Mycophenolate mofetil use in the treatment of noninfectious uveitis.

Mycophenolate mophetil (MMP) is a potent immunomodulatory drug that inhibits the function of T and B lymphocytes. It is used successfully in the treatment of recurrent noninfectious uveitis in adults and children. MMF can be used alone or in combination with other immunomodulatory drugs (biologics or calcineurin inhibitors) for moderate and severe cases of anterior, intermediate and posterior uveitis. It can also be used for treatment of patients with scleritis and ocular cicatricial pemphigoid.

Depsipeptide inhibits migration of primary and metastatic uveal melanoma cell lines in vitro: a potential strategy for uveal melanoma.

Uveal melanoma (UM) is a highly malignant primary intraocular tumour in adults that has a high mortality rate due to haematogenous dissemination. The migration of UM cells through the basement membrane requires the presence of proteolytic enzymes, such as matrix metalloproteinases (MMPs). The expression of MMP-2, MMP-9 and membrane type-1/MMP (MT-1/MMP) in UM cells is a known risk factor for metastatic disease. We tested the effect of depsipeptide (DP) on UM cell migration and the level and activity of MMP-2, MMP-9, MT-1/MMP and tissue inhibitors of matrix metalloproteinases 1 and 2 (TIMP-1 and TIMP-2). Three primary and two metastatic (liver metastasis) UM cell lines were treated with DP (0, 1, 5 and 10 nmol/l) for 24 h. Migration of UM cells was studied in modified Boyden migration chambers for 24 h and only viable cells on both sides of the membrane were counted. Enzyme-linked immunosorbent assays (ELISAs) were used to quantify the level of MMP-2, MMP-9, MT-1/MMP, TIMP-1 and TIMP-2 after the cells had been exposed to DP (0, 1, 5 and 10 nmol/l) for 24 h. In addition, the activities of MMP-2, MMP-9 and MT-1/MMP were determined after DP treatment. A dose-dependent decrease in the migration of viable UM cells was observed for primary and metastatic cell lines (30-50% inhibition). We detected a dose-dependent: (1) decrease in the protein level of MMP-2, MMP-9 and MT-1/MMP; (2) decrease in the activity of MMP-2, MMP-9 and MT-1/MMP; and (3) increase in the protein level of TIMP-1 and TIMP-2. It can be concluded that DP is a potent inhibitor of primary and metastatic UM cell migration in vitro. Our data suggest that this inhibition is mediated by the downregulation of MMPs and the upregulation of TIMPs. DP may be a valuable adjunctive treatment modality for primary and metastatic UM in humans.

Somatostatin inhibits IGF-1 mediated induction of VEGF in human retinal pigment epithelial cells.

Neovascularization stimulated by IGF-1 mediated induction of vascular endothelial growth factor (VEGF) is one of the leading causes of blindness in humans. It plays a central role in the pathogenesis of proliferative diabetic retinopathy (DR), neovascular glaucoma, exudative age-related macular degeneration (AMD) and retinopathy of prematurity. Neovascularization is a multi-step process that involves complex interactions of a variety of mitogenic factors such as VEGF and IGF-I which are produced locally in the human eye by a variety of cells including retinal pigment epithelial (RPE) cells, retinal capillary pericytes, endothelial cells, Mueller cells and ganglion cells. We hypothesized that somatostatin would inhibit the IGF-1 signal transduction pathway in RPE cells, resulting in decreased VEGF production. We have observed expression of somatostatin receptor protein in retinal pigment epithelial (RPE) cells of the human eye using immunohistochemistry and have confirmed expression of somatostatin receptors in cultured human RPE cells using reverse transcriptase-PCR. IGF-1 induced a dose dependent increase in IGF-1R phosphorylation and in VEGF mRNA levels in cultured human RPE cells. Somatostatin and octreotide, a somatostatin analogue, inhibited IGF-1 receptor (IGF-1R) phosphorylation and decreased VEGF production. Both IGF-1R phosphorylation and accumulation of VEGF mRNA were inhibited by physiological levels of somatostatin and octreotide (1 nM). These results demonstrate somatostatin and octreotide mediated attenuation of both IGF-1R signal transduction and VEGF mRNA accumulation via somatostatin receptor type 2 (sst2). Furthermore, these data suggest a rationale for the use of octreotide as a prophylactic and therapeutic option in disease states that cause ocular neovascularization.

