Suppression of S-Antigen-induced Experimental Autoimmune Uveoretinitis in Lewis Rats by Oral Administration with CGS-13080, A Thromboxane Synthetase Inhibitor

Abstract

Oral administration of CGS-13080 [imidazo (1, 5-α) pyridine-5-hexanoic acid], a thromboxane synthetase inhibitor, has been reported to cause a marked reduction in serum thromboxane B 2 concentration in humans and animals. Since thromboxane metabolites play an important role in ocular inflammation, the effect of oral CGS-13080 in the development of experimental autoimmune uveoretinitis in Lewis rats has been investigated. Females were immunized with bovine S-antigen (S-Ag). Treatment was started on day 0 of immunization. Animals were divided into three groups. The control group was fed a standard pellet diet, while the treated groups were fed the standard diet supplemented with either a low dose (0·8 g per 10 kg pellet) or a high dose (1·6 g per 10 kg pellet) of CGS 13080. From day 10 after immunization, the eyes of these rats were examined daily for clinical evidence of experimental autoimmune uveoretinitis. On day 14, the eyes were collected for histologic study. The cellular immune responses were evaluated on the draining inguinal lymph nodes. Blood samples were also collected for the measurement of anti-S-Ag antibody production, thromboxane B 2 and prostaglandin A 2 levels. Clinical disease developed in 73·3% of the control rat group. 30·0% of the low-dose treated group and 17·6% of the high-dose group. The average histologic grade was 1·9 in the control group, 0·65 in low-dose group and 0·32 in high-dose group. Lymphocyte proliferation to S-Ag paralleled the clinical disease scores. Average stimulation indices were 10·9 in the controls, 7·5 in the low-dose group and 2·2 in the high-dose group. In treated groups, serum thromboxane B 2 levels were significantly reduced with a concomitant increase in prostaglandin A 2 levels, suggesting a shunting of cyclic endoperoxide metabolism. There was an increase of serum anti-S-Ag antibody level in all three groups, but no significant difference between control and treated groups. In conclusion, oral CGS-13080 mixed in the diet has an inhibitory effect on the development of experimental autoimmune uveoretinitis. The blockage of the efferent limb of immune response and inhibition of T lymphocytes in response to S-Ag may be involved in the mechanism.