[Macular edema: Understand mechanisms to develop treatments].

Macular edema is an increase in volume of the central area of the retina, responsible for visual acuity. Visual symptoms handicap the lives of millions of patients with macular edema secondary to chronic and sometimes acute retinal disease. Proteins that neutralize the vascular endothelial growth factor (VEGF) pathway or glucocorticoids, at the cost of repeated intraocular injections over years, limit visual symptoms.

Mechanisms of macular edema: Beyond the surface.

Macular edema consists of intra- or subretinal fluid accumulation in the macular region. It occurs during the course of numerous retinal disorders and can cause severe impairment of central vision. Major causes of macular edema include diabetes, branch and central retinal vein occlusion, choroidal neovascularization, posterior uveitis, postoperative inflammation and central serous chorioretinopathy.

Choroidal mast cells in retinal pathology: a potential target for intervention.

Mast cells are important in the initiation of ocular inflammation, but the consequences of mast cell degranulation on ocular pathology remain uncharacterized. We induced mast cell degranulation by local subconjunctival injection of compound 48/80. Initial degranulation of mast cells was observed in the choroid 15 minutes after the injection and increased up to 3 hours after injection.

Anti-vascular endothelial growth factor acts on retinal microglia/macrophage activation in a rat model of ocular inflammation.

Purpose: To evaluate whether anti-vascular endothelial growth factor (VEGF) neutralizing antibodies injected in the vitreous of rat eyes influence retinal microglia and macrophage activation. To dissociate the effect of anti-VEGF on microglia and macrophages subsequent to its antiangiogenic effect, we chose a model of acute intraocular inflammation.

Methods: Lewis rats were challenged with systemic lipopolysaccharide (LPS) injection and concomitantly received 5 µl of rat anti-VEGF-neutralizing antibody (1.

The aldosterone-mineralocorticoid receptor pathway exerts anti-inflammatory effects in endotoxin-induced uveitis.

We have previously shown that the eye is a mineralocorticoid-sensitive organ and we now question the role of mineralocorticoid receptor (MR) in ocular inflammation. The endotoxin-induced uveitis (EIU), a rat model of human intraocular inflammation, was induced by systemic administration of lipopolysaccharide (LPS). Evaluations were made 6 and 24 hours after intraocular injection of aldosterone (simultaneous to LPS injection).

Microglia/macrophages migrate through retinal epithelium barrier by a transcellular route in diabetic retinopathy: role of PKCζ in the Goto Kakizaki rat model.

Diabetic retinopathy is associated with ocular inflammation, leading to retinal barrier breakdown, macular edema, and visual cell loss. We investigated the molecular mechanisms involved in microglia/macrophages trafficking in the retina and the role of protein kinase Cζ (PKCζ) in this process. Goto Kakizaki (GK) rats, a model for spontaneous type 2 diabetes were studied until 12 months of hyperglycemia.

Protective effect of intravitreal administration of tresperimus, an immunosuppressive drug, on experimental autoimmune uveoretinitis.

Purpose: To test the efficiency of locally administrated tresperimus in experimental autoimmune uveoretinitis (EAU).

Methods: EAU was induced in Lewis rats by S-antigen (S-Ag) immunization. Three intravitreal injections of tresperimus (prevention or prevention/treatment protocols) were performed at different time points after immunization.

A peptide inhibitor of c-Jun N-terminal kinase for the treatment of endotoxin-induced uveitis.

Purpose: To evaluate the effect of XG-102 (formerly D-JNKI1), a TAT-coupled dextrogyre peptide that selectively inhibits the c-Jun N-terminal kinase, in the treatment of endotoxin-induced uveitis (EIU).

Methods: EIU was induced in Lewis rats by LPS injection. XG-102 was administered at the time of LPS challenge.

Anti-retinal autoantibodies in experimental ocular and systemic toxoplasmosis.

Background: Patients with ocular toxoplasmosis (OT) develop autoreactivity to several retinal antigens, including retinal S-antigen. By establishing an experimental rabbit model of systemic and of primary and secondary ocular toxoplasmosis, we wished to investigate the onset and development of humoral response to retinal S-antigen.

Methods: Of twelve infection-naïve rabbits, six were left untreated, and the other six were infected subcutaneously with 5,000 tachyzoites of the highly virulent, non-cyst-forming BK-strain of Toxoplasma gondii.

