Research Article: Aqueous cytokine levels are associated with reduced macular thickness after intravitreal ranibizumab for diabetic macular edema

Date Published: March 27, 2017

Publisher: Public Library of Science

Author(s): Tomoyasu Shiraya, Satoshi Kato, Fumiyuki Araki, Takashi Ueta, Tempei Miyaji, Takuhiro Yamaguchi, Demetrios G. Vavvas.


It is controversial whether the administration of anti-vascular endothelial growth factor drugs for diabetic macular edema (DME) affects intraocular inflammatory cytokines. In this study, we measured cytokine concentration in aqueous humor before and after intravitreal injection of ranibizumab (IVR). The aim was to determine changes in cytokine concentration and their effects on DME reduction.

Twelve patients (13 eyes) with DME received two IVR (0.5 mg) with a 1 month interval, and a total of 26 aqueous humor samples were obtained. Macular thickness was measured with an optical coherence tomography (OCT) using thickness-map mode with an Early Treatment Diabetic Retinopathy Study (ETDRS) 9-zone grid that was divided into two zones: a central circle with a diameter of 1 mm (zone1); and an outer circle with a diameter of 6 mm (zone2).

The concentration of eotaxin-1 in aqueous humor samples decreased significantly after IVR. Baseline cytokine concentration was associated with IVR-induced DME reduction. In zone1, higher baseline concentration of interferon-induced protein (IP)-10, and in zone 2, higher baseline concentration of granulocyte-macrophage colony-stimulating factor, IP-10, and tumor necrosis factor (TNF) α; and lower baseline concentration of eotaxin-1, interleukin (IL)-5, and IL-8 were associated with improved DME. Cytokine changes were associated with IVR-induced DME reduction. In zone1, lower concentration of IP-10 compared to baseline or higher concentration of macrophage inflammatory protein (MIP) -α, and in zone 2, lower concentration of IL-5 compared to baseline, IL-8, and IP-10 or higher concentration of eotaxin-1 and MIP-1β were associated with improved DME.

These findings suggest that ranibizumab affects the concentration of cytokines in aqueous humor. Various cytokines contribute to a decrease in retinal thickness, both in the center of the macula and in a larger area of the retina.

Partial Text

Diabetic macular edema (DME) is a complication of diabetic retinopathy that can cause severe visual impairment [1]. Current treatment options for DME include conventional retinal photocoagulation, intravitreal injections of triamcinolone, and vitreous surgery. More recently, anti-angiogenic therapies have been developed. Recent reports have shown that intravitreal injection of bevacizumab (Avastin®; Genentech Inc., San Francisco, CA, USA), a full-length humanized monoclonal anti- vascular endothelial growth factor (VEGF) antibody fragment (Fab) specifically designed for ocular use, effectively reduces DME [2,3].

A total of 26 aqueous humor samples were obtained from 13 eyes performing initial and second IVR. Only those samples with measurable concentration of cytokines and chemokines at baseline and 1 month post-IVR were included in the analysis. Baseline cytokine concentration and cytokine concentration per type of DME were measured for the following molecules: eotaxin-1, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-1Ra, IL-3, IL-5, IL-8, IP-10, MCP-1, monocyte inflammatory protein (MIP)-1α, MIP-1β, and tumor necrosis factor (TNF)-α. Cytokine changes 1 month post-IVR were determined for eotaxin-1, IL-1Ra, IL-5, IL-8, IP-10, MCP-1, MIP-1α, MIP-1β, and TNF-α.

Higher baseline concentration of IP-10 was associated with improved DME in zone1 and zone2. However, as the concentration of IP-10 decreased post-IVR, DME also improved. The concentration of IP-10 in aqueous humor are elevated in patients with diabetic retinopathy [11,12], and are significantly higher in each of the three patterns of DME compared to control [11]. IP-10 (CXCL10) was initially known as an early, transiently expressed, interferon (IFN) γ-inducible gene in a histiocytic lymphoma cell line with monocytic characteristics [20]. Recently, IP-10 has been reported to inhibit angiogenesis [21,22,23]. Liu et al. showed that IP-10 inhibits angiogenesis by reducing VEGF concentration in mice with alkali-induced corneal neovascularization [23]. This study showed that treatment of DME was more effective in eyes with higher baseline concentration of IP-10, but that a decrease of IP-10 concentration post-IVR contributed to a decreased of outer retinal thickness, not only central retinal thickness.




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