Macular Degeneration: Tezel TH

Schaal S, Tezel TH, Kaplan HJ. · No affiliation provided · Ocul Immunol Inflamm. · Pubmed #19065414 No free full text.

This publication has no abstract.

Tezel TH, Kaplan HJ. · No affiliation provided · Ocul Immunol Inflamm. · Pubmed #17365799 No free full text.

This publication has no abstract.

Sohn JH, Bora PS, Jha P, Tezel TH, Kaplan HJ, Bora NS. · Department of Ophthalmology, Jones Eye Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205-7199, USA. · Chem Immunol Allergy. · Pubmed #17264487 No free full text.

Abstract: The complement system is a major component of innate immunity. During an inflammatory reaction, the eye is potentially threatened by homologous complement attack, and unregulated complement activation could lead to tissue damage and vision loss. The complement system is continuously activated at low levels in the normal eye, and intraocular complement-regulatory proteins (CRPs) tightly regulate this spontaneous complement activation so that there is elimination of potential pathogens without the induction of destructive intraocular inflammation. The presence of a complement activation product (iC3b) during the early phase of antigen and antigen-presenting cell contact is essential for the induction of systemic tolerance to antigen injected into the anterior chamber of the eye and the establishment of ocular immune privilege. The complement system and complement-regulatory proteins control intraocular inflammation in autoimmune anterior uveitis and may play an important role in the development of age-related macular degeneration. Thus, in the eye, complement functions as a double-edged sword - on one hand it provides innate immunity against pathogens while simultaneously instructing the adaptive immune response to develop tolerance to such pathogens to avoid inadvertent tissue damage in a critical organ.

Del Priore LV, Tezel TH, Kaplan HJ. · Department of Ophthalmology, The Edward S. Harkness Eye Institute, Columbia University, NY, USA. · Prog Retin Eye Res. · Pubmed #17071125 No free full text.

Abstract: Age-related macular degeneration (AMD) is the leading cause of blindness in the western world. Over the last decade, there have been significant advances in the management of exudative AMD with the introduction of anti-VEGF drugs; however, many patients with exudative AMD continue to lose vision and there are no effective treatments for advanced exudative AMD or geographic atrophy. Initial attempts at macular reconstruction using cellular transplantation have not been effective in reversing vision loss. Herein we discuss the current status of surgical attempts to reconstruct damaged subretinal anatomy in advanced AMD. We reinforce the concept of maculoplasty for advanced AMD, which is defined as reconstruction of macular anatomy in patients with advanced vision loss. Successful maculoplasty is a three-step process that includes replacing or repairing damaged cells (using transplantation, translocation or stimulation of autologous cell proliferation); immune suppression (if allografts are used to replace damaged cells); and reconstruction or replacement of Bruch's membrane (to restore the integrity of the substrate for proper cell attachment). In the current article we will review the rationale for maculoplasty in advanced AMD, and discuss the results of initial clinical attempts at macular reconstruction. We will then discuss the role of Bruch's membrane damage in limiting transplant survival and visual recovery, and discuss the effects of age-related changes within human Bruch's membrane on the initial attachment and subsequent proliferation of transplanted cells. We will discuss attempts to repair Bruch's membrane by coating with extracellular matrix ligands, anatomic reconstitution of the inner collagen layer, and the effects of Bruch's membrane reconstruction of ultrastuctural anatomy and subsequent cell behavior. Lastly, we will emphasize the importance of continued efforts required for successful maculoplasty.

Tezel TH, Bora NS, Kaplan HJ. · Department of Ophthalmology & Visual Sciences, Kentucky Lions Eye Center, University of Louisville, Louisville, KY 40202, USA. · Trends Mol Med. · Pubmed #15350892 No free full text.

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Kaplan HJ, Tezel TH, Berger AS, Del Priore LV. · Department of Ophthalmology and Visual Sciences Washington University School of Medicine, St. Louis, Mo., USA. · Chem Immunol. · Pubmed #10590581 No free full text.

