mean +/- SD) under FK506 at doses with 0.05, 0.1, 0.15 or 0.2 mg/kg/day, the visual acuity was increased in 44% of treated eyes, unchanged in 44% and decreased in 12%. The inflammatory activity in the ocular fundus was improved in 69% and unchanged in 6% of treated eyes. The effects of FK506 on uveitis by the criteria of improvement of visual acuity and uveitis activity was dose-dependent: 0.05 and 0.1 mg/kg/day were ineffective but 0.15 and 0.2 mg/kg/day were effective in most cases. One patient with Behcet's disease converted from cyclosporine developed moderate renal impairment in 4 weeks under FK506 and the therapy was discontinued in 8 weeks, though the uveitis activity as well as visual acuity was markedly improved. Other 7 cases had no side effect of FK506. Although the number of cases was small and observation period was short, the present clinical data indicate that FK506 is effective to treat refractory uveitis.

Topics: Administration, Oral; Adult; Aged; Animals; Antigens; Arrestin; Autoantigens; Autoimmune Diseases; Behcet Syndrome; Drug Evaluation, Preclinical; Eye Proteins; Female; Humans; Injections, Intraperitoneal; Male; Middle Aged; Rats; Rats, Inbred Lew; Tacrolimus; Uveitis; Vasculitis; Visual Acuity

Topics: Adolescent; Adult; Behcet Syndrome; Child; Child, Preschool; Creatinine; Female; Humans; Male; Tacrolimus; Uveitis

To evaluate the effectiveness of tacrolimus in patients with noninfectious intermediate, posterior, or panuveitis needing a two-immunosuppressive-agent regimen.. Design: Retrospective cohort study. Setting: Two tertiary-care uveitis practices at academic medical centers. Patient population: Thirty-two patients with noninfectious intermediate, posterior, or panuveitides in whom single-agent immunosuppression was inadequate to effect successful corticosteroid sparing. Intervention: tacrolimus, added as the second immunosuppressive agent. Main outcome measure: successful corticosteroid sparing, defined as inactive uveitis at a dose of prednisone ≤7.5 mg/day.. Active uveitis was present in 65.6% of patients at initiation of tacrolimus, and the median time to inactive uveitis was 1.5 months (95% confidence interval 1.2, 4.08). The median time to successful corticosteroid sparing was 3.9 months (95% confidence interval 1.41, 6.67), and by 6 months of follow-up successful corticosteroid sparing was achieved in 75% of patients. Tacrolimus was discontinued for side effects in five patients, three for tremor, and two for hyperglycemia. All side effects were reversible with tacrolimus discontinuation.. Tacrolimus seems to have efficacy as a second immunosuppressive agent in two-immunosuppressive drug regimens, when a single agent does not permit successful corticosteroid sparing. Side effects were reversible with tacrolimus discontinuation.

Topics: Humans; Immunosuppression Therapy; Immunosuppressive Agents; Panuveitis; Retrospective Studies; Tacrolimus; Treatment Outcome; Uveitis

This work was aimed to improve the efficacy of tacrolimus in the treatment of endotoxin-induced uveitis (EIU) using propylene glycol modified lipid vesicles termed as proglycosome nano-vesicles (PNVs). PNVs were prepared by modified film hydration method. Experimental uveitis in rabbit eye was induced by an intravitreal injection of 20 μL of the endotoxin solution containing 100 ng of lipopolysaccharide endotoxin. In vivo efficacy of PNVs was determined by studying clinical symptoms of uveitis using slit lamp examination and by quantitatively measuring levels of tumor necrosis factor-alpha, interleukin-6, leukocytes and total proteins in aqueous humor, 24 h after intravitreal injection of endotoxin. Comparison was made with healthy, untreated and tacrolimus solution treated eyes. PNVs developed were nano-sized, deformable and showed sustained release of tacrolimus over period of 12 h. In vivo results indicated statistically significant difference between the effects of PNVs in the treatment of EIU compared to tacrolimus. PNV treatment not only subsides clinical symptoms of uveitis but also prevented breakdown of blood aqueous barrier. Tacrolimus loaded PNVs are potential new topical treatment for uveitis.

Topics: Administration, Topical; Animals; Aqueous Humor; Endotoxins; Lipopolysaccharides; Rabbits; Tacrolimus; Uveitis

Tacrolimus has shown efficacy in eye inflammatory diseases. However, due to the drug lability, its formulation into a stable ophthalmic product remains a challenge. Tacrolimus-loaded nanocapsules (NCs) were designed for ocular instillation. Further, the stability and effects of the formulation were analyzed under different experimental conditions. Physicochemical characterization of the NCs revealed suitable homogeneous size and high encapsulation efficiency. Moreover, the lyophilized formulation was stable at ICH long term and accelerated storage conditions, for at least 18 and 3 months, respectively. The tacrolimus NCs did not elicit any eye irritation in rabbits after single- and multiple-dose applications. Additionally, ex vivo penetration assays on isolated porcine cornea and pharmacokinetics analyses in various rabbit eye compartments demonstrated the superiority of the NCs in retention and permeation into the anterior chamber of the eye compared to the free drug dissolved in oil. Moreover, multiple dose ocular instillation of the NCs in rats allowed high tacrolimus levels in the eye with very low plasma concentrations. Finally, the developed delivery system achieved a significant decrease in four typical inflammatory markers in a murine model of keratitis, an anterior chamber inflammation. Furthermore, these NCs, applied as eye drops, displayed clinical and histological efficacy in the mainly posterior chamber inflammation model of murine, experimental auto-immune uveitis.

