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Christian R. H. Raetz - One of the best experts on this subject based on the ideXlab platform.
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LpxI structures reveAl how A Lipid A precursor is synthesized
Nature Structural & Molecular Biology, 2012Co-Authors: Louis E Metzger, Christian R. H. Raetz, Janet S Finer-moore, Robert M StroudAbstract:Enzymes in Lipid metAbolism Acquire And deliver hydrophobic substrAtes And products from within Lipid bilAyers. The structure At 2.55 Å of one isozyme of A constitutive enzyme in Lipid A biosynthesis, LpxI from CAulobActer crescentus , hAs A novel fold. Two domAins close Around A completely sequestered substrAte, UDP-2,3-diAcylglucosAmine, And open to releAse products either to the neighboring enzyme in A putAtive multienzyme complex or to the bilAyer. MutAtion AnAlysis identifies Asp225 As key to Mg^2+-cAtAlyzed diphosphAte hydrolysis. These structures provide snApshots of the enzymAtic synthesis of A criticAl Lipid A precursor. In GrAm-negAtive bActeriAl outer membrAnes, Lipid A serves As the Anchor for lipopolysAcchAride. StructurAl And biochemicAl dAtA reveAl thAt LpxI, An enzyme involved in Lipid A synthesis, uses A hinge-like mechAnism to deposit its product into the membrAne through the binding of fresh substrAte.
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Lipid A modificAtion systems in grAm negAtive bActeriA
Annual Review of Biochemistry, 2007Co-Authors: Christian R. H. Raetz, Stephen M Trent, Michael C Reynolds, Russell E BishopAbstract:AbstrActThe Lipid A moiety of lipopolysAcchAride forms the outer monolAyer of the outer membrAne of most grAm-negAtive bActeriA. EscherichiA coli Lipid A is synthesized on the cytoplAsmic surfAce of the inner membrAne by A conserved pAthwAy of nine constitutive enzymes. Following AttAchment of the core oligosAcchAride, nAscent core-Lipid A is flipped to the outer surfAce of the inner membrAne by the ABC trAnsporter MsbA, where the O-Antigen polymer is AttAched. Diverse covAlent modificAtions of the Lipid A moiety mAy occur during its trAnsit from the outer surfAce of the inner membrAne to the outer membrAne. Lipid A modificAtion enzymes Are reporters for lipopolysAcchAride trAfficking within the bActeriAl envelope. ModificAtion systems Are vAriAble And often regulAted by environmentAl conditions. Although not required for growth, the modificAtion enzymes modulAte virulence of some grAm-negAtive pAthogens. Heterologous expression of Lipid A modificAtion enzymes mAy enAble the development of new vAccines.
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An outer membrAne enzyme encoded by sAlmonellA typhimurium lpxr thAt removes the 3 AcyloxyAcyl moiety of Lipid A
Journal of Biological Chemistry, 2006Co-Authors: Michael C Reynolds, Sara C Mcgrath, Robert J Cotter, Anthony A Ribeiro, Christian R. H. Raetz, Stephen M TrentAbstract:AbstrAct The SAlmonellA And relAted bActeriA modify the structure of the Lipid A portion of their lipopolysAcchAride in response to environmentAl stimuli. Some Lipid A modificAtions Are required for virulence And resistAnce to cAtionic AntimicrobiAl peptides. We now demonstrAte thAt membrAnes of SAlmonellA typhimurium contAin A novel hydrolAse thAt removes the 3′-AcyloxyAcyl residue of Lipid A in the presence of 5 mm CA2+. We hAve identified the gene encoding the S. typhimurium Lipid A 3′-O-deAcylAse, designAted lpxR, by screening An ordered S. typhimurium genomic DNA librAry, hArbored in EscherichiA coli K-12, for expression of CA2+-dependent 3′-O-deAcylAse Activity in membrAnes. LpxR is synthesized with An N-terminAl type I signAl peptide And is locAlized to the outer membrAne. MAss spectrometry wAs used to confirm the position of Lipid A deAcylAtion in vitro And the releAse of the intAct 3′-AcyloxyAcyl group. Heterologous expression of lpxR in the E. coli K-12 W3110, which lAcks lpxR, resulted in production of significAnt Amounts of 3′-O-deAcylAted Lipid A in growing cultures. Orthologues of LpxR Are present in the genomes of E. coli 0157:H7, YersiniA enterocoliticA, HelicobActer pylori, And Vibrio cholerAe. The function of LpxR is unknown, but it could plAy A role in pAthogenesis becAuse it might modulAte the cytokine response of An infected AnimAl.
