Cyclosporin A eye drops inhibit fibrosis and inflammatory cell infiltration in murine type I allergic conjunctivitis without affecting the early-phase reaction.
OBJECTIVE
To understand the mechanisms of action of cyclosporin A eye drops in severe allergic diseases such as vernal keratoconjunctivitis, the inhibitory effects of cyclosporin A eye drops on fibrosis and inflammatory cell infiltration in murine allergic conjunctivitis were evaluated.


METHODS
BALB/c mice that had been actively sensitized with ovalbumin were challenged with ovalbumin on days 10-14 after initial sensitization. Cyclosporin A (0.1%) or betamethasone (0.1%) eye drops were instilled 1, 4, and 7 hours after each challenge. Ocular tissue was harvested for histological evaluation 24 hours after the last challenge, and conjunctival tissue was collected for the measurement of collagen content and quantitative PCR 8 hours after the last challenge.


RESULTS
Scores for fibrosis and inflammatory cell infiltration and collagen content in the conjunctiva were higher after 5 days of antigen challenge than in normal non-challenged conjunctiva. Instillation of cyclosporin A or betamethasone reduced the antigen-induced increases in scores for fibrosis and inflammatory cell infiltration in the conjunctiva, and cyclosporin A significantly reduced the antigen-induced increase in conjunctival collagen content. Betamethasone also showed a tendency to reduce the increase in collagen content. Cyclosporin A and betamethasone decreased the numbers of CD3(+) and CD4(+) T-cells and eosinophils in the conjunctiva, but did not affect the number of mast cells. Neither type of eye drop suppressed the increase in vascular permeability that occurred for 30 minutes after the last antigen challenge. In quantitative PCR, cyclosporin A suppressed the expression of IL-4 and IL-5 mRNA but did not suppress the expression of transforming growth factor (TGF)-beta 1, whereas betamethasone suppressed the expression of IL-4, IL-5, and TGF-beta 1.


CONCLUSIONS
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.
Shii
Daisuke
D
Research and Development Center, Santen Pharmaceutical Co., Ltd., 8916-16 Takayama-cho, Ikoma-shi, Nara 630-0101, Japan. daisuke.shii@santen.co.jp
Nakagawa
Shizu
S
Shinomiya
Katsuhiko
K
Yoshimi
Miwa
M
Katsuta
Osamu
O
Oda
Tomoko
T
Nakamura
Masatsugu
M
D000818:Animals; D001623:Betamethasone / Q000008:administration & dosage; D002199:Capillary Permeability / Q000187:drug effects; D002464:Cell Migration Inhibition / Q000187:drug effects*; D003094:Collagen / Q000235:genetics; D003233:Conjunctivitis, Allergic / Q000276:immunology / Q000517:prevention & control*; D016572:Cyclosporine / Q000008:administration & dosage*; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology*; D005355:Fibrosis / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009883:Ophthalmic Solutions / Q000008:administration & dosage*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology*
D016207:Cytokines; D007166:Immunosuppressive Agents; D009883:Ophthalmic Solutions; D012333:RNA, Messenger; D016572:Cyclosporine; D003094:Collagen; D001623:Betamethasone