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Tezel TH, Geng L, Lato EB, Schaal S, Liu Y, Dean D, Klein JB, Kaplan HJ. · Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. · Invest Ophthalmol Vis Sci. · Pubmed #19060278 No free full text.

Abstract: PURPOSE: To demonstrate the production of hemoglobin by human retinal pigment epithelium (RPE). METHODS: Proteomic analysis using 10 donor eyes identified hemoglobin as a major constituent of soluble human RPE proteome. Western blot analysis, RT-PCR, and immunocytochemistry were used to confirm the RESULTS: The presence of erythrocyte-specific proteins within primary human RPE cytosol was investigated to rule out phagocytosis as the source of hemoglobin. ELISA was used to determine the rate of hemoglobin secretion from human RPE cells. Globin mRNA expression of human RPE was studied in comparison with a human erythroblast cell line and a spontaneously transformed human RPE cell line (ARPE-19). results. Hemoglobin is a regular constituent of soluble human RPE proteome. RT-PCR and Western blot analysis confirmed the presence of hemoglobin in human RPE. No other erythrocyte-specific proteins were detected within human RPE cytosol. Hemoglobin expression persisted up to seven passages in vitro. Human RPE globin expression exceeded that in human erythroblast and ARPE-19 cells. Immunohistochemistry revealed the presence of hemoglobin within RPE and Bruch's membrane. The hemoglobin release rate was calculated to be 1.9+/-1.2 attomoles per cell per hour. CONCLUSIONS: Hemoglobin expression by human RPE brings a new perspective to the understanding of oxygen transport to the outer retina. Malfunction of RPE-hemoglobin production may underlie the pathophysiology of ocular diseases characterized by subfoveal hypoxia and VEGF upregulation, such as age-related macular degeneration and diabetic retinopathy. Pharmacologic modulations of local hemoglobin production in RPE cells will create new opportunities to interfere with the course of these diseases.

Schaal S, Kaplan HJ, Tezel TH. · Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. · Ophthalmology. · Pubmed #18930553 No free full text.

Abstract: PURPOSE: To determine whether repetitive injections of intravitreal bevacizumab and/or triamcinolone acetate in patients with exudative age-related macular degeneration (AMD) results in a decrease in biological response. DESIGN: Retrospective comparative case series. PARTICIPANTS: Forty-three eyes of 43 patients with exudative AMD. METHODS: Pre- and postinjection optical coherence tomography (OCT) sections of 43 patients with AMD were analyzed to determine the change in the biologic response after each subsequent injection of intravitreal bevacizumab (2.5 mg/100 microL), preservative-free triamcinolone acetonide (pfTA) (4.0 mg/100 microL), or a combination of bevacizumab (1.25 mg/50 microL) and pfTA (2.0 mg/50 microL). The retinal thickness of each OCT sector was determined and expressed as volume. Standardized volumetric change index (SVCI) was determined to identify a statistically significant change. Pre- and postinjection (6 weeks) SVCI differences were plotted as a function of time to determine the biological response after each intravitreal treatment. MAIN OUTCOME MEASURES: Change in SVCI after intravitreal injections and the number of injections required to decrease the biological response by 50% (INJ(50)). RESULTS: There was no difference in the age, gender, and preinjection thickness of the retina in each of the 3 groups. The SVCI after intravitreal bevacizumab injections decreased, indicating a possible tachyphylactic response to bevacizumab. This decrease in biological response was partially alleviated with the addition of pfTA. Combination of pfTA and bevacizumab increased the INJ(50) from 2.9 with bevacizumab alone to 5.1 injections. A biphasic biologic response was observed with pfTA characterized by a rapid increase in efficacy with the second injection, peaking at the third injection and gradually decreasing afterward. CONCLUSIONS: Repeated intravitreal injections of bevacizumab in exudative AMD seemed to be associated with decreased bioefficacy. However, combined pharmacotherapy with triamcinolone acetate lessened this effect. Thus, multitargeted pharmacotherapy in exudative AMD may have a therapeutic benefit. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Sun K, Cai H, Tezel TH, Paik D, Gaillard ER, Del Priore LV. · Department of Ophthalmology, Harkness Eye Institute, Columbia University, New York, NY 10032, USA. · Mol Vis. · Pubmed #18199972 links to  free full text