Topics: Animals; Inflammation; Mice; Nanocapsules; Ophthalmic Solutions; Rabbits; Rats; Swine; Tacrolimus; Uveitis

Corticosteroids and macrolide immunomodulators such as tacrolimus are effective drugs for the topical treatment of inflammatory eye diseases like allergic conjunctivitis or dry eye. However, tacrolimus is practically insoluble in aqueous solutions and is therefore currently formulated as dispersion. This leads to low bioavailability. Here, we present a novel pharmacologically acceptable, aqueous formulation of tacrolimus based on the "Marinosolv formulation platform". Marinosolv allows the solubilization and thereby improvement of the bioavailability of many otherwise practically insoluble drugs, since dissolved drugs permeate faster into tissues, including ocular tissues. To visualize the benefits of Marinosolv in ophthalmic formulations, we investigated the permeation of a fluorescently labeled estradiol dissolved in Marinosolv compared to a formulation containing the compound as dispersion. Permeation was studied ex-vivo and in-vivo in porcine eyes. Further, we evaluated the improved permeation of topically applied tacrolimus dissolved in Marinosolv compared to a commercially available topically applied tacrolimus dispersion. The Marinosolv formulation was also compared to oral tacrolimus treatment, the standard application route for this drug in case of severe posterior uveitis. Finally, the ocular tissue levels of tacrolimus in all groups were determined using HPLC/MS. We demonstrated that tacrolimus dissolved in Marinosolv reached significantly higher levels in ocular tissues compared to the marketed topical product or after oral application and thus may be a suitable novel option for the treatment of several eye diseases, such as allergic conjunctivitis or uveitis. Thus, Marinosolv may be considered as a new vehicle for tacrolimus eye drops.

Topics: Administration, Ophthalmic; Administration, Oral; Animals; Biological Availability; Drug Compounding; Drug Evaluation, Preclinical; Excipients; Immunosuppressive Agents; Models, Animal; Ophthalmic Solutions; Solubility; Sus scrofa; Tacrolimus; Uveitis; Water

Corticosteroids remain the mainstay therapy for uveitis, a major cause of blindness in the working age population. However, a substantial number of patients cannot benefit from the therapy due to steroids resistance or intolerance. Tacrolimus has been used to treat refractory uveitis through systemic administration. The aim of this study was to evaluate the therapeutic potential of 0.03% tacrolimus eyedrop in mouse models of uveitis.. 0.03% tacrolimus in perfluorobutylpentane (F4H5) (0.03% Tacrolimus/SFA) was formulated using a previously published protocol. Tacrolimus suspended in PBS (0.03% Tacrolimus/PBS) was used as a control. In addition, 0.1% dexamethasone (0.1% DXM) was used as a standard therapy control. Endotoxin-induced uveitis (EIU) and experimental autoimmune uveoretinitis (EAU) were induced in adult C57BL/6 mice using protocols described previously. Mice were treated with eyedrops three times/day immediately after EIU induction for 48 h or from day 14 to day 25 post-immunization (for EAU). Clinical and histological examinations were conducted at the end of the experiment. Pharmacokinetics study was conducted in mice with and without EIU. At different times after eyedrop treatment, ocular tissues were collected for tacrolimus measurement.. The 0.03% Tacrolimus/SFA eyedrop treatment reduced the clinical scores and histological scores of intraocular inflammation in both EIU and EAU to the levels similar to 0.1% DXM eyedrop treatment. The 0.03% Tacrolimus/PBS did not show any suppressive effect in EIU and EAU. Pharmacokinetic studies showed that 15 min after topical administration of 0.03% Tacrolimus/SFA, low levels of tacrolimus were detected in the retina (48 ng/g tissue) and vitreous (2.5 ng/ml) in normal mouse eyes, and the levels were significantly higher in EIU eyes (102 ng/g tissue in the retina and 24 ng/ml in the vitreous). Tacrolimus remained detectable in intraocular tissues of EIU eyes 6 h after topical administration (68 ng/g retinal tissue, 10 ng/ml vitreous). Only background levels of tacrolimus were detected in the retina (2-8 ng/g tissue) after 0.03% Tacrolimus/PBS eyedrop administration.. 0.03% Tacrolimus/SFA eyedrop can penetrate ocular barrier and reach intraocular tissue at therapeutic levels in mouse eyes, particularly under inflammatory conditions. 0.03% Tacrolimus/SFA eyedrop may have therapeutic potentials for inflammatory eye diseases including uveitis.

