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| March 2004 | Inside IOVS | Volume 45/3 |
Immunotolerance against Retinal Proteins
Pathogenic autoimmunity is normally avoided by elimination of lymphocytes that are specific against self antigens. The elimination process, designated central immunotolerance, takes place mainly in the thymus. Ham et al. (p. 857) provide evidence to support the notion that autoimmunity against retinal proteins is prevented by this process. An antigen expressed transgenically under control of the rhodopsin promoter is expressed in the thymus as well and eliminates by apoptosis maturing lymphocytes with specificity against it. Similar to this antigen, rhodopsin and all tested retinal proteins are expressed in mammalian thymus and this study suggests that lymphocytes specific against them are eliminated by central tolerance.
Activation of STATs and SOCS in the Lens by Growth Factors
Ebong et al. (p. 872) show that FGF-1, FGF-2, PDGF and IGF1 induce proliferation and transcription in lens, in part, through activation of JAK/STAT signal transduction pathways. Growth factor-induced STAT-activation is followed by rapid induction in expression of SOCS, a novel family of feedback regulators of growth factor activities. Synergistic activation of STATs and SOCS expression by factors implicated in lens development provide mechanistic explanation for synergistic effects of these factors in lens and suggests that intensity and duration of growth factor signals in lens are sensitive to steady-state levels of activated STATs and may be under feedback regulation by SOCS family proteins.
Blocking the Action of VEGF (and a Few of Its Friends) Helps DME
Understanding the molecular signals responsible for diabetic macular edema (DME) would facilitate the development of new treatments. Recently, it has been demonstrated that hypoxia contributes to DME, suggesting that hypoxia-regulated genes may be involved. Vascular endothelial growth factor (VEGF) is upregulated by hypoxia and promotes excessive vascular permeability. As reported in Campochiaro et al. (p. 922), a multicenter, placebo-controlled, double-masked clinical trial showed that oral administration of a kinase inhibitor, PKC412, reduces macular thickness and modestly improves visual acuity in diabetic patients with macular edema. PKC412 blocks VEGF receptors, but also blocks PDGF receptors, the receptor for stem cell factor, and several isoforms of protein kinase C. The results are consistent with the hypothesis that members of the VEGF family play a role in DME. The most common adverse effect was nausea and vomiting, and a small percentage of patients had elevation of liver enzymes.
Caspase-3 and Photoreceptor Degeneration in rd-1 Mouse Retinas
Zeiss et al. (p. 964) evaluated the role of caspase-3 in retinal development and photoreceptor degeneration. Caspase-3 deficiency results in microphthalmia, peripapillary retinal dysplasia, delayed regression of vitreal vasculature, and retarded apoptotic kinetics of the inner nuclear layer. Ablation of caspase-3 in rd-1 mice provides transient photoreceptor protection. Peripapillary dysplastic lesions suggest a delayed fusion of the optic fissure, and inner nuclear layer abnormalities indicate a cell-specific dependency upon the mitochondria-caspase axis during development. Caspase-independent mechanisms are likely to play a role in pathologic rod death.
Microglia and Photoreceptor Degeneration in rd-1 Mouse Retinas
A population of proliferating cells in the outer nuclear layer accompanies photoreceptor death along a central to peripheral gradient in rd-1 retinas. Zeiss and Johnson (p. 971) performed double immunolabeling for PCNA and F4/80, which readily identified these as microglial cells originating from the inner retina. The role of microglia in photoreceptor degeneration is unclear, however their distribution supports their role in mediating the beneficial effects of neurotrophic factors. Cell cycle progression in photoreceptors could not be demonstrated. Therefore, in this model, evidence of photoreceptor cell cycle progression in retinas exposed to neurotrophic factors is likely to result from the therapy itself.
New Source for Retinal Pigment Epithelial (RPE) Cells
Haruta et al. (p. 1020) demonstrate that cynomolgus monkey embryonic stem (ES) cells can generate large, purified populations of pigment epithelial cells that show the well-known characteristics and functions of normal RPE cells. When transplanted subretinally into a rat model of RPE dysfunction, the grafted cells rescued the survival and functions of host photoreceptor cells. Because of the similarities between human and monkey ES cells, the present study raises the possibility that human ES cells constitute an unlimited source of RPE for transplantation in patients with age-related macular degeneration and some forms of retinal degeneration.
Purinergic Vasotoxicity in the Diabetic Retina
Capillary cell death is a hallmark of diabetic retinopathy. Currently, the mechanisms causing this sight-threatening complication remain uncertain. Sugiyama et al. (p. 1026) propose the novel idea that vasoactive molecules, such as extracellular ATP, may become vasotoxic in the diabetic retina. They found that activation of P2X7 purinoceptors not only transduces retinovascular responses to ATP, but also can induce the formation of lethal transmembrane pores. Although high agonist doses are required to open P2X7 pores in non-diabetic retinal microvessels, normally non-lethal concentrations trigger apoptosis in diabetic capillaries. A therapeutic strategy to preserve capillary function in diabetics might be to pharmacologically block P2X7-mediated cell death.