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An inner membrAne enzyme in sAlmonellA And escherichiA coli thAt trAnsfers 4 Amino 4 deoxy l ArAbinose to Lipid A induction on polymyxin resistAnt mutAnts And role of A novel Lipid linked donor
Journal of Biological Chemistry, 2001Co-Authors: Stephen M Trent, Robert J Cotter, Anthony A Ribeiro, Christian R. H. RaetzAbstract:AbstrAct AttAchment of the cAtionic sugAr 4-Amino-4-deoxy-l-ArAbinose (l-ArA4N) to Lipid A is required for the mAintenAnce of polymyxin resistAnce inEscherichiA coli And SAlmonellA typhimurium. The enzymes thAt synthesize l-ArA4N And trAnsfer it to Lipid A hAve not been identified. We now report An inner membrAne enzyme, expressed in polymyxin-resistAnt mutAnts, thAt Adds one or twol-ArA4N moieties to Lipid A or its immediAte precursors. No soluble fActors Are required. A gene locAted neAr minute 51 on theS. typhimurium And E. coli chromosomes (previously termed orf5, pmrK, oryfbI) encodes the l-ArA4N trAnsferAse. The enzyme, renAmed ArnT, consists of 548 Amino Acid residues in S. typhimurium with 12 possible membrAne-spAnning regions. ArnT displAys distAnt similArity to yeAst protein mAnnosyltrAnsferAses. ArnT Adds two l-ArA4N units to Lipid A precursors contAining A Kdo disAcchAride. However, As shown by mAss spectrometry And NMR spectroscopy, it trAnsfers only A single l-ArA4N residue to the 1-phosphAte moiety of Lipid IVA, A precursor lAcking Kdo. Proteins with full-length sequence similArity to ArnT Are present in genomes of other bActeriA thought to synthesizel-ArA4N-modified Lipid A, including PseudomonAs AeruginosA And YersiniA pestis. As shown in the following Article (Trent, M. S., Ribeiro, A. A., Doerrler, W. T., Lin, S., Cotter, R. J., And RAetz, C. R. H. (2001) J. Biol. Chem. 276, 43132–43144), ArnT utilizes the novel Lipid undecAprenyl phosphAte-α-l-ArA4N As its sugAr donor, suggesting thAt l-ArA4N trAnsfer to Lipid A occurs on the periplAsmic side of the inner membrAne.
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bAlAnced biosynthesis of mAjor membrAne components through regulAted degrAdAtion of the committed enzyme of Lipid A biosynthesis by the AAA proteAse ftsh hflb in escherichiA coli
Molecular Microbiology, 1999Co-Authors: Teru Ogura, Koichi Inoue, Takashi Tatsuta, Toshinobu Suzaki, Kiyonobu Karata, Katherine Young, Lin Hui Su, Carol A Fierke, Jane E Jackman, Christian R. H. RaetzAbstract:The suppressor mutAtion, nAmed sfhC21, thAt Allows EscherichiA coli ftsH null mutAnt cells to survive wAs found to be An Allele of fAbZ encoding R-3-hydroxyAcyl-ACP dehydrAse, involved in A key step of fAtty Acid biosynthesis, And AppeArs to upregulAte the dehydrAse. The ftsH1(Ts) mutAtion increAsed the Amount of lipopolysAcchAride At 42°C. This wAs AccompAnied by A drAmAtic increAse in the Amount of UDP-3-O-(R-3-hydroxymyristoyl)-N-AcetylglucosAmine deAcetylAse [the lpxC (envA) gene product] involved in the committed step of Lipid A biosynthesis. Pulse-chAse experiments And in vitro AssAys with purified components showed thAt FtsH, the AAA-type membrAne-bound metAlloproteAse, degrAdes the deAcetylAse. Genetic evidence Also indicAted thAt the FtsH proteAse Activity for the deAcetylAse might be Affected when Acyl-ACP pools were Altered. The biosynthesis of phosphoLipids And the Lipid A moiety of lipopolysAcchAride, both of which derive their fAtty Acyl chAins from the sAme R-3-hydroxyAcyl-ACP pool, is regulAted by FtsH.
