Cyclosporin A Eye Drops Inhibit Fibrosis and Inflammatory Cell Infiltration in Murine Type I Allergic Conjunctivitis without Affecting the Early-Phase Reaction

Shii, Daisuke; Nakagawa, Shizu; Shinomiya, Katsuhiko; Yoshimi, Miwa; Katsuta, Osamu; Oda, Tomoko; Nakamura, Masatsugu

doi:10.1080/02713680902866980

Cited by 18 publications

(16 citation statements)

References 26 publications

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“…We also reported that instillation of CyA after the early phase reaction showed inhibitory effects on the increase in fibrosis scores, collagen content, infiltration by inflammatory cells (CD3 ϩ and CD4 ϩ T cells, eosinophils), and the expression of interleukin (IL)-4 and IL-5 mRNA in the conjunctiva after 5 d of antigen challenge in a murine allergic conjunctivitis model. 19) These results suggest that the inhibition of T cells may be an important factor in the inhibitory effects of CyA during the late phase reaction in allergic conjunctivitis.…”

Section: Discussionmentioning

confidence: 74%

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Inhibitory Effects of Cyclosporine A Eye Drops on Symptoms in Late Phase and Delayed-Type Reactions in Allergic Conjunctivitis Models

Shii

Nakagawa

Yoshimi

et al. 2010

Biological & Pharmaceutical Bulletin

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Cyclosporine A (CyA) is a cyclic polypeptide calcineurin inhibitor that was first purified in the 1970s by Novartis Pharma (formerly Sandoz Pharma, Switzerland) from cultures of the fungus Tolypocladium inflatum. It has long been a trusted agent for suppressing not only graft rejection after transplantation, but also immune reaction disorders often observed in autoimmune diseases. The therapeutic effects of CyA eye drops in the treatment of vernal keratoconjunctivitis (VKC), one of the most severe refractory allergic conjunctival diseases, have been described in several studies. [1][2][3] VKC involves severe allergic inflammation sufficient to cause the formation of proliferative conjunctival giant papillae, hyperemia, edema, swelling, mucous discharge and corneal damage. It has been reported that the infiltration of inflammatory cells such as mast cells, eosinophils, neutrophils, and T cells were detected in the papillae of VKC patients. [4][5][6][7][8] Therefore, in addition to immunoglobulin E (IgE)-mediated allergy induced by mast cells, a late phase reaction mediated by eosinophils and delayed-type allergy induced by T cells are thought to be involved in VKC induction.Fukushima et al. reported the inhibitory effect of CyA eye drops on eosinophil infiltration in a mouse allergic conjunctivitis model. 9) We have also reported that the instillation of CyA inhibited neutrophil infiltration into the conjunctiva in a delayed-type allergic conjunctivitis model in guinea pigs. 10)However, the efficacy of CyA eye drops in treating the symptoms in these allergic conjunctivitis models has not been previously reported. Therefore, to understand how CyA works in VKC therapy, we investigated the effects of CyA eye drops on ocular symptoms in late phase and delayed-type allergic conjunctivitis models in guinea pigs. Animals Five-week-old male guinea pigs (Hartley, Nippon SLC, Shizuoka, Japan) were housed under a 12-h light-12-h dark cycle (07:00-19:00 h), with room temperature maintained at 23Ϯ3°C and humidity at 50Ϯ20%. Food and water were given ad libitum. All experiments were performed in accordance with the Association for Research in Vision and Ophthalmology statement for the Use of Animals in Ophthalmic and Vision Research and approved by the Santen Institutional Animal Care and Use Committee. MATERIALS AND METHODS ReagentsInduction of Late Phase Reaction in the Allergic Conjunctivitis Model Allergic conjunctivitis was induced using the method of Sengoku et al.,11) with some modification. OVA solution (40 mg/ml dissolved in saline) was emulsified with an equal volume of FCA. Then, 1 ml of the mixture was intraperitoneally injected into guinea pigs on days 0 and 7. Twenty-four days after the first immunization, 10 ml of 15% OVA solution was applied topically to the right eye to elicit an allergic reaction. Inhibitory Effects of Cyclosporine A Eye Drops on Symptoms in Late Phase and Delayed-Type Reactions in Allergic Conjunctivitis ModelsDaisuke SHII,* Shizu NAKAGAWA, Miwa YOSHIMI, Osamu KATSUTA, Tomoko ODA, and Masat...

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Section: Discussionmentioning

confidence: 74%

“…18) We also reported that instillation of CyA eye drops at 1, 4 and 7 h after antigen-challenge inhibited eosinophil infiltration into conjunctiva in a murine allergic conjunctivitis model. 19) Therefore, it is suggested that the effects of CyA on the late phase reaction are not mediated by suppressing the early phase reaction.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of Cyclosporine A Eye Drops on Symptoms in Late Phase and Delayed-Type Reactions in Allergic Conjunctivitis Models

Shii

Nakagawa

Yoshimi

et al. 2010

Biological & Pharmaceutical Bulletin

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“…15 Topical steroids reduce corneal inflammation, but also suppress the release of TGF␤ 16 and have been shown to reduce the appearance of corneal myofibroblasts and corneal haze after anterior lamellar keratectomy in rabbits.…”

Section: 11mentioning

confidence: 99%

Myofibroblast Differentiation Modulates Keratocyte Crystallin Protein Expression, Concentration, and Cellular Light Scattering