Topics: Alkanes; Animals; Aqueous Humor; Disease Models, Animal; Eye; Humans; Inflammation; Mice; Mice, Inbred C57BL; Ophthalmic Solutions; Tacrolimus; Uveitis

To assess the safety and efficacy of noncorticosteroid triple immunosuppressive therapy in the treatment of refractory chronic noninfectious childhood uveitis.. Subjects were retrospectively selected from a database. Patients were included if they were diagnosed with chronic, noninfectious uveitis at 16 years of age or under and treated with triple immunosuppressive therapy for at least 6 months (following failure of a combination of 2 immunosuppressants). Patient demographics, diagnoses, duration of uveitis, drug dosages, active joint inflammation, and ophthalmologic data were recorded. Efficacy outcomes for triple therapy were recorded at 6 months.. Thirteen patients with bilateral uveitis were included. Using Standardized Uveitis Nomenclature (SUN) criteria, at 6 months only 11 eyes (42%) had a 2-step improvement in anterior chamber cell inflammation (n = 26). In addition, 2 patients required additional oral corticosteroid treatment. There were 4 significant infectious adverse events during a total of 21.9 patient-years (PY) on triple therapy (0.18 events per PY).. In this group of children with refractory uveitis, addition of a third immunosuppressive agent did not confer substantial benefit in redressing ocular inflammation and was associated with significant infections in a minority of patients.

Topics: Adolescent; Child; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Male; Methotrexate; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Treatment Outcome; Uveitis

To evaluate the in vivo release and ocular toxicity of a tacrolimus-loaded PLGA intravitreal implant.. Tacrolimus-loaded PLGA implants were inserted into the vitreous cavity of rabbits' eye. At different time points, the vitreous was retrieved and the concentration of tacrolimus released from the implants was determined. Clinical examination was performed to evaluate the implant tolerance.. PLGA implants provided controlled and prolonged release of tacrolimus. Approximately 99.97% of the drug was released from the devices at 6 weeks. Ophthalmic examination revealed no evidence of toxic effects of implants.. Tolerance and feasibility of the tacrolimus-loaded PLGA implants, as sustained intraocular drug delivery systems, were demonstrated.

Topics: Animals; Biocompatible Materials; Choroid; Drug Delivery Systems; Feasibility Studies; Female; Immunosuppressive Agents; Intravitreal Injections; Lactic Acid; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Prostheses and Implants; Rabbits; Retina; Sclera; Tacrolimus; Uveitis; Vitreous Body

Uveitis is a sight threatening inflammatory disorder that affects all ages and remains a significant cause of visual loss. Inflammatory activity plays an important role in the whole pathogenesis of uveitis. Treatment of uveitis is mainly driven by corticosteroids that have potential side effects. Recent investigations demonstrated that tacrolimus inhibits T-cell proliferation and suppresses release of inflammatory cytokines. Since tacrolimus is a definite immunosuppressive agent, and since inflammatory process has been involved in uveitis, the compound must have effect on the progression of uveitis through reduction in inflammatory activity. Even results of the clinical trials demonstrate that tacrolimus have useful role in treatment of sight threatening uveitis that is refractory to other therapy. Studies also indicate that long term use of tacrolimus is well tolerated. However, its use in uveitis is limited because of its poor physico-chemical properties including poor aqueous solubility and high molecular weight (822 Da). Therefore, we have proposed that tacrolimus nanoemulsion administered topically is a promising therapeutic approach to treat uveitis. Based on previous evidences, we have hypothesized that nanoemulsion formulation of tacrolimus can improve efficacy and safety profile of tacrolimus.

Topics: Administration, Topical; Emulsions; Humans; Immunosuppressive Agents; Tacrolimus; Uveitis

We aimed to compare the effects of intraperitoneal ghrelin and tacrolimus on vitreous levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6) in an experimental autoimmune uveitis model.. Twenty-four male rats, each weighing 300 g, were assigned into four groups, six rats in each. All the rats, except for those in group 1, were injected intravitreally with concanavalin a to induce experimental uveitis. The development of uveitis was confirmed by the histopathologic examination of two rat globes from each group. The rats in group 2 were not given any treatment after uveitis was induced. The rats in group 3 were administered 1 mg/kg/day of intraperitoneal tacrolimus on days 0, 1, 3, 5 and 7 following the induction of uveitis (on the 14th day of study). The rats in group 4 were given 10 ng/kg/day of intraperitoneal ghrelin for 7 days following the induction of uveitis. On the 21st day of the study, all rats were sacrificed, and the eyes enucleated were subjected to histopathologic examination. Vitreous levels of TNF-α, IL-1 and IL-6 were measured by the enzyme-linked immunosorbent assay method.. The histopathologic evaluation carried out to confirm the development of uveitis revealed destruction in the retinae and ciliary bodies of the immunized rats. The mean vitreous levels of TNF-α, IL-1 and IL-6 were significantly higher in the sham group than in the control group (p < 0.05). The levels of these three cytokines showed a significant decrease in the tacrolimus treatment group (p < 0.05). Cytokine levels decreased in the ghrelin treatment group relative to the control group; however, the decrease was not found statistically significant (p > 0.05).. Tacrolimus could be effective in uveitis treatment by neutralizing or decreasing the levels of cytokines such as TNF-α, IL-1 and IL-6 that have a critical part in the pathogenesis of uveitis. However, ghrelin failed to produce the desired effect. Further studies using different doses and different ways of administration are needed to determine the effective dose of ghrelin in uveitis.

