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Sylvie Julien, Ulrich Schraermeyer; Intravitreal Bevacizumab Activates Müller Cells And Astrocytes And Reduces Carbonic Anhydrase In Retinas Of Monkeys: A Possible Explanation For The Reduction Of Retinal Edema. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2023.
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© ARVO (1962-2015); The Authors (2016-present)
To examine the effect of intravitreal bevacizumab on primate eyes with particular focus on choroidal and retinal vessels.
Five cynomolgus monkeys received an intravitreal injection of 1.25 mg bevacizumab with or without tritium labeling. The eyes were enucleated on days 1, 4, 7 and 14 and prepared for light (left eyes) and electron microscopy (right eyes). Control eyes from 6 monkeys remained untreated. Bevacizumab, GFAP, Vimentin, Iba1, CD32 and carbonic anhydrase were localized by immunocytochemistry. Bevacizumab was additionally localized by autoradiography. Thrombocytes and fibrin were stained by histochemistry. The diameter of the choriocapillaris was measured by morphometry.
Bevacizumab has a very strong immunoreactivity and totally or partially filled the sectioned lumen of many blood vessels. Autoradiography showed localization of bevacizumab at the inner sides of retinal vessel walls. At the electron microscopical level, thrombocytes and granulocytes within the retinal vessels exhibited typical signs of activation such as pseudopodia, vacuoles and degranulation. Electron-dense granules resembling serotonin granules released from thrombocytes were present in the bloodstream and endothelium of most vessels. As detected by electron microscopy, felt-like structures (several µm thick) were attached to the inner sides of retinal veins and interacted with blood cells. Microthrombi were frequently observed, one retinal central vein was thrombotic. The diameter of the choriocapillaris was significantly reduced in all treated eyes compared to the control. Müller cells, astrocytes and microglia were activated, FcgammaRIIa receptors were upregulated on the cell membranes of photoreceptors and apical RPE, the ILM was detached and carbonic anhydrase IX was down-regulated after bevacizumab injection.
Bevacizumab has several unexpected effects on the monkey retina. It interferes with retinal and choroidal blood flow. Carbonic anhydrase activity is known to be involved in retinal fluid absorption. Therefore, reduction of carbonic anhydrase activity and activation of Müller cells may cause removal of retinal edema in human retinas. Bevacizumab is known to interact with FcgammaRIIa receptors on thrombocytes that are lacking in rodents. Therefore monkeys but not rodents are relevant models for preclinical studies with intravitreal full length antibodies or VEGF traps.
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