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Chi-Chao Chan, Xiaoguang Cao, Defen Shen, Yujuan Wang, Jun Zhang, Joo Y. Oh, Darwin J. Prockop, Jingsheng Tuo; Anti-inflammatory Recombinant TSG-6 Stabilizes The Progression Of Focal Retinal Degeneration In A Murine AMD Model. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1228.
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The inflammatory responses are detected in the retina of age-related macular degeneration (AMD) patients and Ccl2-/-/Cx3cr1-/- mice on rd8 background, a model that develops progressive AMD-like retinal lesions including focal photoreceptor degeneration, abnormal retinal pigment epithelium, and A2E accumulation. Tumor necrosis factor-inducible gene 6 protein (TSG-6) is an anti-inflammatory protein and has shown to improve myocardial infarction and chemically injured cornea in mice by suppressing inflammation. In this study, we evaluated the effect of intravitreous injection of recombinant TSG-6 on the retinal lesions of these Ccl2-/-/Cx3cr1-/- mice.
Recombinant TSG-6 (400 ng) was intravitreously injected into the right eyes of 2-month-old Ccl2-/-/Cx3cr1-/- mice. The left eyes were injected with PBS as controls. Funduscopic pictures were taken before injection and sequentially once a month after injection. The mice were sacrificed 2 months after injection. Ocular histopathology was examined. Retinal A2E, a major component of lipofuscin, was measured by HPLC. The microarray of ocular mRNA of 92 immunological genes was performed. The genes showing differentiated expression in microarray were further compared between the injected right eyes and the contralateral (control) eyes by quantitative RT-PCR.
The continuous monitoring of the fundus for 2 months showed a slower progression or alleviation of retinal lesions in the treated right eyes as compared to the untreated left eyes. Among 23 pairs of eyes, 78.3% were improved, 8.7% stayed the same and 13.0% remained progressing in the lesion levels. Histology confirmed the clinical observation. Even though there was no difference in the level of A2E between the treated and the untreated control eyes, microarray analysis of 92 immune genes showed that IL-17a relative expression was substantially decreased after the treatment. The TNF-α expression showed a similar pattern of IL-17a. The results were consistent in duplicated arrays and confirmed by quantitative RT-PCR.
The study showed that intravitreous administration of recombinant TSG-6 might stabilize retinal lesions in Ccl2-/-/Cx3cr1-/- mice on rd8 background. Modulation of ocular immunological gene expressions, especially cytokine IL-17a, could be one of the mechanisms.
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