tacrolimus and Retinitis

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

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

PURPOSE. To evaluate the effects of intravitreal injection of liposomes encapsulating tacrolimus (FK506) on experimental autoimmune uveoretinitis (EAU) in Lewis rats. METHODS. Liposomes containing tacrolimus were prepared by reverse-phase evaporation vesicles. EAU was induced in Lewis rats by subcutaneous injection of interphotoreceptor retinoid-binding protein R16 peptide emulsified in adjuvant. Ten days later, rats were intravitreally injected with saline, tacrolimus, tacrolimus-loaded liposomes, or unloaded liposomes. Clinical signs of inflammation and ocular histologic sections were observed and graded. Retinal function was evaluated by electroretinography (ERG). Tacrolimus concentration was determined in the vitreous body and serum by ELISA. Ocular biodistribution of rhodamine-conjugated liposomes containing tacrolimus (tacrolimus-Rh-lip) was analyzed with a laser scanning confocal microscope. To evaluate the systemic effect of intravitreally injected tacrolimus, delayed-type hypersensitivity (DTH) and lymphocyte proliferation assay (LPA) responses were detected. RESULTS. Treatment of EAU with intravitreal injection of liposomal tacrolimus significantly reduced intraocular inflammation and markedly inhibited the development of EAU, as determined in clinical and histopathologic analyses. No toxic effects could be detected as evaluated by ERG. The concentration of tacrolimus in ocular fluids remained for as long as 14 days after liposomal injection of tacrolimus. Confocal microscopy showed a transretinal distribution of the liposomal particles. DTH and LPA responses were not impaired in liposomal tacrolimus-treated rats. CONCLUSIONS. Intravitreal injection of liposomal tacrolimus was highly effective in suppressing the process of EAU without any side effects on retinal function or systemic cellular immunity. This treatment may represent a new option for the management of intraocular inflammation.

Topics: Animals; Autoimmune Diseases; Disease Models, Animal; Electroretinography; Female; Hypersensitivity, Delayed; Immunosuppressive Agents; Injections; Liposomes; Lymphocyte Activation; Microscopy, Confocal; Rats; Rats, Inbred Lew; Retinitis; T-Lymphocytes; Tacrolimus; Uveitis, Posterior; Vitreous Body

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

The current study was designed to determine whether intravitreal injection of tacrolimus (FK506) modulates the gene expression of neurotrophic factor-related molecules in the retina from eyes with induced experimental autoimmune uveoretinitis (EAU) in rats.. Rats were immunised with interphotoreceptor retinoid binding protein peptide (R14) and given intravitreal injection of tacrolimus on day 12 after immunisation. As control, immunised rats received intravitreal injection of vehicle. On day 15 after immunisation, changes in the genetic programme associated with neuroprotection and inflammatory responses in the retinas from both groups were determined by DNA microarray analyses and confirmed by real-time PCR analyses.. The gene expression of inflammatory responses was markedly reduced in tacrolimus-treated eyes. Genes for molecules associated with neuroprotection (oestrogen receptor, erythropoietin receptor, gamma-aminobutyric acid receptor, protein kinase C, glial cell line-derived neurotrophic factor receptor, fibroblast growth factor and neuropeptide Y receptor) were upregulated in the retinas from tacrolimus-treated eyes.. Intravitreal injection of tacrolimus modulated the genes related to neuroprotection in the retina during the ongoing process of EAU. This treatment may be useful for the neuroprotection of retina with severe uveitis as well as for immunosuppression in the uveitic eyes.

Topics: Animals; Autoimmune Diseases; Disease Models, Animal; Female; Gene Expression Profiling; Immunosuppressive Agents; Injections; Nerve Growth Factors; Oligonucleotide Array Sequence Analysis; Rats; Rats, Inbred Lew; Retinitis; RNA, Messenger; Tacrolimus; Up-Regulation; Uveitis, Anterior; Vitreous Body

Topics: Acyclovir; Antiviral Agents; Cytomegalovirus Infections; Foscarnet; Humans; Immunosuppression Therapy; Phosphonoacetic Acid; Retinitis; Retrospective Studies; Tacrolimus; Transplantation Immunology

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

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