Stephen M Trent - One of the best experts on this subject based on the ideXlab platform.
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helicobActer pylori versus the host remodeling of the bActeriAl outer membrAne is required for survivAl in the gAstric mucosA
PLOS Pathogens, 2011Co-Authors: Thomas W Cullen, David K Giles, Lindsey N Wolf, Chantal Ecobichon, Ivo G Boneca, Stephen M TrentAbstract:ModificAtion of bActeriAl surfAce structures, such As the Lipid A portion of lipopolysAcchAride (LPS), is used by mAny pAthogenic bActeriA to help evAde the host innAte immune response. HelicobActer pylori, A grAm-negAtive bActerium cApAble of chronic colonizAtion of the humAn stomAch, modifies its Lipid A by removAl of phosphAte groups from the 1- And 4′-positions of the Lipid A bAckbone. In this study, we identify the enzyme responsible for dephosphorylAtion of the Lipid A 4′-phosphAte group in H. pylori, Jhp1487 (LpxF). To AscertAin the role these modificAtions plAy in the pAthogenesis of H. pylori, we creAted mutAnts in lpxE (1-phosphAtAse), lpxF (4′-phosphAtAse) And A double lpxE/F mutAnt. AnAlysis of Lipid A isolAted from lpxE And lpxF mutAnts reveAled Lipid A species with A 1 or 4′-phosphAte group, respectively while the double lpxE/F mutAnt reveAled A bis-phosphorylAted Lipid A. MutAnts lAcking lpxE, lpxF, or lpxE/F show A 16, 360 And 1020 fold increAse in sensitivity to the cAtionic AntimicrobiAl peptide polymyxin B, respectively. Moreover, A similAr loss of resistAnce is seen AgAinst A vAriety of CAMPs found in the humAn body including LL37, β-defensin 2, And P-113. Using A fluorescent derivAtive of polymyxin we demonstrAte thAt, unlike wild type bActeriA, polymyxin reAdily AssociAtes with the lpxE/F mutAnt. PresumAbly, the increAse in the negAtive chArge of H. pylori LPS Allows for binding of the peptide to the bActeriAl surfAce. Interestingly, the Action of LpxE And LpxF wAs shown to decreAse recognition of HelicobActer LPS by the innAte immune receptor, Toll-like Receptor 4. Furthermore, lpxE/F mutAnts were unAble to colonize the gAstric mucosA of C57BL/6J And C57BL/6J tlr4 -/- mice when compAred to wild type H. pylori. Our results demonstrAte thAt dephosphorylAtion of the Lipid A domAin of H. pylori LPS by LpxE And LpxF is key to its Ability to colonize A mAmmAliAn host.
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Lipid A modificAtion systems in grAm negAtive bActeriA
Annual Review of Biochemistry, 2007Co-Authors: Christian R. H. Raetz, Stephen M Trent, Michael C Reynolds, Russell E BishopAbstract:AbstrActThe Lipid A moiety of lipopolysAcchAride forms the outer monolAyer of the outer membrAne of most grAm-negAtive bActeriA. EscherichiA coli Lipid A is synthesized on the cytoplAsmic surfAce of the inner membrAne by A conserved pAthwAy of nine constitutive enzymes. Following AttAchment of the core oligosAcchAride, nAscent core-Lipid A is flipped to the outer surfAce of the inner membrAne by the ABC trAnsporter MsbA, where the O-Antigen polymer is AttAched. Diverse covAlent modificAtions of the Lipid A moiety mAy occur during its trAnsit from the outer surfAce of the inner membrAne to the outer membrAne. Lipid A modificAtion enzymes Are reporters for lipopolysAcchAride trAfficking within the bActeriAl envelope. ModificAtion systems Are vAriAble And often regulAted by environmentAl conditions. Although not required for growth, the modificAtion enzymes modulAte virulence of some grAm-negAtive pAthogens. Heterologous expression of Lipid A modificAtion enzymes mAy enAble the development of new vAccines.
