|Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 1998: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1997: ¥3,000,000 (Direct Cost: ¥3,000,000)
Upon ligation with Fas-ligand, cell-surface Fas transmits apoptosis-signals in lymphocytes and cerarnide is considered to act as a second messenger in this pathway. We reported last year that oral administration of a novel immunosuppressant FTY72O, which has a very close structural similarity with ceramide, successfully improved glomerulonephritis and prolonged survival rates of lupusprone MRL-lpr/lpr mice. The purpose of the study this year, therefore, is to examine whether ceramide itself could be used for treatment of MRL-lpr/lpr mice when administered orally.
Because ceramides with long side-chains can not penetrate cell membranes and induce apoptosis in vitro, we selected cell-permeable C2-ceramide in this study. Two mgfkg body weight of C2-ceramide dissolved in olive-oil were administered orally three times a week to 15 MRL-lpr/lpr mice of 4-month old. The same number of MRL-lpr/lpr mice was received either olive-oil alone as a negative control or dexamethasone (2 mg/kg) as a positive control for treatment. Anti-DNA antibody titer in sera, survival curve and renal pathology were examined for the efficacy of the treatments.
At the age of eight months, MRL-lpr/lpr mice treated with C2-ceramide showed a longer survival curve, decreased number of T cells with a CD^<3+>CD^<4->CD^<8-> phenotype, and a lower level of serum anti-DNA antibody than those treated with olive-oil alone. These parameters were all statistically signficant. IgG deposited in glomeruli from mice treated with C2-ceramide was far less than that from mice administered with olive-oil alone. Level of these mprovements induced by oral C2-ceramide was almost comparable with that induced by dexamethasone. Liver damage and hyperglycemia which were desasterous side-effects of systemic anti-Fas antibody and dexamethasone administration, respectively, were not observed.
C2-ceramide seems to deserve further attention for a possible therapeutic regimen with less side-effect.