[Roles of cytokines in the development of severe allergic conjunctival diseases: analyses using animal models].

Conjunctival papillary formation and corneal damage, which are seen in severe types of allergic conjunctival diseases, are mediated by eosinophils. Eosinophils themselves are not able to recognize a specific antigen (Ag) and thus, Ag-specific T cells are thought to be important for eosinophilic infiltration into the conjunctiva. Cytokines, which are produced by Ag-specific T cells followed by Ag recognition, are considered to be involved in eosinophilic infiltration. Therefore, we investigated the involvement of cytokines, which are produced by immunocompetent cells and conjunctival cells, in the infiltration of inflammatory cells into the conjunctiva, using an animal model for allergic conjunctival diseases (experimental immune-mediated blepharoconjunctivitis, EC). The peak of expression of Th 2 cytokines such as interleukin (IL)-4 in the rat conjunctiva was 6 and 12 hours after Ag challenge. In contrast, expression of Th1 cytokines such as interferon (IFN)-gamma persisted up to 48 hours after Ag challenge. The kinetic change of IL-4 was concordant with eosinophilic infiltration into the conjunctiva and that of IFN-gamma was in accord with infiltration of macrophages. To investigate the roles of these cytokines, we induced conjunctivitis in cytokine knockout mice. The infiltration of inflammatory cells was attenuated in IL-4 knockout mice, whereas it was augmented in IFN-gamma knockout mice. To further elucidate the roles of these cytokines, we induced and analyzed EC in Brown Norway rats. Eosinophilic infiltration was increased in EC induced by the transfer of T cells, which were stimulated by IL-4. In addition, systemic treatment with IFN-gamma inhibited eosinophilic infiltration in EC induced by active immunization, but did not affect infiltration of inflammatory cells in EC induced by passive immunization. These results demonstrate that IL-4 and IFN-gamma are involved in the infiltration of eosinophils and macrophages, respectively. In addition, IFN-gamma exerts its suppressive effects on the development of EC only during the induction phase of EC. Further detailed studies investigating the roles of cytokines in the conjunctiva will elucidate the developing mechanism of allergic conjunctival diseases. These studies will provide important clues for a therapeutic approach in targeting cytokines.