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Infliximab exerts a dose-dependent effect on retinal safety in the albino rabbit

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Abstract

Purpose

To assess the retinal toxicity of an intravitreal injection of infliximab, a monoclonal antibody to tumor necrosis factor α, in a rabbit model.

Materials and methods

Two groups of adult albino rabbits (n = 5) received intravitreal injections of infliximab (0.1 ml) in the study eye and balanced salt solution (BSS, 0.1 ml) in the control eye at baseline. Group 1 was administered with 1.5 mg/0.1 ml, and group 2 was injected with 7.5 mg/0.1 ml of infliximab solution. Electroretinography (ERG) was performed at baseline and at 1, 7, 30, and 45 days after the injection. Visual evoked potentials (VEPs) were recorded at 7 and 45 days after the injection. After the last electrophysiological assessment, the rabbits were euthanized and retinal histopathology and immunhistochemistry for glial fibrillary acidic protein (GFAP) were performed.

Results

ERG responses demonstrated no significant deficit in retinal function in eyes injected with infliximab. Mean dark-adapted a-wave and b-wave maximal amplitude and semi-saturation constant values at baseline and throughout the 45 days of follow-up after the injection indicated no remarkable difference in outer retinal function between the control and experimental eyes. VEP responses were similar at each time point (7 and 45 days). No difference was seen in retinal histopathology and immunocytochemistry sections in eyes receiving the 1.5 mg/0.1 ml dose compared to the control eyes. However, increased GFAP labeling in retinal Müller cells was detected in rabbit eyes treated with the 7.5 mg/0.1 ml dose.

Conclusions

Intravitreal injection of 1.5 mg/0.1 ml infliximab dose has no toxic effect on the integrity (functional or structural) of the retina in rabbits. A higher dose of 7.5 mg/0.1 ml may be slightly toxic as suggested by positive Müller cell GFAP expression. Additional studies of retinal toxicity at higher doses and after multiple injections are needed to establish the retinal safety of intravitreal infliximab therapy in humans.

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References

  1. Frater-Schroder M, Risau W, Hallmann R, Gautschi P, Bohlen P (1987) Tumor necrosis factor type alpha, a potent inhibitor of endothelial cell growth in vitro, is angiogenic in vivo. Proc Natl Acad Sci USA 84(15):5277–5281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Rosenbaum JT, Howes EL Jr, Rubin RM, Samples JR (1988) Ocular inflammatory effects of intravitreally-injected tumor necrosis factor. Am J Pathol 133(1):47–53

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Armstrong D, Augustin AJ, Spengler R, Al-Jada A, Nickola T, Grus F, Koch F (1998) Detection of vascular endothelial growth factor and tumor necrosis factor alpha in epiretinal membranes of proliferative diabetic retinopathy, proliferative vitreoretinopathy and macular pucker. Ophthalmologica 212(6):410–414

    Article  CAS  PubMed  Google Scholar 

  4. Majka S, McGuire PG, Das A (2002) Regulation of matrix metalloproteinase expression by tumor necrosis factor in a murine model of retinal neovascularization. Invest Ophthalmol Vis Sci 43(1):260–266

    PubMed  Google Scholar 

  5. Derevjanik NL, Vinores SA, Xiao WH, Mori K, Turon T, Hudish T, Dong S, Campochiaro PA (2002) Quantitative assessment of the integrity of the blood-retinal barrier in mice. Invest Ophthalmol Vis Sci 43(7):2462–2467

    PubMed  Google Scholar 

  6. Vinores SA, Xiao WH, Shen J, Campochiaro PA (2007) TNF-alpha is critical for ischemia-induced leukostasis, but not retinal neovascularization nor VEGF-induced leakage. J Neuroimmunol 182(1–2):73–79. doi:10.1016/j.jneuroim.2006.09.015

    Article  CAS  PubMed  Google Scholar 

  7. Koizumi K, Poulaki V, Doehmen S, Welsandt G, Radetzky S, Lappas A, Kociok N, Kirchhof B, Joussen AM (2003) Contribution of TNF-alpha to leukocyte adhesion, vascular leakage, and apoptotic cell death in endotoxin-induced uveitis in vivo. Invest Ophthalmol Vis Sci 44(5):2184–2191

