IMMUNOSUPPRESSION MEDIATED BY AN INHIBITOR OF S-ADENOSYL-L-HOMOCYSTEINE HYDROLASE - PREVENTION AND TREATMENT OF COLLAGEN-INDUCED ARTHRITIS

The potent irreversible inhibitor of S-adenosyl-L-homocysteine hydrola se (Z)-5'-fluoro-4',5'-didehydro-5'-deoxyadenosine (MDL 28,842) was ex amined for its effect on the development and treatment of collagen-ind uced arthritis in mice. We have previously shown that MDL 28,842 inhib its T cell activation without affecting B cell activation. Animals wer e dosed with MDL 28,842 at 5, 2.5, or 1 mg/kg/day p.o. in water beginn ing 1 day before immunization with chick type II collagen (CII) and co ntinuing through day 51 postimmunization. None of the animals treated with MDL 28,842 at 5 or 2.5 mg/kg/day developed arthritis compared wit h 87.5% of the controls. Animals treated with 1 mg/kg MDL 28,842 had a delay in the development of the disease and a decreased incidence of arthritis (55%) during the course of treatment. After the treatment wa s discontinued, 40% of the mice in the 5-mg/kg treatment group, 60% of the mice who had previously received 2.5 mg/kg MDL 28,842, and 27% of the mice in the 1-mg/kg treatment group remained free of any signs of arthritis. Treatment with MDL 28,842 also lowered serum anti-CII IgG levels. In addition, T cells taken from animals immunized with CII and treated with 2.5-mg/kg/day MDL 28,842 had a lower proliferative respo nse to denatured CII in vitro than controls. Therapeutically, MDL 28,8 42 was administered to animals at 2.5 mg/kg/day p.o., beginning at the first clinical signs of arthritis and continuing for 4 wk. Over the c ourse of treatment, there was significantly less clinical disease in a nimals given MDL 28,842. In addition, at the end of treatment, hind pa ws were removed from the animals and examined radiographically and his tologically for joint pathology. Animals treated with MDL 28,842 had s ignificantly fewer bone lesions than control animals. These results su ggest that inhibitors of S-adenosyl-L-homocysteine hydrolase may be ef fective anti-arthritic agents.