Topics: Animals; Autoimmune Diseases; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Ghrelin; Immunosuppressive Agents; Injections, Intraperitoneal; Interleukin-1; Interleukin-6; Male; Rats; Tacrolimus; Tumor Necrosis Factor-alpha; Uveitis; Vitreous Body

To evaluate the therapeutic effects of topical tacrolimus ointment on refractory inflammatory ocular surface diseases.. Retrospective interventional consecutive case series.. In Severance Hospital, Seoul, South Korea, 0.02% tacrolimus ointment was topically applied 1 to 3 times per day, depending on disease severity, for up to 31 months in eyes of 12 consecutive patients with refractory inflammatory ocular surface diseases who had previously been treated with steroid therapy. Seven patients had chronic cicatrizing conjunctivitis (6 cases caused by Stevens-Johnson syndrome and 1 attributable to ocular cicatricial pemphigoid); 4 had scleritis (3 necrotizing scleritis, 1 recurrent nodular scleritis); and 1 patient had Mooren ulcer with corneal perforation. The therapeutic outcomes after tacrolimus treatment were evaluated according to the following criteria: change in clinical findings (eg, decrease of hyperemia, ocular pain, epithelial defect, and pseudomembrane), intraocular pressure (IOP), and need for steroid therapy.. In all 3 groups, tacrolimus showed an immunosuppressive effect, especially on scleritis and Mooren ulcer. These effects included suppression of corneoscleral melting and reduction of hyperemia. In chronic cicatrizing conjunctivitis, simultaneous topical tacrolimus while tapering steroid therapy suppressed inflammatory relapse. The elevated IOP in steroid responders recovered to normal range after successful tapering of steroid. No adverse side effects were noted after 1.5 to 31 months of continuous tacrolimus treatment.. The use of topical tacrolimus ointment is effective in controlling refractory inflammatory ocular surface disease, and can reduce the need for steroid use while reducing inflammation recurrence.

Topics: Administration, Topical; Adolescent; Adult; Aged; Child; Drug Resistance; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Retrospective Studies; Tacrolimus; Treatment Outcome; Uveitis; Young Adult

To determine whether intravitreal injection of tacrolimus suppresses ongoing experimental autoimmune uveoretinitis (EAU) in rats.. Rats were immunised with interphotoreceptor retinoid-binding protein peptide (R14) and given an intravitreal injection of tacrolimus on day 12 after immunisation. Intraocular inflammation was assessed by slit-lamp biomicroscopy and histopathological examination. Interferon gamma and tumour necrosis factor alpha protein levels in the ocular tissues were measured. Gene expression of chemokines was determined in ocular tissues by reverse transcription-polymerase chain reaction. To evaluate the systemic effect of intravitreal injection of tacrolimus, delayed-type hypersensitivity was measured by ear swelling.. Clinical and pathological scores showed that ocular inflammation of tacrolimus-treated eyes was markedly less than that of vehicle-treated eyes. The amount of interferon gamma and tumour necrosis factor alpha was considerably inhibited in tacrolimus-treated eyes. The gene expression of monocyte chemattractant protein-1 (MCP-1) and regulated upon activation, normal T cell expressed and secreted (RANTES) was markedly reduced in tacrolimus-treated eyes. Delayed-type hypersensitivity responses were not impaired in tacrolimus-treated rats.. Intravitreal injection of tacrolimus was highly effective in suppressing the ongoing process of EAU without any side effects on systemic cellular immunity. This treatment may be useful in the management of patients with severe uveitis.

Topics: Animals; Autoimmune Diseases; Cells, Cultured; Chemokines; Eye; Female; Gene Expression Regulation; Hypersensitivity, Delayed; Immunity, Cellular; Immunosuppressive Agents; Injections; Interferon-gamma; Macrophages; Rats; Rats, Inbred Lew; Retinitis; RNA, Messenger; Tacrolimus; Treatment Outcome; Tumor Necrosis Factor-alpha; Uveitis; Vitreous Body

To evaluate the long-term efficacy and tolerance of tacrolimus for the treatment of uveitis.. Retrospective case series.. Sixty-two consecutive patients with noninfectious uveitis treated with tacrolimus at a single academic referral center between April 2000 and April 2004.. A standard data set was obtained from patients' medical records and analyzed according to the recommendations of the Standardization of Uveitis Nomenclature Working Group.. (1) Rate of tapering oral prednisone to 10 mg daily, (2) requirement for alternative second-line immunosuppressive therapy, and (3) rate of tacrolimus dose reduction or discontinuation due to side effects.. In this cohort with well-established ocular inflammation, patients successfully tapered their oral prednisone to 10 mg daily at an average rate of 1.62 per patient-year (PY), with an 85% probability of achieving < or =10 mg after 1 year 2 months of treatment. Tacrolimus was discontinued due to intolerance at a rate of 0.13/PY. This was predominantly due to noncardiovascular adverse events, and rates of introducing or increasing concomitant treatment for hypertension, hypercholesterolemia, and diabetes mellitus were all below 0.05/PY. Creatinine rises of > or =30% were also notably uncommon (0.05/PY).. Tacrolimus's efficacy for the treatment of uveitis is maintained long-term, and its cardiovascular risk profile is excellent.

