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| October 2005 | Inside IOVS | Volume 46/10 |
TGFb Regulates Uveal Melanoma Adhesion to Hepatic Endothelial Cells
Uveal melanomas are aggressive ocular cancers that characteristically metastasize to the liver. Survival following identification of hepatic metastases is much reduced, and there are no effective treatments. Why uveal melanomas specifically target the liver is unclear. Woodward et al. (p. 3473) show here that transforming growth factor (TGF)b can influence the interaction between melanoma cells and endothelial cells by increasing the adherence of poorly invasive uveal melanomas to hepatic endothelium, but not to dermal endothelium. TGFb could therefore assist in the targeting of the liver by uveal melanomas, and further exploration of the mechanisms of its regulation may prove useful in the development of future therapeutic options.
The Sclera Knows What the Retina Sees
Most human myopia is due to excessive enlargement of the posterior scleral shell. Experimentally induced myopia in animal models, which mimics this enlargement, produces scleral remodeling and a change in the mechanical properties of the scleral tissue. Siegwart and Norton (p. 3484) show selective regulation of matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) mRNA levels in the sclera during experimentally induced myopia in tree shrews that is associated with the visual input the eye receives and the physical changes that occur in the sclera. A more detailed understanding of scleral gene expression during experimentally induced myopia in animal models provides direction for eventual therapies to control human myopia.
b-Carotene Conversion in the Retinal Pigment Epithelium
The key step in vitamin A biosynthesis is the oxidative cleavage of b-carotene into retinal by the enzyme b,b-carotene-15,15'-monooxygenase (BCO). It is generally thought that b-carotene is converted to vitamin A in the intestine and then transported to target tissues including eye via blood supply. Chichili et al. (p. 3562) show that retinal pigment epithelial (RPE) cells can convert b-carotene into vitamin A. b-carotene cleavage in the RPE might be an alternative pathway to ensure the supply of retinoid to photoreceptor cells for the maintenance of normal vision. This will be particularly important in individuals with impaired vitamin A transport.
Direct Molecular Approach to Corneal Endothelial Cell Replication
In human cornea, diminishing cell density in the endothelial monolayer with age and in disease states is an important cause of loss of corneal transparency. McAlister et al. (p. 3597) tested a direct molecular approach to induction of increased corneal endothelial cell density in which the cell cycle transcription factor E2F2 was overexpressed in endothelium of human corneas. Following exposure to recombinant adenovirus vector to transfer E2F2 cDNA, progression from G1 to S phase of the cell cycle and increased cell density were demonstrated. Vector-mediated overexpression of transcription factors such as E2F2 has great potential as a non-surgical approach to disorders resulting in endothelial decompensation.
Targeted Deletion of AP-2a in the Corneal Epithelium
AP-2a is a developmentally important transcription factor that is expressed in the more basally located cells of the corneal epithelium and has been shown to play a role in corneal epithelial repair. Dwivedi et al. (p. 3623) have created a conditional knockout of AP-2a in the corneal epithelium to examine its requirement in corneal epithelial differentiation. In the absence of AP-2a, Le-AP-2a mutant mice exhibited prominent defects in corneal epithelial stratification, cell adhesion, and basement membrane deposition. These defects led to abnormalities in the corneal stroma including activation of stromal fibroblasts. AP-2a is thus required for normal differentiation and integrity of the corneal epithelium.
Detection of Autopathogenic T Cells in Experimental Autoimmune Uveitis
Karabekian et al. (p. 3769) describe generation of a dimeric MHC-antigen reagent that specifically binds to the antigen receptor of autopathogenic cells, which cause autoimmune uveitis in the mouse model. By fluorescently labeling the reagent, cells that carry the specific antigen receptor can be detected and studied. Furthermore, cells that have bound the reagent become specifically unresponsive to the antigen in question. Self antigens involved in ocular diseases are increasingly being identified, and chimeric molecules of this type have potential not only as research tools, but ultimately as diagnostic and potentially therapeutic reagents in the clinic.
Laser Targeted Gene Transfer
Adenovirus gene transfer of an antiangiogenesis and antivasopermeability expression construct is a promising approach for the treatment of various ocular diseases. Anzai et al. (p. 3883) showed that eyes treated with laser photocoagulation and photodynamic therapy, established clinical treatments for retinochoroidal neovascularization and macular edema, manifest increased transduction efficiency in areas of the retina that are targeted by laser treatment. Gene transduction in photocoagulated eyes was enhanced and extended to at least 135 days following virus delivery and was increased even at a dose of 3 x 105 particles per eye. This finding suggests a new and promising strategy for the treatment of retinochoroidal neovascularization and macular edema.
Multiple Pathways in Photoreceptor Apoptosis
Caspase-independent photoreceptor apoptosis has been described in a number of in vivo models of retinal degeneration including the rd mouse. If programmed cell death, the final common pathway in many retinal degenerations, is to become a target for therapeutic intervention, the actual pathways involved require elucidation. The results presented by Doonan et al. (p. 3530) suggest that multiple pathways involving calcium influx and activation of calpains and cathepsins play a role in photoreceptor apoptosis. The ability of these cells to employ multiple death pathways provides an ongoing challenge in the prevention of retinal degenerations and suggests that further investigation is required to identify a common upstream target.
How Adenovirus Ad19 Avoids Host Ocular Immune Response
Adenovirus (Ad) is the major cause of viral conjunctivitis worldwide: Group C serotypes (e.g., Ad5) can produce mild, self-limiting conjunctivitis while Group D serotypes (e.g., Ad19) can cause more serious keratoconjunctivitis. Harvey et al. (p. 3657) performed microarray analysis of human conjunctival epithelial cells, infected with a clinical isolate of Ad5, and identified upregulated host defense genes. These included CXCL10 and CXCL11, encoding interferon-dependent peptides IP-10 and I-TAC. IP-10 has direct antiviral effects against Ad5 but not Ad19. Moreover, preliminary data suggest that the upregulation of IP-10 is blunted during Ad19 infection. Immune evasion by Ad19 therefore includes suppression of, and decreased vulnerability to, innate immune peptides. This evasion, which likely facilitates the oculotropic capability of Ad19, is currently being investigated.
Heritability of Cilioretinal Arteries
Knowing whether a variation in the distribution of retinal vessels is attributable to genetic or environmental factors may facilitate elucidation of the pathogenesis of retinal vascular disease. Taarnhoj et al. (p. 3850) examined the fundi of 112 pairs of healthy monozygotic and dizygotic twins by visual assessment of gray-scale fundus photographs. Statistical analysis yielded a heritability of 71% for the presence of cilioretinal arteries, the remaining variance being attributable to random and environmental factors.
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