S-adenosyl-L-homocysteine hydrolase inhibitor mediates immunosuppressive effects in vivo: Suppression of delayed type hypersensitivity ear swelling and peptidoglycan polysaccharide-induced arthritis

A specific and potent inhibitor of S-adenosyl-L-homocysteine (AdoHcy) hydro lase, 9-[(1'R,2'S,3'R)-2',3'-dihydroxycyclopentanyl] adenine (DHCaA), was e valuated for its immunosuppressive efficacy on murine T-cell proliferation in vitro and in several animal models, including delayed type hypersensitiv ity ear swelling and peptidoglycan polysaccharide-induced arthritis. The co ncanavalin A-induced [H-3] thymidine incorporation into T cells was strongl y inhibited by DHCaA with a 50% inhibition concentration (IC50) of 0. 3 muM . In vivo, a dose-dependent reduction (39, 62, and 73%) of ear swelling was observed when 2,4 dinitrofluorobenzene-treated mice were orally administer ed with DHCaA at 1, 5, and 10 mg/kg, respectively. This inhibition in ear s welling dose dependently corresponded to the inhibition of AdoHcy hydrolase activity in the spleen. The more potent the AdoHcy hydrolase inhibitor, th e stronger the immunosuppressive efficacy observed. In rat peptidoglycan po lysaccharide-induced arthritis, orally dosed DHCaA significantly suppressed inflamed paw volumes with minimal effective dose of 0.1 mg/kg. At a dose o f 1 mg/kg, DHCaA almost completely inhibited paw swelling. This inhibition of paw swelling was associated with an inhibition of interleukin-1 beta pro duction in joint tissues. Histopathological evaluation of the joints in rat s treated with 1 mg/kg showed a significant improvement in the reduction of the histopathological grading score from untreated scores of 10.44 to 4.78 . Results from this study indicate that inhibitors of AdoHcy hydrolase coul d be effective anti-inflammatory agents.