New formulation of vasoactive intestinal peptide using liposomes in hyaluronic acid gel for uveitis.

We evaluated the benefits of a novel formulation of vasoactive intestinal peptide (VIP) based on the incorporation of VIP-loaded rhodamine-conjugated liposomes (VIP-Rh-Lip) within hyaluronic acid (HA) gel (Gel-VIP-Rh-Lip) for the treatment of endotoxin-induced uveitis (EIU) in comparison with VIP-Rh-Lip alone. In vitro release study and rheological analysis showed that interactions between HA chains and liposomes resulted in increased viscosity and reinforced elasticity of the gel. In vivo a single intravitreal injection of Gel-VIP-Rh-Lip was performed in rats 7 days prior to uveitis induction by subcutaneous lipopolysaccharide injection.

Local ocular immunomodulation resulting from electrotransfer of plasmid encoding soluble TNF receptors in the ciliary muscle.

Purpose: Plasmid electrotransfer in the ciliary muscle allows the sustained release of therapeutic proteins within the eye. The aim of this study was to evaluate whether the ocular production of TNF-alpha soluble receptor, using this nonviral gene therapy method, could have a beneficial local effect in a model of experimental autoimmune uveoretinitis (EAU).

Methods: Injection of a plasmid encoding a TNF-alpha p55 receptor (30 microg) in the ciliary muscle, combined with electrotransfer (200 V/cm), was carried out in Lewis rat eyes 4 days before the induction of EAU by S-antigen.

Protective effect of intravitreal injection of vasoactive intestinal peptide-loaded liposomes on experimental autoimmune uveoretinitis.

Purpose: The aim of this study was to investigate the effect of a single intravitreal (i.v.t.

Animal models of intraocular lymphomas.

Primary intraocular lymphoma is a high-grade non-Hodgkin lymphoma whose pathogenesis is still unclear. Few animal models exist in order to study this condition. Although intraocular lymphomas in humans are usually B cell lymphomas, most of these models are T cell lymphomas.

Primate model of uveoretinitis and vasculitis/experimental autoimmune uveoretinitis induced in cynomolgus monkeys by retinal s antigen.

Purpose: We aimed to describe the clinical and angiographic changes in an experimental model of autoimmune uveoretinitis and vasculitis in primates.

Methods: Six cynomolgus monkeys received a single subcutaneous immunization with 100 microg of human S antigen with complete Freund's adjuvant.

Results: All the animals had a bilateral long-term disease occurring usually in 1 eye approximately 4 weeks after immunization, the second eye being involved 1-5 weeks later.

Pathological aspects of spontaneous uveitis and retinopathy in HLA-A29 transgenic mice and in animal models of retinal autoimmunity: relevance to human pathologies.

Purpose: A major increased risk of developing birdshot chorioretinopathy is reported in humans who are HLA-A29-positive. To better characterize this disease, an animal model of HLA-A29-associated disease was developed and the pathology arising spontaneously in these transgenic mice was compared to animal models of autoimmune uveoretinitis and to human pathology.

Materials And Methods: HLA-A2902 cDNA (A29c) was obtained from a patient suffering from birdshot retinochoroidopathy and used for transgene construct to generate HLA-A29 transgenic mice.

Downregulation of endotoxin-induced uveitis by intravitreal injection of vasoactive intestinal Peptide encapsulated in liposomes.

Purpose: To reestablish the immunosuppressive microenvironment of the eye, disrupted by ocular inflammation during endotoxin-induced uveitis (EIU), by means of intravitreal injection of vasoactive intestinal peptide (VIP) in saline or encapsulated in liposomes, to increase its bioavailability and efficiency.

Methods: EIU was induced in Lewis rats by subcutaneous injection of lipopolysaccharide (LPS). Simultaneously, animals were intravitreally injected with saline, saline/VIP, VIP-loaded liposomes (VIP-Lip), or unloaded liposomes.

Impaired th1/tc1 cytokine production of tumor-infiltrating lymphocytes in a model of primary intraocular B-cell lymphoma.

Purpose: Primary intraocular lymphoma is a high-grade non-Hodgkin lymphoma with a pathogenesis that is still unclear. Microenvironment is known to be crucial in controlling tumor growth and maintenance. To study the immune microenvironment in intraocular lymphomas and to characterize the cytokine polarization of infiltrating T-lymphocytes, a new murine model of intraocular B-cell lymphoma was developed.

