Immunosuppressive effects of (2R,5R)-6-heptyne-2,5-diamine, an inhibitor of polyamine synthesis: II. Beneficial effects on the development of a lupus-like disease in MRL-lpr/lpr mice.
(2R,5R)-6-heptyne-2,5-diamine (MAP; MDL 72175), a potent irreversible inhibitor of L-ornithine decarboxylase (ODC), possesses immunosuppressive activities in vitro as the result of inhibition of lymphocyte polyamine biosynthesis. The effects of MAP were now studied in vivo in MRL-lpr/lpr female mice, an animal model for human systemic lupus erythematosus (SLE). Administration of MAP (0.2% in drinking water; drug intake: 0.25-0.35 g/kg body weight/day) to female mice for 15 weeks, starting 8 weeks after birth, reduced by 47% the number of spleen cells, retarded development of lymphadenopathy and, at that time, markedly prolonged the survival of the mice. At week 23, MAP reduced plasma IgG concentrations by 50% whereas, in contrast, those of IgM were elevated 1.5-fold. No statistically significant effects of MAP were observed on plasma levels of anti-DNA autoantibodies although serum anti-RNP and anti-Sm titres tended downwards during treatment. Neither glomerular lesions nor proteinuria were improved by MAP administration. Finally chronic administration of MAP for 45 weeks prolonged the median survival time from 29.75 to 35.5 weeks.
Claverie
N
N
Merrell Dow Research Institute, Strasbourg, France.
Pasquali
J L
JL
Mamont
P S
PS
Danzin
C
C
Weil-Bousson
M
M
Siat
M
M
D000480:Alkynes; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D003959:Diamines / Q000627:therapeutic use*; D005260:Female; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D007678:Kidney Glomerulus / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000473:pathology; D008206:Lymphatic Diseases / Q000517:prevention & control; D051379:Mice; D008815:Mice, Inbred Strains; D065108:Ornithine Decarboxylase Inhibitors; D012436:S-Adenosylmethionine / Q000031:analogs & derivatives / Q000652:urine; D013163:Splenomegaly / Q000517:prevention & control; D013997:Time Factors
D000480:Alkynes; D001323:Autoantibodies; D003959:Diamines; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D065108:Ornithine Decarboxylase Inhibitors; C012702:S-adenosyl-3-methylthiopropylamine; D012436:S-Adenosylmethionine; C039613:6-heptyne-2,5-diamine