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

Abstract

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...

Cytokines in Tears during the Secondary Keratoconjunctival Responses Induced by Allergic Reaction in the Nasal Mucosa

“…The conjunctival provocation tests with allergens, performed directly on the conjunctiva, confirm the role of an allergic reaction occurring in the conjunctiva due to a direct exposure of conjunctival tissue to an inhalant allergen [3,8,12,15,16,17,21,38,42]. …”

“…Different hypersensitivity mechanisms activated by direct exposure of the conjunctiva to external allergens result then in the development of different types of primary KCR, such as an IKCR, LKCR or DYKCR [1,2,3,4,8,9,10,11,12,13,14,15,16,17,38,41,42,43]. Similarly, different hypersensitivity mechanisms taking place in the nasal mucosa leading to the development of different types of nasal response can then, under certain circumstances, induce different types of the SKCR, such as an SIKCR, SLKCR or SDYKCR [7,8,9,10,11,12,38].…”

“…an immediate/early (IKCR), late (LKCR) or delayed (DYKCR) response [2,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18]. …”

“…The cytokines in the tears of the KC patients have already been studied from various points of view [1,5,6,14,15,16,17,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36]. Nevertheless, there is a dearth of data related to the course of the cytokine changes in tears during the individual KCR types of the primary KC form [1,2,3,9,10,11,12,13,15,17,19,20,37,38,39,40,41,42,43].…”

Ameliorative Effect of Thymoquinone on Ovalbumin-induced Allergic Conjunctivitis in Balb/c Mice

“…6 Thus, exacerbation of the symptom scores may reflect the phase of an allergic reaction both in human and animal models. 5,18 Ocular symptoms such as swelling, hyperemia and discharge were found in mice after allergen exposure compared with the control group. TQ suppressed the ocular symptoms significantly in the mice with AC disease.…”