Reversal of the abnormal development of T cell subpopulations in the thymus of autoimmune MRL-lpr/lpr mice by a polyamine biosynthesis inhibitor.
Polyamines--putrescine, spermidine, and spermine--are a group of positively charged organic molecules that are present in all living cells. They are important regulators of cell growth and differentiation, but the precise mechanism of their action is not known. Ornithine decarboxylase (ODC) is a key enzyme in the biosynthesis of polyamines. Recent studies demonstrated that down-regulation of polyamine biosynthesis by irreversible inhibition of ODC with difluoromethylornithine (DFMO0 is a novel therapeutic approach for the treatment of murine lupus in autoimmune MRL-lpr/lpr mice. Since murine lupus in this strain is associated with a major alteration in thymic T cell subopulations, we questioned whether abnormal polyamine biosynthesis contributes to aberrant T cell maturation in the thymus of MRL-lpr/lpr mice. Thymocytes were analyzed for cell surface markers, CD4 and CD8 by 2-color flow cytometry using their respective monoclonal antibodies. The proportion of thymocyte subsets in disease-free mice (8-10 week of age) was approximately 72% double positive (DP; CD4+CD8+) cells, 5-7% double negative (DN; CD4-CD8-) cells, 11-16% CD4+ cells and 7-8% CD8+ cells. At 14 weeks of age, a stage of clinical disease expression, thymocytes were marked by the presence of approximately 40% DN cells and approximately 25% DP cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Thomas
T J
TJ
Program in Clinical Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick 08903.
Gunnia
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UB
Thomas
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D000818:Animals; D015551:Autoimmunity; D016516:CD4-CD8 Ratio; D004195:Disease Models, Animal; D000518:Eflornithine / Q000494:pharmacology* / Q000627:therapeutic use; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D011700:Putrescine / Q000096:biosynthesis*; D013095:Spermidine / Q000096:biosynthesis*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects*; D013950:Thymus Gland / Q000502:physiology*
D065108:Ornithine Decarboxylase Inhibitors; D009955:Ornithine Decarboxylase; D013095:Spermidine; D011700:Putrescine; D000518:Eflornithine