Depsipeptide (FR901228) inhibits proliferation and induces apoptosis in primary and metastatic human uveal melanoma cell lines.

PURPOSE: Uveal melanoma (UM) is the most common primary malignant ocular tumor in adults. No effective chemotherapy regimens are available for either intraocular or metastatic uveal melanoma. Therefore, the ability of the histone deacetylase inhibitors (HDACIs), depsipeptide, sodium butyrate (NaB) and trichostatin A (TSA), to induce apoptosis and inhibit cell growth of UM cell lines in vitro was examined. METHODS: Three primary and two metastatic UM cell lines were treated in vitro with different concentrations of histone deacetylase inhibitors (HDACIs). Cell proliferation was studied in 24-well plates. Induction of apoptosis was studied by flow cytometry. Changes in gene expression of Fas/FasL, p21(Waf/Cip1), and p27(Kip1) were studied by RT-PCR. Western blot analysis was used to study histone acetylation, Fas/FasL, p21(Waf/Cip1), p27(Kip1) and caspase-3 protein levels. Real-time PCR was used to study changes in bcl-2/bax gene expression. RESULTS: A dose-dependent increase in histone acetylation was observed in all cell lines. This corresponded to significant inhibition of cell growth and induction of apoptosis in all melanoma cell lines in a concentration-dependent manner. Western blot analysis revealed dose-dependent increases in the amount of caspase-3, Fas/FasL, p21(Waf/Cip1), and p27(Kip1) proteins. However, no changes in bcl-2/bax gene expression were detected by real-time PCR. CONCLUSIONS: HDACIs are potent inhibitors of primary and metastatic UM cell growth in vitro. The apoptosis is probably mediated through the Fas/FasL signaling pathway, whereas bcl-2 appears not to be involved. These data support further clinical evaluation of depsipeptide and other HDACIs in patients with primary and metastatic UM.

Expression of somatostatin receptors 1 and 2 in human choroid plexus and arachnoid granulations: implications for idiopathic intracranial hypertension.

OBJECTIVE: To investigate the localization of somatostatin receptor types 1 and 2 in human choroid plexus (CP) and arachnoid granulations (AGs) by immunohistochemistry. METHODS: A prospective study was performed in an institutional setting. Immunohistochemistry was performed on 15 samples of CP and 12 samples of AGs from 15 patients who died with no signs or symptoms of intracranial disease (age range, 52-81 years). The CP samples were dissected from the lateral ventricles and AG samples were dissected from the superior sagittal sinus. RESULTS: We demonstrated the presence of both somatostatin receptor types 1 and 2 in all samples of normal human CP and AGs. CONCLUSIONS: Analogous to their demonstration and to their function in kidney and ocular tissues, these receptors may be involved in the processes of cerebrospinal fluid production and absorption, and may play a role in the increased intracranial pressure of idiopathic intracranial hypertension. CLINICAL RELEVANCE: Somatostatin analogues have been used to treat idiopathic intracranial hypertension, a disorder of cerebrospinal fluid homeostasis. Data are scarce regarding the cell-specific distribution of somatostatin receptors in normal human CP and AGs, the sites of cerebrospinal fluid production and egress.

The wayward implant: orbital silicone plate extrusion associated with squamous epithelial downgrowth and infection.

We report an unusual case of orbital implant migration in which the silicone plates were found to be enveloped in a pseudocapsule surprisingly infected and lined by squamous epithelium of probable conjunctival origin. An epithelial 'plug' found in the inferior fornix portion of the pseudocapsule might have been responsible for bacterial entry into the cavity. We discuss the literature regarding pseudocapsule formation around silicone implants and the phenomenon of capsular contracture. Both the infection and the epithelial downgrowth may have facilitated the implant migration.