Topics: Adolescent; Adult; Azathioprine; Child; Cyclosporine; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Prednisone; Recurrence; Retrospective Studies; Tacrolimus; Treatment Outcome; Uveitis

We report a case of lichenoid sarcoidosis in a young girl treated by oral tacrolimus and methylprednisolone. The patient had had a skin eruption from 1 year of age and had developed uveitis at 2 years of age. Her sight had become affected by the uveitis at 8 years of age. When she was 14, she was admitted to the ophthalmology department of our hospital to start treatment with tacrolimus (FK506). She was referred to the department of dermatology for her skin lesions, which were flat, pinkish or normal skin-colored papules scattered on her extremities and the backs of her hands. Upon histology, epithelioid granulomas were seen in the upper dermis and around the erector pili muscles. She received tacrolimus (FK506) 6 mg/day for 3 months for her uveitis. The eye lesions subsided somewhat, and the skin lesions were almost healed after the 3-month course of tacrolimus. However, 4 months after stopping the tacrolimus, her skin and eye lesions relapsed. At that point, she was started on methylprednisolone 16 mg/day for her uveitis. With the methylprednisolone treatment, the inflammation of the eye lesion immediately healed, as did the skin lesions.

Topics: Administration, Oral; Adolescent; Diagnosis, Differential; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Leg; Methylprednisolone; Sarcoidosis; Skin Diseases; Tacrolimus; Uveitis

To examine the immunosuppressive and neuroprotective effects of intravitreal injection of tacrolimus in experimental uveitis.. Tacrolimus (40 microg) was injected intravitreally in rabbits to examine safety. Experimental uveitis was induced in rabbits by systemic immunization with bovine serum albumin (BSA) followed by intravitreal challenge with BSA. On day 1 after BSA challenge, tacrolimus (20 or 40 microg) or betamethasone (400 microg) was injected intravitreally in one eye and balanced salt solution in the contralateral eye. The eyes were evaluated by slit-lamp biomicroscopy, electroretinography, and histopathology.. No local or systemic adverse reaction was observed in normal rabbits. In experimental uveitis, intravitreal injection of tacrolimus significantly reduced intraocular inflammation in histopathological analysis (p < 0.03). Amplitudes on the electroretinogram were restored (p < 0.01), and retinal thickness was preserved in tacrolimus-treated eyes (p < 0.03).. In experimental uveitis, intravitreal injection of tacrolimus effectively suppresses ocular inflammation and preserves retinal architecture.

Topics: Animals; Betamethasone; Disease Models, Animal; Electroretinography; Glucocorticoids; Immunosuppressive Agents; Injections; Male; Neuroprotective Agents; Rabbits; Serum Albumin, Bovine; Tacrolimus; Uveitis; Vitreous Body

To evaluate the efficacy of a biodegradable polymeric scleral plug containing the immunosuppressive agent, FK506, in a rabbit model for experimental uveitis.. The scleral plugs were prepared by dissolving poly(DL-lactide-co-glycolide; PLGA) and FK506 (weight, 8.5 mg; length, 5 mm; 1% FK506). The release of FK506 was evaluated in vitro by spectrophotometry on days 1, 3, 7, 14, 21, and 35. In vivo, FK506 concentrations of the vitreous were measured by high performance liquid chromatography 2 and 4 weeks after intravitreous plug implantation in pigmented rabbits. Sixteen pigmented rabbits were immunized twice subcutaneously with 10 mg of Mycobacterium tuberculosis H37Ra antigen. Twelve days later, the right eyes of all rabbits were challenged with an intravitreal injection of 50 micro g of antigen. After the first challenge, the 16 eyes of 16 pigmented rabbits were divided into two groups. Scleral plugs were implanted into the vitreous of the right eye of eight rabbits. Eight control rabbits received a sham device. The aqueous protein concentrations and cell counts were determined on postchallenge days 7, 14, and 28. To simulated chronic inflammation, the eyes were rechallenged with intravitreal antigen on day 14 and were observed for 1 month. Inflammation of the anterior chamber and the vitreous were graded clinically by two masked observers. Retinal function was evaluated by electroretinography (ERG) and histologic examination.. Clinical scores (anterior chamber cells, flare, and vitreous opacity) showed that treated eyes had significantly less inflammation than untreated eyes (P<0.001). Quantitative analysis of inflammatory cells (P<0.001) and protein concentrations (P<0.0001) in the anterior chamber showed significant decreases in treated eyes. Histopathologic examination showed marked inflammation and tissue disorganization in the untreated eyes. No retinal toxicity was detected, histopathologically and electroretinographically. After antigen rechallenge, inflammation in experimental eyes was still less than in control eyes.. Intravitreal sustained-release of FK506 from a biodegradable polymeric scleral plug was highly effective in suppressing the inflammation of experimental uveitis in a rabbit model for at least 6 weeks. This device may be useful in the management of patients with severe chronic uveitis.