Abstract: PURPOSE: We have shown previously that aging of human Bruch's membrane affects the attachment, survival and gene expression profile of the overlying retinal pigment epithelium (RPE). Herein we determine the effects of Bruch's membrane aging on RPE phagocytosis of rod outer segments. METHODS: Explants of human Bruch's membrane were prepared from cadaver donor eyes (aged 9-81years) within 48 h of death, and 6 mm punches were embedded with the basal lamina in a 96-well plate. Approximately 50,000 ARPE-19 cells per well were seeded onto the explant surface and cultured for two weeks until they reached confluence. In addition, ARPE-19 were also seeded onto RPE-derived extracellular matrix (RPE-ECM) that was unmodified or modified by nonenzymatic nitration. Bovine rod outer segments were purified by sucrose gradient centrifugation, labeled with 10 ug/ml fluorescein isothiocyanate, and added to ARPE-19 cultured on Bruch's membrane or RPE-ECM for 24 h. Phagocytic activity was quantified by flow cytometry of harvested cells. RESULTS: The ability of RPE to phagocytose rod outer segments decreased as a function of aging of Bruch's membrane; mean phagocytotic activity of ARPE-19 on younger Bruch's membrane was significantly higher than on older Bruch's membrane (129.7 +/- 34.8 versus 67.4 +/- 4.2 arbitrary units, respectively; p<0.01). Nitrite treatment of RPE-ECM decreased rod outer segment phagocytosis compared to untreated RPE-ECM and mimicked the effects of aging of human Bruch's membrane. CONCLUSIONS: Aging of human Bruch's membrane decreases rod outer segment phagocytosis by ARPE-19. This effect can be mimicked by nonenzymatic nitration of extracellular matrix in vitro. Our observations may have implications for understanding the role of aging changes within Bruch's membrane on pathogenesis of age-related macular degeneration and other disorders.

Tezel TH, Bodek E, Sönmez K, Kaliappan S, Kaplan HJ, Hu Z, Garen A. · Department of Ophthalmology & Visual Sciences, Kentucky Lions Eye Center, University of Louisville School of Medicine, Louisville, KY 40202, USA. · Ocul Immunol Inflamm. · Pubmed #17365800 No free full text.

Abstract: PURPOSE: ICON is a fusion protein composed of factor VII, the natural ligand for tissue factor, conjugated to the Fc domain of a human IgG1 immunoglobulin. It binds to the tissue factor expressed on neovascular endothelia and initiates a cytolytic immune attack that destroys the neovascular tissue. We previously showed that mouse factor VII-Fc chimeric antibody (mICON) dramatically decreases the frequency of choroidal neovascularization in a laser-induced choroidal neovascularization model in mice. Herein, we determined the safety and efficacy of mICON in destroying subretinal choroidal neovascularization in pig eyes. METHODS: mICON (150-1200 microg) was administered into the midvitreous cavity of the pig eye either before (on Day 0) or after (on Day 10) induction of choroidal neovascularization with laser photocoagulation. On Day 14, the incidence of choroidal neovascularization was determined using confocal microscopy. We also determined the binding specificity (% binding to choroidal neovascularization/% binding to non-choroidal neovascularization areas) of mICON to tissue factor expressed on endothelial cells of laser-induced choroidal neovascularization. RESULTS: We observed that mICON selectively destroyed choroidal neovascularization in a dose-dependent manner (r = -0.93; EDB50B = 571.3 microg). Obliteration of the choroidal neovascular complex was more prominent at doses > 300 microg (p < 0.05). No systemic or local complications (including retinal tear/detachment, inflammation, infection, cataract, or glaucoma) were observed. Binding specificities of hICON (2.2 +/- 0.2) and mICON (3.4 +/- 0.4) were significantly higher than that of anti-von Willebrand antibody (0.1 +/- 0.01, p < 0.001). CONCLUSIONS: Both hICON and mICON bound to the neovascular endothelia of choroidal neovascularization with greater specificity than anti-von Willebrand antibody. Furthermore, mICON can selectively obliterate already established choroidal neovascularization, which suggests that it may be useful for immunotherapy in patients with exudative (wet) macular degeneration.