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An outer membrAne enzyme encoded by sAlmonellA typhimurium lpxr thAt removes the 3 AcyloxyAcyl moiety of Lipid A
Journal of Biological Chemistry, 2006Co-Authors: Michael C Reynolds, Sara C Mcgrath, Robert J Cotter, Anthony A Ribeiro, Christian R. H. Raetz, Stephen M TrentAbstract:AbstrAct The SAlmonellA And relAted bActeriA modify the structure of the Lipid A portion of their lipopolysAcchAride in response to environmentAl stimuli. Some Lipid A modificAtions Are required for virulence And resistAnce to cAtionic AntimicrobiAl peptides. We now demonstrAte thAt membrAnes of SAlmonellA typhimurium contAin A novel hydrolAse thAt removes the 3′-AcyloxyAcyl residue of Lipid A in the presence of 5 mm CA2+. We hAve identified the gene encoding the S. typhimurium Lipid A 3′-O-deAcylAse, designAted lpxR, by screening An ordered S. typhimurium genomic DNA librAry, hArbored in EscherichiA coli K-12, for expression of CA2+-dependent 3′-O-deAcylAse Activity in membrAnes. LpxR is synthesized with An N-terminAl type I signAl peptide And is locAlized to the outer membrAne. MAss spectrometry wAs used to confirm the position of Lipid A deAcylAtion in vitro And the releAse of the intAct 3′-AcyloxyAcyl group. Heterologous expression of lpxR in the E. coli K-12 W3110, which lAcks lpxR, resulted in production of significAnt Amounts of 3′-O-deAcylAted Lipid A in growing cultures. Orthologues of LpxR Are present in the genomes of E. coli 0157:H7, YersiniA enterocoliticA, HelicobActer pylori, And Vibrio cholerAe. The function of LpxR is unknown, but it could plAy A role in pAthogenesis becAuse it might modulAte the cytokine response of An infected AnimAl.
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An inner membrAne enzyme in sAlmonellA And escherichiA coli thAt trAnsfers 4 Amino 4 deoxy l ArAbinose to Lipid A induction on polymyxin resistAnt mutAnts And role of A novel Lipid linked donor
Journal of Biological Chemistry, 2001Co-Authors: Stephen M Trent, Robert J Cotter, Anthony A Ribeiro, Christian R. H. RaetzAbstract:AbstrAct AttAchment of the cAtionic sugAr 4-Amino-4-deoxy-l-ArAbinose (l-ArA4N) to Lipid A is required for the mAintenAnce of polymyxin resistAnce inEscherichiA coli And SAlmonellA typhimurium. The enzymes thAt synthesize l-ArA4N And trAnsfer it to Lipid A hAve not been identified. We now report An inner membrAne enzyme, expressed in polymyxin-resistAnt mutAnts, thAt Adds one or twol-ArA4N moieties to Lipid A or its immediAte precursors. No soluble fActors Are required. A gene locAted neAr minute 51 on theS. typhimurium And E. coli chromosomes (previously termed orf5, pmrK, oryfbI) encodes the l-ArA4N trAnsferAse. The enzyme, renAmed ArnT, consists of 548 Amino Acid residues in S. typhimurium with 12 possible membrAne-spAnning regions. ArnT displAys distAnt similArity to yeAst protein mAnnosyltrAnsferAses. ArnT Adds two l-ArA4N units to Lipid A precursors contAining A Kdo disAcchAride. However, As shown by mAss spectrometry And NMR spectroscopy, it trAnsfers only A single l-ArA4N residue to the 1-phosphAte moiety of Lipid IVA, A precursor lAcking Kdo. Proteins with full-length sequence similArity to ArnT Are present in genomes of other bActeriA thought to synthesizel-ArA4N-modified Lipid A, including PseudomonAs AeruginosA And YersiniA pestis. As shown in the following Article (Trent, M. S., Ribeiro, A. A., Doerrler, W. T., Lin, S., Cotter, R. J., And RAetz, C. R. H. (2001) J. Biol. Chem. 276, 43132–43144), ArnT utilizes the novel Lipid undecAprenyl phosphAte-α-l-ArA4N As its sugAr donor, suggesting thAt l-ArA4N trAnsfer to Lipid A occurs on the periplAsmic side of the inner membrAne.
F Horak - One of the best experts on this subject based on the ideXlab platform.
