Immunotherapy in ocular diseases
Mochizuki, M.
Nippon Ganka Gakkai Zasshi 96(12): 1608-1634
1992
ISSN/ISBN: 0029-0203 PMID: 1283052 Document Number: 388270
Basic and clinical studies on immunotherapy in immune-mediated ocular disorders, i.e. uveitis, allograft rejection in corneal transplantation and allergic conjuctivitis, were carried out using a variety of immunosuppressants, including immunophilin ligands (FK506 and cyclosporine). 1. In an animal model for uveitis, experimental autoimmune uveitis (EAU), immunophilin ligands were demonstrated in the rat and monkey to have unique immunological activities: (1) intense and prolonged suppression of EAU development, (2) therapeutic effects by treating animals only after disease onset, (3) selective suppression of cellular immune respone to S-antigen, (4) induction of immunological tolerance and activation of antigen specific suppressor cells. Combination therapy with low doses of immunophilin ligand and other immunosuppressant was tested to achieve better effects with less side effects. A low dose of cyclosporine (2 mg/kg/day) with bucillamine (20 mg/kg/day) which suppresses antigen-presenting activity by macrophages caused much stronger suppression of EAU than the therapy with either cyclosporine or bucillamine alone. Similarly, a low dose of FK506 (0.1 mg/kg/day) with dexamethasone (0.01 mg/kg/day) caused stronger suppression of EAU. A multi-center clinical open trial of FK506 in refractory uveitis was carried out in Japan. A total of 40 cases of active uveitis in the posterior segment of the eye were treated with FK506 (0.05, 0.1 or 0.2 mg/kg/day) and the mean observation period was 26.2 +- 12.4 weeks. FK506 therapy improed uveitis in 60% of all cases including 47% of patients resistant to previous therapy with cyclosporine. FK506 significantly suppressed the number of uveitis attacks in patients with Behcet's disease. As for the side effects, 22.5% of patients showed abnormal values of renal function on FK506. The trough level of FK506 in whole blood correlated with adverse side effects as well as with therapeutic effect on uveitis, and it should be maintained between 15 and 25 ng/ml. 2. Effects of immunophilin ligands on the allograft rejection in corneal transplantation was examined in the rat. Fisher rat were used as donors and Lewis rats as recipients. This combination caused 100% rejection by 2 apprx 3 weeks after surgery as indicated by (1) edema, opacity and neovascularization in the graft, (2) infiltration of a variety of immune cells demonstrated by immunohistological examination and (3) high mixed leukocyte reaction (MLR). Systemic administration of cyclosporine (10 mg/kg/day) or FK506 (0.3, 1,3 mg/kg/day) suppressed the allograft rejection. In addition, topical instillation of FK506 (0.3%) was effective to prolong the graft survival as long as the topical therapy continued. This data suggests that systemic or topical immunophilin ligands can be used for the treatment of allograft rejection in corneal transplantation. Recently, it was reported that immunophilin ligands suppress IgE receptor-mediated signal transduction which results in the exocytosis of secretory granules from basophilis or mast cells. However, no studies have been carried out to test their in vitro effects on immediate hypersensitivity. Therefore, the effects of topical FK506 on passive allergic conjunctivitis were examined in the rat. Topical FK506 significantly suppressed allergic conjunctivitis as well as degranulation of mast cells in the subconjunctival tissues and the effect was stronger than that of 0.1% betamethasone or 2% DSCG. This data thus indicates that topical immunophilin ligands can be beneficial for the therapy of severe allergic conjunctivitis such as vernal conjunctivitis.