Methyl-acetylenicputrescine (MAP), an inhibitor of polyamine biosynthesis, reduces the frequency and cytolytic activity of alloantigen-induced LyT 2.2 positive lymphocytes in vivo.
The objective of the present investigation was to examine the effect of (2R,5R)-6-heptyne-2,5-diamine (methyl-acetylenicputrescine; MAP), an irreversible inhibitor of ODC, on the induction of alloreactivity in vivo. Treatment of mice with MAP (0.5-0.01% in drinking water) inhibited CTL induction in a dose-dependent manner with an IC50 of approximately 144 mg/kg/day. MAP treatment reduced the frequency of LyT2+ (cytolytic/suppressor) splenic lymphocytes by greater than 75%. In contrast, MAP did not alter the number of L3T4+ (helper/inducer) lymphocytes. MAP treatment reduced lymphocyte putrescine and spermidine levels by 61 and 40%, respectively. The inhibitory effect of MAP on CTL induction could be reversed by simultaneous administration of putrescine (500 mg/kg). These data indicate that the observed inhibitory effect of MAP on CTL induction is mediated through inhibition of polyamine biosynthesis. Furthermore, results of the present investigation suggest that inhibition of polyamine biosynthesis may provide a unique target for immunosuppression.
Bowlin
T L
TL
Merrell Dow Research Institute, Cincinnati, OH 45215.
McKown
B J
BJ
Schroeder
K K
KK
D000480:Alkynes; D000818:Animals; D003959:Diamines / Q000494:pharmacology*; D004306:Dose-Response Relationship, Immunologic; D007274:Injections, Intraperitoneal; D007519:Isoantigens / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011700:Putrescine / Q000008:administration & dosage / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*
D000480:Alkynes; D003959:Diamines; D007519:Isoantigens; C039613:6-heptyne-2,5-diamine; D011700:Putrescine