Control of Eye-Size and Myofibroblasts in the Sclera
Physiological control of eye-size is fundamental to the refractive development of the eye, with abnormal enlargement of the eye resulting in myopia. Phillips and McBrien (p. 758) suggest a novel physiological process for regulating eye-size based on myofibroblasts. They show that stretching the sclera (by raising intraocular pressure) reduces the axial length of tree shrew eyes but increases the axial length of chick eyes. The detection of contractile myofibroblasts in sclera of tree shrew, but not chick, suggests that the observed eye shortening results from activation of scleral myofibroblasts. Myofibroblasts, known to be present in human sclera, may provide a basis for future interventions aimed at counteracting the axial elongation of human myopic eyes.
A Mouse Cone Photoreceptor Cell Line
With increased life expectancy, macular degeneration will be inflicting a major population worldwide. Research in prevention and/or treatment is vital but investigations in vivo are costly and time consuming. However, cell culture offers a valuable alternative. Tan et al. (p. 764) describe an immortalized mouse photoreceptor-derived cell line (661W). Cellular and molecular analyses show that these cells express cone but not rod photoreceptor markers, which suggest that these cells arise from a cone photoreceptor lineage. The 661W cell line will be valuable in investigations involving the role of specific genes in cone photoreceptor function and age related changes.
Pharmacological IOP Reduction Measurements Following Refractive Surgery
Although the relationship between applanation tonometry and corneal thickness has often been evaluated, to date no study has evaluated the relative weight of different central corneal thickness and corneal curvature values, commonly found in the human population, on tonometric measurements of the decrease in intraocular pressure induced by ocular hypotensive drugs. Tamburrelli et al. (p. 846) demonstrate that refractive surgery provides an excellent model to study in vivo, in the same patient, the effect of such variations in corneal thickness on the intraocular pressure readings after the administration of ocular hypotensive drugs. An erroneous impression of reduced pharmacological efficacy may be avoided if the measured intraocular pressure is corrected by a proper nomogram.
Major Intrinsic Protein (MIP)/Aquaporin-0 Interacts with gE-Crystallin
This paper characterizes the interaction between two lens fiber specific proteins required for lens transparency, major intrinsic protein (MIP)/Aquaporin-0, a plasma membrane- water channel protein, and gE-crystallin, a cytosolic protein. The authors presented biochemical evidence for the interaction between MIP and gE-crystallin and visualized their interaction in mammalian cells by confocal fluorescence microscopy. The authors found that the interaction between MIP and gE-crystallin resulted in the recruitment of gE-crystallin to the plasma membrane. This study by Fan et al. (p. 863) has important implications for understanding how this interaction may play an important role in MIP and/or gE-crystallin functions in the normal lens.
Protein Kinase C b and Retinal Pathophysiology
Diabetes increases retinal protein kinase C b (PKCb) levels and impairs the retinal oxygenation response to a hyperoxic inhalation challenge, but the association between these biochemical and functional abnormalities has not been explored. Using functional magnetic resonance imaging and PKCb knockout mice, Luan et al. (p. 937) found evidence in diabetic mice of an association only about the optic nerve head. These data raise the possibility that specific pharmacologic intervention using inhibitors specific to PKCb may only be regionally effective in treating retinal pathophysiology associated with diabetic retinopathy.
Retinal Pigment Epithelial Sheet Transplants in Pigs
Del Priore et al. (p. 985) have determined the morphology of retinal pigment epithelial (RPE) sheets from female porcine donors after subretinal transplantation into the nondebrided male porcine eye without immune suppression. Allogeneic RPE sheets survive in the subretinal space up to three months after surgery and the choriocapillaris remains patent in the transplant bed. There is no infiltration of the graft site with inflammatory cells. Further work is needed to produce uniform repopulation of a sizable portion of Bruch's membrane with a monolayer of transplanted RPE.
Fluorophore Assisted Retinal Break Detection
Jackson and Marshall (p. 993) show that it is possible to selectively stain full-thickness retinal breaks. A fluorophore tagged antibody to glial fibrillary acidic protein (Cy3 anti-GFAP) was injected into the vitreous cavity of porcine eyes with rhegmatogenous retinal detachments. Retinal breaks were viewed through a barrier filter fitted to the operating microscope with laser endoillumination. Retinal breaks were selectively stained with a high level of specificity. Ex vivo studies indicated that this occurred because Cy3 anti-GFAP was binding damaged glia at the margin of retinal breaks. This raises the prospect of fluorophore assisted retinal break detection during retinal detachment surgery.
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