Topics: Absorbable Implants; Animals; Antigens, Bacterial; Aqueous Humor; Biocompatible Materials; Cell Count; Chromatography, High Pressure Liquid; Disease Models, Animal; Drug Delivery Systems; Electroretinography; Eye Proteins; Immunosuppressive Agents; Lactic Acid; Mycobacterium tuberculosis; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Rabbits; Sclera; Sclerostomy; Tacrolimus; Uveitis; Vitreous Body

A case of intraocular posttransplant lymphoproliferative disorder (PTLD) is described in a 9-year-old female who underwent orthotopic liver transplantation at the age of 18 months. The prevalence of ophthalmic involvement in PTLD can be expected to rise with the increasing number of major organ transplantations, as well as improved survivorship. Children are particularly at risk for this posttransplant complication because they are usually seronegative for the Epstein-Barr virus (EBV) prior to transplant. Accurate diagnostic classification of PTLD to include confirmation of EBV infection carries significant therapeutic and prognostic implications.

Topics: Child; Diagnosis, Differential; DNA, Viral; Epstein-Barr Virus Infections; Eye Infections, Viral; Female; Graft Rejection; Granuloma; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Iris Diseases; Liver Transplantation; Lymphoproliferative Disorders; Tacrolimus; Uveitis

Liposome preparations of FK506 improve the penetration of topically administered drug into the aqueous humor. The purpose of the experiment was to compare topically administered highdose oil-dissolved FK506 (OD-FK506) and low-dose liposome-bound FK506 (LB-506) for the treatment of endotoxin-induced uveitis (EIU).. Endotoxin-induced uveitis was produced in female Lewis rats with Salmonella typhimurium endotoxin. Four hours prior to endotoxin injection, one eye received 20 mul eyedrops every four hours containing either high-dose OD-FK506 at 3 mg/ml (N = 20), low-dose LB-FK506 at 0.16 mg/ml (N = 19), prednisolone acetate 1% (N = 20), or empty liposomes (N = 20). Eyes were enucleated 24 hours after endotoxin injection and inflammatory cells were counted on histologic sections by two masked observers.. The mean number of infiltrating inflammatory cells per section +/- S.E.M. was 127.8 +/- 20.1, 76.8 +/- 16.7, 75.0 +/- 19.1, and 3.6 +/- 0.4 for animals treated with empty liposomes, LB-FK506, OD-FK506, and prednisolone acetate, respectively. The difference in inflammation between the empty liposome controls and the LB-FK506- and OD-FK506-treated animals was statistically significant (p = 0.03 and p = 0.02, respectively). The difference in inflammation between the high-dose OD-FK506- and low-dose LB-FK506-treated animals was not statistically significant (0 = 0.94).. In this study, low-dose LB-FK506 and high-dose (OD-FK506) were both effective in inhibiting EIU. Higher concentrations of LB-FK506 are being developed and should augment the therapeutic effect of topical FK506.

Topics: Administration, Topical; Animals; Dose-Response Relationship, Drug; Drug Carriers; Endotoxins; Female; Immunosuppressive Agents; Liposomes; Rats; Rats, Inbred Lew; Tacrolimus; Uveitis

Basic and clinical studies on immunotherapy in immune-mediated ocular disorders, i.e. uveitis, allograft rejection in corneal transplantation and allergic conjunctivitis, were carried out using a variety of immunosuppressants, including immunophilin ligands (FK506 and cyclosporine). 1. In an animal model for uveitis, experimental autoimmune uveitis (EAU), immunophilin ligands were demonstrated in the rat and monkey to have unique immunological activities: (1) intense and prolonged suppression of EAU development, (2) therapeutic effects by treating animals only after disease onset, (3) selective suppression on cellular immune response to S-antigen, (4) induction of immunological tolerance and activation of antigen specific suppressor cells. Combination therapy with low doses of immunophilin ligand and other immunosuppressant was tested to achieve better effects with less side effects. A low dose of cyclosporine (2 mg/kg/day) with bucillamine (20 mg/kg/day) which suppresses antigen-presenting activity by macrophages caused much stronger suppression of EAU than the therapy with either cyclosporine or bucillamine alone. Similarly, a low dose of FK506 (0.1 mg/kg/day) with dexamethasone (0.01 mg/kg/day) caused stronger suppression of EAU. A multi-center clinical open trial of FK506 in refractory uveitis was carried out in Japan. A total of 40 cases of active uveitis in the posterior segment of the eye were treated with FK506 (0.05, 0.1 or 0.2 mg/kg/day) and the mean observation period was 26.2 +/- 12.4 weeks. FK506 therapy improved uveitis in 60% of all cases including 47% of patients resistant to previous therapy with cyclosporine. FK506 significantly suppressed the number of uveitis attacks in patients with Behçet's disease. As for the side effects, 22.5% of patients showed abnormal values of renal function on FK506. The trough level of FK506 in whole blood correlated with adverse side effects as well as with therapeutic effect on uveitis, and it should be maintained between 15 and 25 ng/ml. 2. Effects of immunophilin ligands on the allograft rejection in corneal transplantation was examined in the rat. Fisher rat were used as donors and Lewis rats as recipients. This combination caused 100% rejection by 2-3 weeks after surgery as indicated by (1) edema, opacity and neovascularization in the graft, (2) infiltration of a variety of immune cells demonstrated by immunohistological examination and (3) high mixed leukocyte reaction (MLR). Systemic administration o