Protein kinase Czeta (PKCzeta) regulates ocular inflammation and apoptosis in endotoxin-induced uveitis (EIU): signaling molecules involved in EIU resolution by PKCzeta inhibitor and interleukin-13.

We show that inhibitory effect of interleukin-13 on endotoxin-induced uveitis in the Lewis rat is dependent on signaling activity of protein kinase Czeta (PKCzeta). To understand the effect of interleukin-13 or PKCzeta inhibitor treatment, the activation status of rat bone marrow-derived macrophages was studied in vitro. At 6 hours, lipopolysaccharide-stimulated macrophages produced tumor necrosis factor-alpha (TNF-alpha) with nuclear factor kappaB (NF-kappaB)/p65 expression.

Regulatory T cells control uveoretinitis induced by pathogenic Th1 cells reacting to a specific retinal neoantigen.

In many clinical cases, uveitis develops secondary to an infection. This could result from peripheral activation followed by ocular penetration and reactivation of T cells specific for microbial Ags expressed in the retina. To gain insights into the pathophysiology of uveitis, we developed a new mouse model based on stable retinal expression of influenza virus hemagglutinin (HA) neoantigen by adeno-associated virus-mediated gene transfer.

Oligonucleotide-polyethylenimine complexes targeting retinal cells: structural analysis and application to anti-TGFbeta-2 therapy.

Purpose: The aim of this study was to characterize oligonucleotide-polyethylenimine (ODN/PEI) complex preparation for potential transfection of retinal cells in vitro and in vivo.

Methods: The effect of medium preparation [HEPES-buffered saline (HBS), water] on particle size and morphology was evaluated. Cultured Lewis rat retinal Müller glial (RMG) cells were transfected using fluorescein isothiocyanate (FITC)-ODN/PEI complexes specifically directed at transforming growth factor beta (TGFbeta)-2.

Tetracycline-inducible viral interleukin-10 intraocular gene transfer, using adeno-associated virus in experimental autoimmune uveoretinitis.

Members of the adeno-associated virus (AAV) family are good candidates for the treatment of ocular diseases because of their relative lack of pathogenicity. We studied the effect of intraocular injection of AAV2-viral IL-10 (vIL-10) on retinal S-antigen-induced experimental autoimmune uveoretinitis (EAU) in Lewis rats. We demonstrated that AAV2/2-GFP injected into the vitreous body transduced the iris and ciliary body, or anterior uvea, and the retina.

Intraocular injection of tamoxifen-loaded nanoparticles: a new treatment of experimental autoimmune uveoretinitis.

In this study, we tested the efficiency of an intravitreal injection of tamoxifen, a non-steroidal estrogen receptor modulator, in retinal soluble antigen (S-Ag)-induced experimental autoimmune uveoretinitis (EAU). To increase the bioavailability of tamoxifen, we incorporated tamoxifen into polyethylene glycol (PEG)-coated nanoparticles (NP-PEG-TAM). The localization of the nanoparticles within the eye was investigated using fluorescent-labeled PEG-coated nanoparticles after injection into the vitreous cavity of rats with EAU.

Cornea graft endothelial cells undergo apoptosis by way of an alternate (caspase-independent) pathway.

Purpose: To look for apoptosis pathways involved in corneal endothelial cell death during acute graft rejection and to evaluate the potential role of nitric oxide in this process.

Materials And Methods: Corneal buttons from Brown-Norway rats were transplanted into Lewis rat corneas. At different time intervals after transplantation, apoptosis was assessed by diamino-2-phenylindol staining and annexin-V binding on flat-mount corneas, and by terminal transferase dUTP nick end labeling (TUNEL), caspase-3 dependent and leukocyte elastase inhibitor (LEI)/LDNase II caspase-independent pathways on sections.

Cytokines in immunotherapy of experimental uveitis.

A better understanding of the basic mechanisms of uveitis and of the role of cytokines in experimental ocular inflammation autoimmune diseases should allow us to define new approaches for therapy. Modulation of the cytokine network by either blocking cytokine activity or administration of regulatory Th2 cytokines has shown its efficacy in several experimental autoimmune diseases including uveitis. However, cytokines present pleiotropic activities and thus may exert different effects depending on the autoimmune diseases, making interventions on their production complex.