Tezel TH, Del Priore LV, Berger AS, Kaplan HJ. · Department of Ophthalmology & Visual Sciences, Kentucky Lions Eye Center, University of Louisville School of Medicine, Louisville, Kentucky, USA. · Am J Ophthalmol. · Pubmed #17303061 No free full text.

Abstract: PURPOSE: To improve visual function by retinal pigment epithelial (RPE) cell transplantation and systemic immunosuppression at the time of surgical removal of subfoveal choroidal neovascularization in exudative age-related macular degeneration (AMD). DESIGN: An interventional case series of RPE transplantation in exudative AMD. METHODS: Twelve patients (one eye only) underwent subfoveal membranectomy with transplantation of a sheet of adult human allogeneic RPE cells at a single institution and were followed for one year. Eligibility criteria included age >60, best-corrected acuity < or =20/63 and subfoveal neovascularization < or =9 disk areas on preoperative fluorescein angiography. All patients were started on triple immunosuppression postoperatively. The primary outcome measure was best-corrected vision, with contrast sensitivity and reading speed as secondary outcome measures. RESULTS: The best-corrected visual acuity (P = .085), contrast sensitivity (P = .204), and the reading speed (P = .077) did not change significantly at one year compared with preoperative values. Transplants showed no signs of rejection in patients who were able to continue the immunosuppressants for six months. Postoperative surgical complications included cataract progression requiring surgery (three of eight phakic eyes), retinal detachment (three eyes), intraoperative retinal breaks (two eyes), and macular pucker (two eyes). None of the patients developed cystoid macular edema on postoperative fluorescein angiography or postoperative inflammation. CONCLUSIONS: A sheet of adult human allogeneic RPE can be transplanted into the subretinal space in AMD patients at the time of subfoveal membranectomy. Systemic immune suppression appeared to prevent rejection of the transplanted tissue, but did not lead to an improvement in visual function.

Cai H, Shin MC, Tezel TH, Kaplan HJ, Del Priore LV. · Department of Ophthalmology, Harkness Eye Institute, Columbia University, 635 W. 165th Street, New York, NY 10032, USA. · Arch Ophthalmol. · Pubmed #16966623 links to  free full text

Abstract: OBJECTIVE: To determine the gene expression profiles of primary retinal pigment epithelium (RPE) and iris pigment epithelium (IPE) using microarrays. METHODS: Primary RPE and IPE from 6 human donor eyes were collected, and total RNA was isolated. Differences in gene expression were determined using a human genechip (human U95Av2 [12 600 probes]; Affymetrix Inc, Santa Clara, Calif). RESULTS: Hierarchical cluster analysis differentiated the gene expression profiles of RPE and IPE clusters into 2 distinct groups. A mean +/- SD of 5308 +/- 416 gene probes were expressed in RPE vs 6130 +/- 205 in IPE. Sixty-eight genes were expressed only in RPE; 154 genes were expressed only in IPE. Twenty-two additional genes had greater than 3-fold increased expression in RPE vs IPE, and 147 genes had greater than 3-fold decreased expression in RPE vs IPE. CONCLUSION: There are major differences in the gene expression profiles of primary RPE vs IPE.Clinical Relevance The different gene expression profiles of primary RPE vs IPE harvested from the same donor eyes infer that it may be difficult for IPE to replace all aspects of damaged RPE function in transplantation studies.