    Article  PubMed  Google Scholar 

  8. Nakamura S, Yamakawa T, Sugita M, Kijima M, Ishioka M, Tanaka S, Ohno S (1994) The role of tumor necrosis factor-alpha in the induction of experimental autoimmune uveoretinitis in mice. Invest Ophthalmol Vis Sci 35(11):3884–3889

    CAS  PubMed  Google Scholar 

  9. Caspi RR, Roberge FG, McAllister CG, el-Saied M, Kuwabara T, Gery I, Hanna E, Nussenblatt RB (1986) T cell lines mediating experimental autoimmune uveoretinitis (EAU) in the rat. J Immunol 136(3):928–933

    CAS  PubMed  Google Scholar 

  10. Sartani G, Silver PB, Rizzo LV, Chan CC, Wiggert B, Mastorakos G, Caspi RR (1996) Anti-tumor necrosis factor alpha therapy suppresses the induction of experimental autoimmune uveoretinitis in mice by inhibiting antigen priming. Invest Ophthalmol Vis Sci 37(11):2211–2218

    CAS  PubMed  Google Scholar 

  11. Robertson M, Liversidge J, Forrester JV, Dick AD (2003) Neutralizing tumor necrosis factor-alpha activity suppresses activation of infiltrating macrophages in experimental autoimmune uveoretinitis. Invest Ophthalmol Vis Sci 44(7):3034–3041

    Article  PubMed  Google Scholar 

  12. Fleisher LN, Ferrell JB, McGahan MC (1990) Ocular inflammatory effects of intravitreally injected tumor necrosis factor-alpha and endotoxin. Inflammation 14(3):325–335

    Article  CAS  PubMed  Google Scholar 

  13. De Vos AF, Van Haren MA, Verhagen C, Hoekzema R, Kijlstra A (1995) Systemic anti-tumor necrosis factor antibody treatment exacerbates endotoxin-induced uveitis in the rat. Exp Eye Res 61(6):667–675

    Article  PubMed  Google Scholar 

  14. Santos Lacomba M, Marcos Martin C, Gallardo Galera JM, Gomez Vidal MA, Collantes Estevez E, Ramirez Chamond R, Omar M (2001) Aqueous humor and serum tumor necrosis factor-alpha in clinical uveitis. Ophthalmic Res 33(5):251–255. doi:10.1159/000055677

  15. Ozdamar Y, Berker N, Bahar G, Soykan E, Bicer T, Ozkan SS, Karakaya J (2009) Inflammatory mediators and posterior segment involvement in ocular Behcet disease. Eur J Ophthalmol 19(6):998–1003

    PubMed  Google Scholar 

  16. Theodossiadis PG, Markomichelakis NN, Sfikakis PP (2007) Tumor necrosis factor antagonists: preliminary evidence for an emerging approach in the treatment of ocular inflammation. Retina 27(4):399–413. doi:10.1097/MAJ.0b013e3180318fbc

    Article  PubMed  Google Scholar 

  17. Oh H, Takagi H, Takagi C, Suzuma K, Otani A, Ishida K, Matsumura M, Ogura Y, Honda Y (1999) The potential angiogenic role of macrophages in the formation of choroidal neovascular membranes. Invest Ophthalmol Vis Sci 40(9):1891–1898

    CAS  PubMed  Google Scholar 

  18. Abu El-Asrar AM, Abboud EB, Aldibhi H, Al-Arfaj A (2005) Long-term safety and efficacy of infliximab therapy in refractory uveitis due to Behcet’s disease. Int Ophthalmol 26(3):83–92. doi:10.1007/s10792-006-9006-9

    Article  PubMed  Google Scholar 

  19. Arias L, Caminal JM, Badia MB, Rubio MJ, Catala J, Pujol O (2010) Intravitreal infliximab in patients with macular degeneration who are nonresponders to antivascular endothelial growth factor therapy. Retina 30(10):1601–1608. doi:10.1097/IAE.0b013e3181e9f942