Topics: Adolescent; Adult; Aged; Animals; Conjunctivitis, Allergic; Corneal Transplantation; Female; Graft Rejection; Humans; Immunosuppressive Agents; Immunotherapy; Male; Middle Aged; Rats; Rats, Inbred Lew; Rats, Inbred Strains; Tacrolimus; Uveitis

FK506 is a new immunosuppressive agent which has been found more potent than cyclosporine based on the dosage. FK506 was examined here for its effect on the development of uveitis in primates immunized with S-antigen. FK506 successfully inhibited uveitis in monkeys, even when administered three weeks after the first immunization, at the time when the immunopathogenic mechanism of uveitis is assumed to be developed. All four monkeys injected with 0.5 mg/kg/day of FK506 did not develop uveitis, 2 out of 4 treated with the 0.25 mg and 3 out of 4 of those receiving the 0.125 mg also did not develop disease. FK506 suppressed to some extent the cellular and humoral immune responses to S-antigen. The main side effect of FK506 was weight loss. We consider that this drug may be considered as a new potential therapeutic agent for immune-mediated ocular disease in humans.

Topics: Animals; Antigens; Arrestin; Disease Models, Animal; Eye Proteins; Female; Fluorescein Angiography; Fundus Oculi; Immunity, Cellular; Injections, Intramuscular; Lymphocyte Activation; Macaca fascicularis; Macaca mulatta; Male; Phosphodiesterase Inhibitors; Tacrolimus; Uveitis

Topics: Animals; Autoimmune Diseases; Immunization; Kidney; Liver; Liver Function Tests; Macaca mulatta; Mycobacterium tuberculosis; Retinitis; Tacrolimus; Uveitis; Weight Loss

Topics: Antigens, CD; CD4 Antigens; Cell Adhesion; Cell Adhesion Molecules; Cells, Cultured; HLA-DR Antigens; Humans; Immunohistochemistry; Intercellular Adhesion Molecule-1; Lymphocytes; Pigment Epithelium of Eye; Retinitis; Tacrolimus; Uveitis

The effects of a novel immunosuppressant, FK 506, on the efferent limb of the immune response were studied in the experimental autoimmune uveoretinitis (EAU) in the rat, using two different treatment schedules. First, rats actively immunized with S-antigen were treated with FK 506 only after the onset of EAU. FK 506 (1 or 3 mg kg-1 day-1) reduced the intensity of EAU as compared to that of non-treated rats. Especially, a daily dose of 3 mg kg-1 completely suppressed further development of EAU. It is, therefore, suggested that FK 506 treatment is effective in suppressing the ongoing process of the immune response, even after the disease has been initiated. Second, FK 506 (0.3 mg kg-1 day-1) was given only to the recipient rats which received IRBP-sensitized lymphocytes. None of FK 506-treated recipients developed EAU, while all control recipients developed the disease approximately 4 days after the cell transfer. The immune responses of FK 506-treated rats in the two experiments were also significantly suppressed. The antibody levels to S-antigen, the antigen-specific proliferative responses of lymphocytes, and even the proliferative responses to Con A were markedly suppressed in the rats in which FK 506 was given only during the efferent limb of the immune response.

Topics: Animals; Anti-Bacterial Agents; Antigens; Arrestin; Autoantigens; Autoimmune Diseases; Cell Division; Disease Models, Animal; Eye; Eye Proteins; Immunosuppressive Agents; Lymphocytes; Male; Rats; Rats, Inbred Lew; Retinitis; Tacrolimus; Uveitis

The authors previously reported that FK506 effectively suppressed the induction of experimental autoimmune uveoretinitis (EAU) in rats with much lower doses than cyclosporine A. This study was aimed at analyzing the immune status of the FK506-treated and EAU-suppressed rats and examining the hypothesis whether the agent could induce antigen-specific suppressor T (Ts) cells. It was found that spleens from S-antigen-immunized and FK506-treated rats contained a population of Ts cells inhibiting the proliferative responses of S-antigen-sensitized lymphocytes to S-antigen, yet these cells did not affect the proliferative responses of interphotoreceptor retinoid-binding protein (IRBP)-sensitized lymphocytes to IRBP. The helper T (Th) cells did not exhibit such suppressor activities. Furthermore, transfer of Ts cells from S-antigen-immunized and FK506-treated rats to naive syngenic rats induced partial inhibition of EAU induction or delay of EAU onset after immunizing the recipient rats with S-antigen. Lymphocytes from the EAU-suppressed recipients showed low proliferative response to S-antigen and low levels of antibody to S-antigen. These data thus indicate that FK506 treatment after S-antigen immunization induces an activation of Ts cells specific to S-antigen and that the Ts cells might contribute, at least in part, to the uniquely prolonged and intensive immunosuppression by FK506.