Bora PS, Hu Z, Tezel TH, Sohn JH, Kang SG, Cruz JM, Bora NS, Garen A, Kaplan HJ. · Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, KY 40202, USA. · Proc Natl Acad Sci U S A. · Pubmed #12589025 links to  free full text

Abstract: Age-related macular degeneration (AMD) is the leading cause of blindness after age 55 in the industrialized world. Severe loss of central vision frequently occurs with the exudative (wet) form of AMD, as a result of the formation of a pathological choroidal neovasculature (CNV) that damages the macular region of the retina. We tested the effect of an immunotherapy procedure, which had been shown to destroy the pathological neovasculature in solid tumors, on the formation of laser-induced CNV in a mouse model simulating exudative AMD in humans. The procedure involves administering an Icon molecule that binds with high affinity and specificity to tissue factor (TF), resulting in the activation of a potent cytolytic immune response against cells expressing TF. The Icon binds selectively to TF on the vascular endothelium of a CNV in the mouse and pig models and also on the CNV of patients with exudative AMD. Here we show that the Icon dramatically reduces the frequency of CNV formation in the mouse model. After laser treatment to induce CNV formation, the mice were injected either with an adenoviral vector encoding the Icon, resulting in synthesis of the Icon by vector-infected mouse cells, or with the Icon protein. The route of injection was i.v. or intraocular. The efficacy of the Icon in preventing formation of laser-induced CNV depends on binding selectively to the CNV. Because the Icon binds selectively to the CNV in exudative AMD as well as to laser-induced CNV, the Icon might also be efficacious for treating patients with exudative AMD.

Del Priore LV, Kaplan HJ, Tezel TH, Hayashi N, Berger AS, Green WR. · Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA. · Am J Ophthalmol. · Pubmed #11292411 No free full text.

Abstract: PURPOSE: To report the histopathology after retinal pigment epithelial cell transplantation and subfoveal membranectomy in age-related macular degeneration. METHODS: An 85-year-old white woman with bilateral choroidal neovascularization underwent subfoveal membranectomy combined with transplantation of a sheet of human adult retinal pigment epithelium (retinal pigment epithelium) under the foveal center in the right eye. The patient was immunosuppressed postoperatively with prednisone, cyclosporine, and azathioprine. The patient died from congestive heart failure 114 days after surgery. RESULTS: A patch of hyperpigmentation was visible at the transplant site under the foveola after surgery. Mound-like clusters of individual round, large densely pigmented cells were present in the subretinal space and outer retina in this area. There was loss of the photoreceptor outer segments and native retinal pigment epithelium in the center of the transplant bed, with disruption of the outer nuclear layer predominantly over regions of multilayered pigmented cells. Cystic spaces were present in the inner and outer retina. A residual intra-Bruchs membrane component of the original choroidal neovascular complex was present under the transplant site. CONCLUSIONS: The transplant site contained clusters of round, pigmented cells that did not form a uniform monolayer in most areas. The morphology at the transplant site is consistent with the lack of visual improvement seen after surgery in this patient.

Tezel TH, Del Priore LV. · Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA. · Invest Ophthalmol Vis Sci. · Pubmed #10067982 links to  free full text

Abstract: PURPOSE: To determine the morphology of human retinal pigment epithelium (RPE) after reattachment to different ultrastructural layers of human Bruch's membrane (BM). METHODS: Bruch's membrane explants were prepared from eyes of 23 human donors (age range, 11-89 years). The basal lamina of the RPE, inner collagenous layer, and elastin layer were removed sequentially by mechanical and enzymatic techniques. First-passage cells of human RPE (15,000 cells/6 mm explant) from three donors (ages, 52, 64, and 80 years) were plated onto different layers of human BM, and the explants were examined by scanning and transmission electron microscopy up to 21 days later. RESULTS: RPE flattened and extended footplates 6 hours after plating onto basal lamina. Cells remained round 6 and 24 hours after plating onto the inner collagenous, elastin, or outer collagenous layer. The RPE cells became confluent 14 days after plating onto basal lamina but did not become confluent up to 21 days after plating onto the inner collagenous or elastin layer. Sparse round cells were observed 21 days after plating onto deeper layers, suggesting extensive loss of RPE. CONCLUSIONS: The morphology and subsequent behavior of the RPE reattached to BM depends on the anatomic layer of BM available for cell reattachment. The results suggest that the ability of transplanted RPE to repopulate BM in age-related macular degeneration and other disorders may depend on the layer of BM available to serve as a substrate for cell reattachment.