    Article  PubMed  Google Scholar 

  20. Wu L, Arevalo JF, Hernandez-Bogantes E, Regatieri CV, Roca JA, Farah ME (2013) Intravitreal tumor necrosis factor-alpha inhibitors for neovascular age-related macular degeneration suboptimally responsive to antivascular endothelial growth factor agents: a pilot study from the Pan American Collaborative Retina Study Group. J Ocul Pharmacol Ther 29(3):366–371. doi:10.1089/jop.2012.0203

    Article  CAS  PubMed  Google Scholar 

  21. Bazzoni F, Beutler B (1996) The tumor necrosis factor ligand and receptor families. N Engl J Med 334(26):1717–1725. doi:10.1056/NEJM199606273342607

    Article  CAS  PubMed  Google Scholar 

  22. Nadkarni S, Mauri C, Ehrenstein MR (2007) Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta. J Exp Med 204(1):33–39. doi:10.1084/jem.20061531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wu L, Hernandez-Bogantes E, Roca JA, Arevalo JF, Barraza K, Lasave AF (2011) intravitreal tumor necrosis factor inhibitors in the treatment of refractory diabetic macular edema: a pilot study from the Pan-American Collaborative Retina Study Group. Retina 31(2):298–303. doi:10.1097/IAE.0b013e3181eac7a6

    Article  CAS  PubMed  Google Scholar 

  24. Farvardin M, Afarid M, Mehryar M, Hosseini H (2010) Intravitreal infliximab for the treatment of sight-threatening chronic noninfectious uveitis. Retina 30(9):1530–1535. doi:10.1097/IAE.0b013e3181d3758a

    Article  PubMed  Google Scholar 

  25. Farvardin M, Afarid M, Shahrzad S (2012) Long-term effects of intravitreal infliximab for treatment of sight-threatening chronic noninfectious uveitis. J Ocul Pharmacol Ther 28(6):628–631. doi:10.1089/jop.2011.0199

    CAS  PubMed  Google Scholar 

  26. Markomichelakis N, Delicha E, Masselos S, Sfikakis PP (2012) Intravitreal infliximab for sight-threatening relapsing uveitis in Behcet disease: a pilot study in 15 patients. Am J Ophthalmol 154(3):534–541.e1. doi:10.1016/j.ajo.2012.03.035

  27. Gupta SR, Phan IT, Suhler EB (2011) Successful treatment of refractory sympathetic ophthalmia in a child with infliximab. Arch Ophthalmol 129(2):250–252. doi:10.1001/archophthalmol.2010.358

    Article  PubMed  Google Scholar 

  28. Wu L, Arevalo JF, Hernandez-Bogantes E, Roca JA (2012) Intravitreal infliximab for refractory pseudophakic cystoid macular edema: results of the Pan-American Collaborative Retina Study Group. Int Ophthalmol 32(3):235–243. doi:10.1007/s10792-012-9559-8

    Article  PubMed  Google Scholar 

  29. Giansanti F, Ramazzotti M, Vannozzi L, Rapizzi E, Fiore T, Iaccheri B, Degl’ Innocenti D, Moncini D, Menchini U (2008) A pilot study on ocular safety of intravitreal infliximab in a rabbit model. Invest Ophthalmol Vis Sci 49(3):1151–1156. doi:10.1167/iovs.07-0932

    Article  PubMed  Google Scholar 

  30. Theodossiadis PG, Liarakos VS, Sfikakis PP, Charonis A, Agrogiannis G, Kavantzas N, Vergados IA (2009) Intravitreal administration of the anti-TNF monoclonal antibody infliximab in the rabbit. Graefes Arch Clin Exp Ophthalmol 247(2):273–281. doi:10.1007/s00417-008-0967-4

    Article  CAS  PubMed  Google Scholar 

  31. Zayit-Soudry S, Zemel E, Loewenstein A, Perlman I (2010) Safety evaluation of repeated intravitreal injections of bevacizumab and ranibizumab in rabbit eyes. Retina 30(4):671–681. doi:10.1097/IAE.0b013e3181c0858c

    Article  PubMed  Google Scholar 

  32. Hood DC, Birch DG (1992) A computational model of the amplitude and implicit time of the b-wave of the human ERG. Vis Neurosci 8(2):107–126

