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The immunopharmacology of SDZ MRL 953, a new lipid a derivative
Abstracts
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48 SDZ MRL 953 RAISES GRANULOcrr~ COb%ITS, ACCELERATES G~k~Ol,O~rrg RECOVERY AND ENHANCES Bl~-rz~rM. CLEARANCE IN CYCLOPEOSPHAMIDE - TREATED MICE. J. Hildebrandt and E. Liehl. Sandoz Forschungsinstitut, A 1235 Vienna/Austria, Brunnerstr. 59 B6D2F 1 mice were myelosuppressed by cyclophosphamide injection (200mg/kg s.c.) and were infectfid with Pseudomonas aeruginosa, Escherichia coli or Staphylococcus aureus four days later. Within 48 hours, > 954 of the infected mice died, but when treated with SDZ MRL 953 ( 5 mg/kg i.p.) one and three days prior to infection, i00 ~ of the mice survived. Bacterial inoculation of SDZ MRL 953-treated mice induced a prompt rise in total WBC counts by a factor of 2 - 8. The increase was mainly a result of the number of circulating granulocytes which rose from &00-600/ul blood up to 8000-12000/~I blood within 48 to 72 hours. In the untreated, infected mice, total WBCs and granulocytes were about 100 times lower in the blood of the few animals which survived up to 24 and 48 hours. Bacterial counts (CFUs) in the peripheral blood of the infected and SDZ MRL 953-treated animals declined rapidly to undetectable levels within 72 hours after infection. These data show that augmentation of resistance to microbial infections in myelosuppressed mice by treatment with SDZ MRL 953 is mediated by stimulation of the hematopoiesis and, as shown elsewhere, by activation of mature phagocytic cells for enhanced phagocytosis and intracellular killing of bacteria.
49. The Immunopharmacology of SDZ MRL 953, a New Lipid A D e r i v a t i v e E. L i e h l , C. Lam, J . H i l d e b r a n d t , E. Schfitze, J . F . J e a n n i n , N . v . J e n e y Sandoz F o r s c h u n g s i n s t i t u t Ges.m.b.H., 1235 Vienna, A u s t r i a , Europe *INSERM Unit6 252, 21033 Dijon, France SDZ MRL 953, a s y n t h e t i c a c y l a t e d glucosamine m o n o s a c c h a r i d e - l - p h o s p h a t e , i s an LPS mimic e x e r t i n g s t r o n g LPS-like immunostimulatory a c t i v i t y but with a g r e a t l y reduced e n d o t o x i c p o t e n t i a l f o r p y r o g e n i c i t y and shock i n d u c t i o n . In vivo, a s t r o n g b a c t e r i a l r e s i s t a n c e i s induced v i a the i n d u c t i o n of hemopoietic growth f a c t o r s and f u n c t i o n a l a c t i v a t i o n of monocytes and g r a n u l o c y t e s . S i m u l t a n e o u s l y , a n t i e n d o t o x i c - and a n t i - s e p t i c shock a c t i v i t y i s observed, mediated by i n d u c t i o n of e a r l y phase LPS t o l e r a n c e . In such a n i m a l s , the i n d u c i b i l i t y of p r o i n f l a m m a t o r y c y t o k i n e s by LPS i s d o v n r e g u l a t e d , while b a c t e r i a l k i l l i n g by phagocytes remains at a high level. SDZ MRL 953 also inhibits the progression of tumor growth in various animal models, possibly by IL-6 induction and activation of tumor cell cytotoxic macrophages. Thus, SDZ MRL 953 seems to be a promising agent for the prophylactic treatment of patients at risk for infections and septic shock due to neutropenia, and has a great potential in adjuvant tumor therapy.
5(1. SDZ MIIL 953 Induces Tolerance to Lethal Effects of Endotoxin Vhile Immunity Against Microbial Infections. C. Lam, E. Schfitze, E. Quakyi Forschungsinstitut, A-1235 Vienna, Austria.
Enh--cing Nonspeeifie and E. Liehl. Sandoz
Induction of tolerance to lethal effects of lipopolysaecharides (LPS) was investigated as a novel approach for the management of immunocompromised patients at risk of gram-negative sepsis. SDZ MRL 953, a novel monosaccharidic lipid A analog, which has little or none of the toxicity of LPS, was administered to mice prophylactically before the animals were challenged with lethal dose of LPS plus D-galactosamine or infected i.p. with 10 x LDI^ 0 of micro-organisms. The analog induced a transient resistance (-1 week) to the lethal effects of LPS and enhanced immunity to the infections. The effects were time- and dose-dependent. Optimal protection was observed when the analog was administered prophylactically on three consecutive days. Peritoneal macrophages (Me) from the tolerized mice produced only a fraction of the LPS-induced TNF that was released by cells from placebo groups. However, they were primed for interferon-yinduced nitric oxide synthesis and were more effective in killing an isolate of Escherichia coli than control cells. Again, the Me from mice tolerized by repeated pre-dosing with SDZ MRL 953 produced significantly less TNF and were more effective in killing bacteria than cells from control animals. In conclusion, the present results show that SDZ MRL 953 enhances microbicidal capacity of Me while rendering the cells hyporesponsive to LPS.