Jester

Brown

Pappa

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The purpose of this study was to determine whether myofibroblast differentiation altered keratocyte crystallin protein concentration and increased cellular light scattering. METHODS. Serum-free cultured rabbit corneal keratocytes and TGF␤ (5 ng/mL) induced myofibroblasts were harvested and counted and protein/RNA extracted. Expression of myofibroblast and keratocyte markers was determined by real-time PCR and Western blot analysis. The cell volume of calcein AMloaded keratocytes and myofibroblasts was determined by using nonlinear optical microscopy. Cellular light scattering of transformed myofibroblasts expressing human keratocyte crystallins was measured by reflectance confocal microscopy. RESULTS. Differentiated myofibroblasts showed a significant decrease in RNA levels for the keratocyte markers ALDH1A1, lumican, and keratocan and a significant increase in the myofibroblast marker ␣-smooth muscle actin. Volumetric and protein measurements showed that myofibroblast differentiation significantly increased cytoplasmic volume (293%; P Ͻ 0.001) and water-soluble and -insoluble protein content per cell (respectively, 442% and 431%; P Ͻ 0.002) compared to keratocytes. Western blot analysis showed that the level of ALDH1A1 protein per cell was similar between myofibroblasts and keratocytes, but was substantially reduced as a percentage of total water-soluble protein. Light scattering measurements showed that induced expression of corneal crystallins significantly decreased light scattering. CONCLUSIONS. These data suggest that myofibroblast differentiation leads to a marked increase in cell volume and dilution of corneal crystallins associated with an increase in cellular light scattering. (Invest Ophthalmol Vis Sci. 2012;53:770 -778) DOI: 10.1167/iovs.11-9092 P revious studies have shown that differentiation of keratocytes into myofibroblasts is regulated in part by transforming growth factor (TGF)-␤.1,2 Under serum-free culture conditions, rabbit, bovine, and human corneal keratocytes maintain a quiescent phenotype, dendritic morphology, and high expression of phenotypic markers, including keratocan, lumican, and the corneal crystallins, aldehyde dehydrogenase isozymes 3A1 and 1A1 (ALDH3A1/1A1) and transketolase (TKT). 3-5Treatment of cultured keratocytes with TGF␤ leads to cell spreading, actin filament assembly, and downregulated expression of keratocyte-specific genes that is coupled with the de novo upregulated expression of ␣-smooth muscle actin (␣-SMA), the phenotypic marker for myofibroblast differentiation. 6 Myofibroblasts play a critical role in corneal wound healing that involves deposition and organization of extracellular matrix leading to wound contraction. [7][8][9] Neutralizing antibodies to TGF␤ have been shown to block the appearance of myofibroblasts in corneal wounds and significantly reduce corneal scarring and the development of corneal haze. 10,11The loss of transparency after corneal injury and scarring has long been associated with the deposition of abnormally arranged and disorg...

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“…A significant difference was also observed between the levels of the other objective symptoms in both of the groups according to the month. In previous studies, it has been shown that Olopatadine was effective in improving conjunctival hyperemia and edema [15,25]. In the study performed by Khurana et al, it was reported that Olopatadine was effective in treating papillary conjunctivitis related to contact lens wear [24].…”

Section: Discussionmentioning

confidence: 94%

“…Several comparative studies between antiallergy medications and design model studies suggested topical treatment of Olopatadine hydrochloride for use in allergic eye diseases. The effects of Olopatadine in the treatment of allergic conjunctivitis on signs such as itching and redness were shown [14][15][16]. When the antihistaminic medications were compared, it was reported that Olopatadine hydrochloride 0.1% caused less discomfort for patients during the use of the drug [3].…”

Section: Discussionmentioning

confidence: 99%

Topical Use of Olopatadine and Cyclosporine a in Treatment of Vernal Keratoconjunctivitis

Knatova¹,

Kantarcı²,

Akata³

et al. 2016

Ann Clin Anal Med

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with Cyclosporine A ophthalmic solution (0.05%) in treating the signs and symptoms of VKC. Material and Method: Twenty-five patients with VKC were included in a prospective study. One eye of each patient was treated with Olopatadine while the other eye was treated with Cyclosporine A. Subjective symptoms of the patients such as itching, tearing, foreign body sensation, and mucus discharge were recorded and scored. The objective signs, such as the presence of giant papillae on the tarsal conjunctiva, bulbar conjunctival hyperemia, keratitis, limbal hypertrophy, corneal vascularization, and conjunctival cicatrization, were scored. Results: There was no significant difference between the Olopatadine group and the Cyclosporine A group regarding subjective symptoms at the 3rd, 6th, 12th, and 18th month. There was a significant improvement in the subjective symptoms of both groups. No significant difference was seen between the groups with regard to objective signs. A significant improvement was observed in the Cyclosporine group in the late period of the study. Discussion: In long-term therapy of VKC, similar effects were seen regarding improvement in the subjective symptoms during the use of topical Olopatadine and Cyclosporine A. In terms of improvement regarding the objective signs, Cyclosporine A was seen to be more effective in the late period.

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Cyclosporin A Eye Drops Inhibit Fibrosis and Inflammatory Cell Infiltration in Murine Type I Allergic Conjunctivitis without Affecting the Early-Phase Reaction

Abstract: The results suggest that cyclosporin A eye drops inhibited fibrosis and inflammatory cell infiltration by the suppression of Th2 cytokine production in repeatedly antigen-challenged conjunctiva without affecting the early-phase reaction.

Cited by 18 publications

References 26 publications

Inhibitory Effects of Cyclosporine A Eye Drops on Symptoms in Late Phase and Delayed-Type Reactions in Allergic Conjunctivitis Models

Inhibitory Effects of Cyclosporine A Eye Drops on Symptoms in Late Phase and Delayed-Type Reactions in Allergic Conjunctivitis Models

Myofibroblast Differentiation Modulates Keratocyte Crystallin Protein Expression, Concentration, and Cellular Light Scattering

Topical Use of Olopatadine and Cyclosporine a in Treatment of Vernal Keratoconjunctivitis

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