    Article  CAS  PubMed  Google Scholar 

  33. Perlman I (2009) Testing retinal toxicity of drugs in animal models using electrophysiological and morphological techniques. Documenta ophthalmologica Advances in Ophthalmology 118(1):3–28. doi:10.1007/s10633-008-9153-6

    Article  PubMed  Google Scholar 

  34. Loewenstein A, Zemel E, Lazar M, Perlman I (1993) Drug-induced retinal toxicity in albino rabbits: the effects of imipenem and aztreonam. Invest Ophthalmol Vis Sci 34(12):3466–3476

    CAS  PubMed  Google Scholar 

  35. Nork TM, Ghobrial MW, Peyman GA, Tso MO (1986) Massive retinal gliosis. A reactive proliferation of Muller cells. Arch Ophthalmol 104(9):1383–1389

    Article  CAS  PubMed  Google Scholar 

  36. Penn JS, Thum LA, Rhem MN, Dell SJ (1988) Effects of oxygen rearing on the electroretinogram and GFA-protein in the rat. Invest Ophthalmol Vis Sci 29(11):1623–1630

    CAS  PubMed  Google Scholar 

  37. Ekstrom P, Sanyal S, Narfstrom K, Chader GJ, van Veen T (1988) Accumulation of glial fibrillary acidic protein in Muller radial glia during retinal degeneration. Invest Ophthalmol Vis Sci 29(9):1363–1371

    CAS  PubMed  Google Scholar 

  38. Li Q, Zemel E, Miller B, Perlman I (2002) Early retinal damage in experimental diabetes: electroretinographical and morphological observations. Exp Eye Res 74(5):615–625. doi:10.1006/exer.2002.1170

    Article  CAS  PubMed  Google Scholar 

  39. Chavez AE, Roncagliolo M, Kuhrt H, Reichenbach A, Palacios AG (2003) The retinal anatomy and function of the myelin mutant taiep rat. Brain Res 964(1):144–152

    Article  CAS  PubMed  Google Scholar 

  40. Green DG, Kapousta-Bruneau NV (1999) A dissection of the electroretinogram from the isolated rat retina with microelectrodes and drugs. Vis Neurosci 16(4):727–741

    Article  CAS  PubMed  Google Scholar 

  41. Karwoski CJ, Xu X (1999) Current source-density analysis of light-evoked field potentials in rabbit retina. Vis Neurosci 16(2):369–377

    Article  CAS  PubMed  Google Scholar 

  42. Lei B, Perlman I (1999) The contributions of voltage- and time-dependent potassium conductances to the electroretinogram in rabbits. Vis Neurosci 16(4):743–754

    Article  CAS  PubMed  Google Scholar 

  43. Rowe-Rendleman CL, Durazo SA, Kompella UB, Rittenhouse KD, Di Polo A, Weiner AL, Grossniklaus HE, Naash MI, Lewin AS, Horsager A, Edelhauser HF (2014) Drug and gene delivery to the back of the eye: from bench to bedside. Invest Ophthalmol Vis Sci 55(4):2714–2730. doi:10.1167/iovs.13-13707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Ophthalmology, Rambam Health Care Campus, Haifa, Israel

    Shiri Zayit-Soudry & Michael Mimouni

  2. Ruth and Bruce Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel

    Igor Vainer, Esther Zemel, Michael Mimouni & Ido Perlman

  3. California Retina Consultants and Research Foundation, Santa Barbara, CA, USA

    Melvin Rabena & Dante J. Pieramici

  4. Rappaport Institute for Biomedical Research, Technion Israel Institute of Technology, Haifa, Israel

    Esther Zemel & Ido Perlman

  5. Department of Ophthalmology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Anat Loewenstein

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  1. Shiri Zayit-Soudry
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  2. Igor Vainer
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Correspondence to Shiri Zayit-Soudry.

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Zayit-Soudry, S., Vainer, I., Zemel, E. et al. Infliximab exerts a dose-dependent effect on retinal safety in the albino rabbit. Doc Ophthalmol 135, 175–185 (2017). https://doi.org/10.1007/s10633-017-9606-x

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