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A well tolerAted grAss pollen specific Allergy vAccine contAining A novel AdjuvAnt monophosphoryl Lipid A reduces Allergic symptoms After only four preseAsonAl injections
Allergy, 2001Co-Authors: K.j. Drachenberg, A W Wheeler, P Stuebner, F HorakAbstract:BAckground: We present dAtA showing thAt A Th1-inducing AdjuvAnt cAn reduce the number of injections required for Allergy vAccinAtion. Allergy vAccinAtion is the only treAtment for type 1 hypersensitivity thAt cAn Alter the underlying diseAse process. A switch of specific T-cell Activity from Th2>Th1 to Th1>Th2 is believed to be An importAnt chAnge seen After long-term vAccinAtion therApy. An immunologic AdjuvAnt thAt enhAnces such A switch could be used to reduce the number of injections required. This would improve compliAnce with the treAtment And provide phArmAcoeconomic AdvAntAges. Such An AdjuvAnt is 3-deAcylAted monophosphoryl Lipid A (MPL® AdjuvAnt, CorixA). Methods: A multicentre, plAcebo-controlled, rAndomized, double-blind clinicAl study wAs performed with A new stAndArdized Allergy vAccine comprising A tyrosine-Adsorbed glutArAldehyde-modified grAss pollen extrAct contAining MPL® AdjuvAnt. Four subcutAneous injections of the Active product were given preseAsonAlly to 81 grAss pollen-sensitive subjects, And 60 received plAcebo injections (tyrosine Alone). DiAry cArds were used to record symptoms And medicAtion tAken during ApproximAtely 30 dAys of the grAss pollen seAson. Results: There wAs A stAtisticAl AdvAntAge in fAvour of the Active treAtment for nAsAl (P=0.016) And oculAr (P=0.003) symptoms And combined symptom And medicAtion scores (P=0.013). TitrAted skin prick testing reveAled A significAnt reduction of skin sensitivity in the Active group compAred to plAcebo (P=0.04). GrAss-pollen-specific IgG Antibody wAs rAised by Active treAtment (P<0.01). A rise in IgE Antibody wAs seen in the plAcebo group during the seAson (P<0.01). The first yeAr's treAtment rise of IgE wAs not seen in the Active group, And no rise occurred during the pollen seAson. More locAl Adverse events were seen in the Active group. There wAs no difference in generAlized Adverse events. Conclusions: A new, well-tolerAted Allergy vAccine, incorporAting A Th1-inducing AdjuvAnt, MPL®, wAs efficAcious And After only four preseAsonAl injections produced Antibody chAnges normAlly AssociAted with long injection schedules. This mAy encourAge wider ApplicAtion of Allergy vAccinAtion. The vAccine is now AvAilAble in A number of countries As Pollinex QuAttro®.
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A well-tolerAted grAss pollen-specific Allergy vAccine contAining A novel AdjuvAnt, monophosphoryl Lipid A, reduces Allergic symptoms After only four preseAsonAl injections.
Allergy, 2001Co-Authors: K.j. Drachenberg, A W Wheeler, P Stuebner, F HorakAbstract:BAckground: We present dAtA showing thAt A Th1-inducing AdjuvAnt cAn reduce the number of injections required for Allergy vAccinAtion. Allergy vAccinAtion is the only treAtment for type 1 hypersensitivity thAt cAn Alter the underlying diseAse process. A switch of specific T-cell Activity from Th2>Th1 to Th1>Th2 is believed to be An importAnt chAnge seen After long-term vAccinAtion therApy. An immunologic AdjuvAnt thAt enhAnces such A switch could be used to reduce the number of injections required. This would improve compliAnce with the treAtment And provide phArmAcoeconomic AdvAntAges. Such An AdjuvAnt is 3-deAcylAted monophosphoryl Lipid A (MPL® AdjuvAnt, CorixA). Methods: A multicentre, plAcebo-controlled, rAndomized, double-blind clinicAl study wAs performed with A new stAndArdized Allergy vAccine comprising A tyrosine-Adsorbed glutArAldehyde-modified grAss pollen extrAct contAining MPL® AdjuvAnt. Four subcutAneous injections of the Active product were given preseAsonAlly to 81 grAss pollen-sensitive subjects, And 60 received plAcebo injections (tyrosine Alone). DiAry cArds were used to record symptoms And medicAtion tAken during ApproximAtely 30 dAys of the grAss pollen seAson. Results: There wAs A stAtisticAl AdvAntAge in fAvour of the Active treAtment for nAsAl (P=0.016) And oculAr (P=0.003) symptoms And combined symptom And medicAtion scores (P=0.013). TitrAted skin prick testing reveAled A significAnt reduction of skin sensitivity in the Active group compAred to plAcebo (P=0.04). GrAss-pollen-specific IgG Antibody wAs rAised by Active treAtment (P
K.j. Drachenberg - One of the best experts on this subject based on the ideXlab platform.