Topics: Animals; Anti-Bacterial Agents; Antigens; Arrestin; Autoimmune Diseases; Concanavalin A; Epitopes; Eye Proteins; Immunization; Immunosuppressive Agents; Immunotherapy, Adoptive; Lymphocyte Activation; Male; Rats; Rats, Inbred Lew; Retinitis; Retinol-Binding Proteins; Spleen; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Tacrolimus; Uveitis

The effects of two novel immunosuppressants, FK506 and 15-deoxyspergualin (15-DSG), on experimental autoimmune uveoretinitis (EAU) were evaluated in the rat. Rats were immunized with retinal soluble antigen (S-antigen) and treated with FK506 or 15-DSG, and the disease induction as well as the immune responses to the antigen were examined. The results were compared with animals treated with cyclosporine (CsA) which has been widely used to treat refractory uveitis in humans. A dose-response study showed that FK506 suppressed EAU induction at doses 10-30 times lower CsA when given on days 0-14 postimmunization, while 15-DSG suppressed the disease development at doses very similar to CsA. As with CsA, FK506 suppressed EAU induction when given only in the induction phase (days 0-5 postimmunization) or in the effector phase (days 7-12), but at doses much lower than CsA. On the other hand, 15-DSG suppressed EAU only at toxic doses with these schedules. The antigen specific mitotic response of lymphocytes was markedly suppressed by the three agents, while the antigen specific antibodies in sera were suppressed by 15-DSG and FK506 but not by CsA at doses effective in suppressing the disease induction. More significant findings were uniquely prolonged immunosuppressive effects of FK506: EAU induction as well as the immune responses to S-antigen were suppressed long after the cessation of drug treatment.

Topics: Animals; Antibodies; Antigens; Arrestin; Autoimmune Diseases; Body Weight; Cyclosporine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation, Preclinical; Enzyme-Linked Immunosorbent Assay; Eye; Eye Proteins; Guanidines; Immunosuppressive Agents; Male; Rats; Rats, Inbred Lew; Tacrolimus; Uveitis

In order to evaluate two new immunosuppressive agents, FR900506 (FK 506) and 15-Deoxyspergualine (15-DSG), the kinetics of infiltrating cells in the eyes of Lewis rats with experimental autoimmune uveoretinitis (EAU) were studied. Rats were immunized with retinal S-antigen and treated with different doses of either FK 506 or 15-DSG. The inflammatory ocular tissues obtained at various intervals during the process of EAU were examined using an immunoperoxidase technique. The results were compared with those eyes developing EAU without treatment or with suboptimal doses or a suboptimal dose of Cyclosporine (CsA). Both FK 506 and 15-DSG, like CsA, delayed the cellular kinetics during the course of EAU. However, FK 506 had the greatest effect on the kinetics of T lymphocyte subsets by causing the greatest increase in the recruitment time of the T suppressor/cytotoxic population. FK506 treatment resulted not only in the highest inhibition of expression of IL-2 receptors on T cells, but also in the prevention of the expression of MHC class II antigens on ocular resident cells. Treatment with 15-DSG resulted in general immunosuppression on various infiltrating inflammatory cells.

Topics: Animals; Antigens; Arrestin; Autoimmune Diseases; Cyclosporine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation; Eye Proteins; Guanidines; Immunoenzyme Techniques; Immunosuppressive Agents; Macrophages; Male; Rats; Rats, Inbred Lew; Retina; T-Lymphocyte Subsets; Tacrolimus; Uveitis

A comparative study was carried out between cyclosporine and a new immunosuppressive agent, FK506, isolated from the Streptomyces organism. This agent has the capacities to suppress the development of S-antigen-induced experimental autoimmune uveoretinitis (EAU) as well as immune responses to S-antigen in rats immunized with the antigen. When administered daily beginning on the day of immunization and for 14 days thereafter, FK506 at doses between 0.1 and 1 mg/kg suppressed EAU in a dose-dependent manner. Complete inhibition of EAU was achieved at doses of 1, 3 and 10 mg/kg. Cyclosporine (1-20 mg/kg) also produced a dose-dependent suppression of EAU and only the highest dose (20 mg/kg) caused complete inhibition of the disease. On the basis of the dose-response study, the capacity of FK506 in preventing EAU induction is 10-30 times more intense than that of cyclosporine. In addition, the FK506 (1 and 3 mg/kg) was found to be effective in preventing EAU even when administered only in the early induction phase (days 0-5) or late effector phase (days 7-12). Similar effects were obtained by cyclosporine at a daily dose of 30 mg/kg. Furthermore, none of the rats immunized with S-antigen and treated with FK506 (1 mg/kg) on days 0-14 developed EAU when reimmunized with S-antigen on day 30. In contrast, similarly treated rats were fully susceptible to the induction of experimental allergic encephalomyelitis, or even to EAU when immunized with another retinal antigen, interphotoreceptor retinoid-binding protein. Therefore, as with cyclosporine, as demonstrated in our previous study, FK506 has the capacity to induce immunological unresponsiveness specific to the S-antigen.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antibody Formation; Antigens; Arrestin; Autoimmune Diseases; Cyclosporins; Eye Proteins; Immunization; Immunosuppressive Agents; Male; Pyridines; Rats; Rats, Inbred Lew; Retinitis; Tacrolimus; Time Factors; Uveitis