727
48 SDZ MRL 953 RAISES GRANULOcrr~ COb%ITS, ACCELERATES G~k~Ol,O~rrg RECOVERY AND ENHANCES Bl~-rz~rM. CLEARANCE IN CYCLOPEOSPHAMIDE - TREATED MICE. J. Hildebrandt and E. Liehl. Sandoz Forschungsinstitut, A 1235 Vienna/Austria, Brunnerstr. 59 B6D2F 1 mice were myelosuppressed by cyclophosphamide injection (200mg/kg s.c.) and were infectfid with Pseudomonas aeruginosa, Escherichia coli or Staphylococcus aureus four days later. Within 48 hours, > 954 of the infected mice died, but when treated with SDZ MRL 953 ( 5 mg/kg i.p.) one and three days prior to infection, i00 ~ of the mice survived. Bacterial inoculation of SDZ MRL 953-treated mice induced a prompt rise in total WBC counts by a factor of 2 - 8. The increase was mainly a result of the number of circulating granulocytes which rose from &00-600/ul blood up to 8000-12000/~I blood within 48 to 72 hours. In the untreated, infected mice, total WBCs and granulocytes were about 100 times lower in the blood of the few animals which survived up to 24 and 48 hours. Bacterial counts (CFUs) in the peripheral blood of the infected and SDZ MRL 953-treated animals declined rapidly to undetectable levels within 72 hours after infection. These data show that augmentation of resistance to microbial infections in myelosuppressed mice by treatment with SDZ MRL 953 is mediated by stimulation of the hematopoiesis and, as shown elsewhere, by activation of mature phagocytic cells for enhanced phagocytosis and intracellular killing of bacteria.
49. The Immunopharmacology of SDZ MRL 953, a New Lipid A D e r i v a t i v e E. L i e h l , C. Lam, J . H i l d e b r a n d t , E. Schfitze, J . F . J e a n n i n , N . v . J e n e y Sandoz F o r s c h u n g s i n s t i t u t Ges.m.b.H., 1235 Vienna, A u s t r i a , Europe *INSERM Unit6 252, 21033 Dijon, France SDZ MRL 953, a s y n t h e t i c a c y l a t e d glucosamine m o n o s a c c h a r i d e - l - p h o s p h a t e , i s an LPS mimic e x e r t i n g s t r o n g LPS-like immunostimulatory a c t i v i t y but with a g r e a t l y reduced e n d o t o x i c p o t e n t i a l f o r p y r o g e n i c i t y and shock i n d u c t i o n . In vivo, a s t r o n g b a c t e r i a l r e s i s t a n c e i s induced v i a the i n d u c t i o n of hemopoietic growth f a c t o r s and f u n c t i o n a l a c t i v a t i o n of monocytes and g r a n u l o c y t e s . S i m u l t a n e o u s l y , a n t i e n d o t o x i c - and a n t i - s e p t i c shock a c t i v i t y i s observed, mediated by i n d u c t i o n of e a r l y phase LPS t o l e r a n c e . In such a n i m a l s , the i n d u c i b i l i t y of p r o i n f l a m m a t o r y c y t o k i n e s by LPS i s d o v n r e g u l a t e d , while b a c t e r i a l k i l l i n g by phagocytes remains at a high level. SDZ MRL 953 also inhibits the progression of tumor growth in various animal models, possibly by IL-6 induction and activation of tumor cell cytotoxic macrophages. Thus, SDZ MRL 953 seems to be a promising agent for the prophylactic treatment of patients at risk for infections and septic shock due to neutropenia, and has a great potential in adjuvant tumor therapy.
5(1. SDZ MIIL 953 Induces Tolerance to Lethal Effects of Endotoxin Vhile Immunity Against Microbial Infections. C. Lam, E. Schfitze, E. Quakyi Forschungsinstitut, A-1235 Vienna, Austria.
Enh--cing Nonspeeifie and E. Liehl. Sandoz
Induction of tolerance to lethal effects of lipopolysaecharides (LPS) was investigated as a novel approach for the management of immunocompromised patients at risk of gram-negative sepsis. SDZ MRL 953, a novel monosaccharidic lipid A analog, which has little or none of the toxicity of LPS, was administered to mice prophylactically before the animals were challenged with lethal dose of LPS plus D-galactosamine or infected i.p. with 10 x LDI^ 0 of micro-organisms. The analog induced a transient resistance (-1 week) to the lethal effects of LPS and enhanced immunity to the infections. The effects were time- and dose-dependent. Optimal protection was observed when the analog was administered prophylactically on three consecutive days. Peritoneal macrophages (Me) from the tolerized mice produced only a fraction of the LPS-induced TNF that was released by cells from placebo groups. However, they were primed for interferon-yinduced nitric oxide synthesis and were more effective in killing an isolate of Escherichia coli than control cells. Again, the Me from mice tolerized by repeated pre-dosing with SDZ MRL 953 produced significantly less TNF and were more effective in killing bacteria than cells from control animals. In conclusion, the present results show that SDZ MRL 953 enhances microbicidal capacity of Me while rendering the cells hyporesponsive to LPS.