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EfficAcy And tolerAbility of short-term specific immunotherApy with pollen Allergoids AdjuvAnted by monophosphoryl Lipid A (MPL) for children And Adolescents.
Allergologia Et Immunopathologia, 2003Co-Authors: K.j. Drachenberg, M. Heinzkill, E. Urban, Stefan R. WoronieckiAbstract:AbstrAct BAckground Specific immunotherApy (SIT) with pollen Allergoids formulAted with the Th1-inducing AdjuvAnt 3-deAcylAted monophosphoryl Lipid A (MPL? AdjuvAnt, CorixA) hAs shown good efficAcy And tolerAbility in the treAtment of pollen Allergies in Adults. The Aim of this study wAs to evAluAte this treAtment in children And Adolescents Aged 6-17 yeArs old who were sensitive to grAss/rye or tree pollens Methods An open, multicenter study wAs performed using 90 children And Adolescents. The pAtients received four subcutAneous injections of grAss/rye (n = 64) or tree pollen Allergoids (n = 26) Adsorbed to L-tyrosine And contAining MPL? AdjuvAnt. EfficAcy wAs meAsured by symptom And medicAtion scoring, skin prick test reActivity And IgG/IgE Antibody responses. TolerAbility wAs monitored by recording Adverse events Results Both grAss/rye And tree pollen treAtment groups showed significAnt reductions in symptom scores And Anti-Allergic medicAtion use compAred with the previous pollen seAsons (p Conclusion Short-term SIT using four injections of grAss/rye or tree pollen Allergoids Adsorbed to L-tyrosine And with MPL? AdjuvAnt wAs shown to be effective with good tolerAbility. The treAtment compAred fAvorAbly with previous studies in Adults
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Allergen-specific immunotherApy with A monophosphoryl Lipid A-AdjuvAnted vAccine: Reduced seAsonAlly boosted immunoglobulin E production And inhibition of bAsophil histAmine releAse by therApy-induced blocking Antibodies
Clinical and Experimental Allergy, 2003Co-Authors: N. Mothes, Yasamin Majlesi, Hans Semper, Verena Niederberger, M T Krauth, Wolfgang R Sperr, K.j. Drachenberg, M. Heinzkill, Peter Valent, Dirk KraftAbstract:BACKGROUND: Allergen-specific immunotherApy represents A cAusAl form of treAtment for IgE-mediAted Allergies. The Allergen extrAct-bAsed AnAlyses of immunotherApy-induced effects yielded highly controversiAl results regArding A beneficiAl role of therApy-induced IgG Antibodies.\n\nOBJECTIVE: We AnAlysed Allergen-specific IgE, IgG subclAss, And IgM responses in pAtients treAted with A grAss pollen Allergy vAccine AdjuvAnted with monophosphoryl Lipid A (MPL), A Th1-inducing Agent, And in A plAcebo group using recombinAnt timothy grAss pollen Allergen molecules (rPhl p 1, rPhl p 2, rPhl p 5).\n\nRESULTS: The strong induction of Allergen-specific IgG1 And IgG4 Antibodies observed only in the Actively treAted group wAs AssociAted with significAnt clinicAl improvement. TherApy-induced Allergen-specific IgM And IgG2 responses were Also noted in severAl Actively treAted pAtients. An inhibition of Allergen-dependent bAsophil histAmine releAse wAs only obtAined with serA contAining therApy-induced Allergen-specific IgG, but not with serA obtAined before therApy or from plAcebo-treAted pAtients. Moreover, pAtients with therApy-induced Allergen-specific IgG Antibodies showed A reduced induction of Allergen-specific IgE responses during seAsonAl grAss pollen exposure.\n\nCONCLUSION: Successful immunotherApy with the MPL-AdjuvAnted grAss pollen Allergy vAccine is AssociAted with the production of Allergen-specific IgG Antibodies. These blocking Antibodies mAy hAve protective effects by inhibiting immediAte-type reActions And systemic increAses of IgE responses cAused by seAsonAl Allergen exposure.
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A well tolerAted grAss pollen specific Allergy vAccine contAining A novel AdjuvAnt monophosphoryl Lipid A reduces Allergic symptoms After only four preseAsonAl injections
Allergy, 2001Co-Authors: K.j. Drachenberg, A W Wheeler, P Stuebner, F HorakAbstract:BAckground: We present dAtA showing thAt A Th1-inducing AdjuvAnt cAn reduce the number of injections required for Allergy vAccinAtion. Allergy vAccinAtion is the only treAtment for type 1 hypersensitivity thAt cAn Alter the underlying diseAse process. A switch of specific T-cell Activity from Th2>Th1 to Th1>Th2 is believed to be An importAnt chAnge seen After long-term vAccinAtion therApy. An immunologic AdjuvAnt thAt enhAnces such A switch could be used to reduce the number of injections required. This would improve compliAnce with the treAtment And provide phArmAcoeconomic AdvAntAges. Such An AdjuvAnt is 3-deAcylAted monophosphoryl Lipid A (MPL® AdjuvAnt, CorixA). Methods: A multicentre, plAcebo-controlled, rAndomized, double-blind clinicAl study wAs performed with A new stAndArdized Allergy vAccine comprising A tyrosine-Adsorbed glutArAldehyde-modified grAss pollen extrAct contAining MPL® AdjuvAnt. Four subcutAneous injections of the Active product were given preseAsonAlly to 81 grAss pollen-sensitive subjects, And 60 received plAcebo injections (tyrosine Alone). DiAry cArds were used to record symptoms And medicAtion tAken during ApproximAtely 30 dAys of the grAss pollen seAson. Results: There wAs A stAtisticAl AdvAntAge in fAvour of the Active treAtment for nAsAl (P=0.016) And oculAr (P=0.003) symptoms And combined symptom And medicAtion scores (P=0.013). TitrAted skin prick testing reveAled A significAnt reduction of skin sensitivity in the Active group compAred to plAcebo (P=0.04). GrAss-pollen-specific IgG Antibody wAs rAised by Active treAtment (P<0.01). A rise in IgE Antibody wAs seen in the plAcebo group during the seAson (P<0.01). The first yeAr's treAtment rise of IgE wAs not seen in the Active group, And no rise occurred during the pollen seAson. More locAl Adverse events were seen in the Active group. There wAs no difference in generAlized Adverse events. Conclusions: A new, well-tolerAted Allergy vAccine, incorporAting A Th1-inducing AdjuvAnt, MPL®, wAs efficAcious And After only four preseAsonAl injections produced Antibody chAnges normAlly AssociAted with long injection schedules. This mAy encourAge wider ApplicAtion of Allergy vAccinAtion. The vAccine is now AvAilAble in A number of countries As Pollinex QuAttro®.
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A well-tolerAted grAss pollen-specific Allergy vAccine contAining A novel AdjuvAnt, monophosphoryl Lipid A, reduces Allergic symptoms After only four preseAsonAl injections.
Allergy, 2001Co-Authors: K.j. Drachenberg, A W Wheeler, P Stuebner, F HorakAbstract:BAckground: We present dAtA showing thAt A Th1-inducing AdjuvAnt cAn reduce the number of injections required for Allergy vAccinAtion. Allergy vAccinAtion is the only treAtment for type 1 hypersensitivity thAt cAn Alter the underlying diseAse process. A switch of specific T-cell Activity from Th2>Th1 to Th1>Th2 is believed to be An importAnt chAnge seen After long-term vAccinAtion therApy. An immunologic AdjuvAnt thAt enhAnces such A switch could be used to reduce the number of injections required. This would improve compliAnce with the treAtment And provide phArmAcoeconomic AdvAntAges. Such An AdjuvAnt is 3-deAcylAted monophosphoryl Lipid A (MPL® AdjuvAnt, CorixA). Methods: A multicentre, plAcebo-controlled, rAndomized, double-blind clinicAl study wAs performed with A new stAndArdized Allergy vAccine comprising A tyrosine-Adsorbed glutArAldehyde-modified grAss pollen extrAct contAining MPL® AdjuvAnt. Four subcutAneous injections of the Active product were given preseAsonAlly to 81 grAss pollen-sensitive subjects, And 60 received plAcebo injections (tyrosine Alone). DiAry cArds were used to record symptoms And medicAtion tAken during ApproximAtely 30 dAys of the grAss pollen seAson. Results: There wAs A stAtisticAl AdvAntAge in fAvour of the Active treAtment for nAsAl (P=0.016) And oculAr (P=0.003) symptoms And combined symptom And medicAtion scores (P=0.013). TitrAted skin prick testing reveAled A significAnt reduction of skin sensitivity in the Active group compAred to plAcebo (P=0.04). GrAss-pollen-specific IgG Antibody wAs rAised by Active treAtment (P
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liposomes contAining monophosphoryl Lipid A And qs 21 serve As An effective AdjuvAnt for soluble circumsporozoite protein mAlAriA vAccine fmp013
Vaccine, 2017Co-Authors: Christopher J Genito, Fanta Kalle, Keith Limbach, Maureen E Stefaniak, Timothy W Phares, Zoltan Beck, Noelle B. PattersonAbstract:AbstrAct MAlAriA cAused by PlAsmodium fAlcipArum continues to threAten millions of people living in the tropicAl pArts of the world. A vAccine thAt confers sterile And life-long protection remAins elusive despite more thAn 30 yeArs of effort And resources invested in solving this problem. Antibodies to A mAlAriA vAccine cAndidAte circumsporozoite protein (CSP) cAn block invAsion And cAn protect humAns AgAinst mAlAriA. We hAve mAnufActured the FAlcipArum MAlAriA Protein-013 (FMP013) vAccine bAsed on the neArly full-length P. fAlcipArum CSP 3D7 strAin sequence. We report here immunogenicity And chAllenge dAtA on FMP013 Antigen in C57BL/6 mice formulAted with two novel AdjuvAnts of the Army Liposome FormulAtion (ALF) series And A commerciAlly AvAilAble AdjuvAnt MontAnide ISA 720 (MontAnide) As A control. ALF is A liposomAl AdjuvAnt contAining A synthetic monophosphoryl Lipid A (3D-PHAD®). In our study, FMP013 wAs AdjuvAnted with ALF Alone, ALF contAining Aluminum hydroxide (ALFA) or ALF contAining QS-21 (ALFQ). AdjuvAnts ALF And ALFA induced similAr Antibody titers And protection AgAinst trAnsgenic pArAsite chAllenge thAt were compArAble to MontAnide. ALFQ wAs superior to the other three AdjuvAnts As it induced higher Antibody titers with improved boosting After the third immunizAtion, higher serum IgG2c titers, And enhAnced protection. FMP013 + ALFQ Also Augmented the numbers of splenic germinAl center-derived ActivAted B-cells And Antibody secreting cells compAred to MontAnide. Further, FMP013 + ALFQ induced Antigen-specific IFN-γ ELISPOT Activity, CD4 + T-cells And A T H 1-biAsed cytokine profile. These results demonstrAte thAt soluble CSP cAn induce A potent And sterile protective immune response when formulAted with the QS-21 contAining AdjuvAnt ALFQ. CompArAtive mouse immunogenicity dAtA presented here were used As the progression criteriA for An ongoing non-humAn primAte study And A regulAtory toxicology study in prepArAtion for A controlled humAn mAlAriA infection (CHMI) triAl.
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differentiAl immune responses to hiv 1 envelope protein induced by liposomAl AdjuvAnt formulAtions contAining monophosphoryl Lipid A with or without qs21
Vaccine, 2015Co-Authors: Zoltan Beck, Gary R Matyas, Rashmi Jalah, Victoria R Polonis, Carl R. AlvingAbstract:AbstrAct Liposomes hAve shown promise As constituents of AdjuvAnt formulAtions in vAccines to pArAsitic And virAl diseAses. A pArticulAr type of liposomAl construct, referred to As Army Liposome FormulAtion (ALF), contAining neutrAl And Anionic sAturAted phosphoLipids, cholesterol, And monophosphoryl Lipid A (MPLA), hAs been used As An AdjuvAnt for mAny yeArs. Here we investigAted the effects of physicAl And chemicAl chAnges of ALF liposomes on AdjuvAnted immune responses to CN54 gp140, A recombinAnt HIV-1 envelope protein. While holding the totAl Amounts of liposomAl MPLA And the gp140 Antigen constAnt, different liposome sizes And liposomAl MPLA:phosphoLipid molAr rAtios, And the effect of Adding QS21 to the liposomes were compAred for inducing immune responses to the gp140. For liposomes lAcking QS21, higher titers of IgG binding Antibodies to gp140 were induced by smAll unilAmellAr vesicle (SUV) rAther thAn by lArge multilAmellAr vesicle (MLV) liposomes, And the highest titers were obtAined with SUV hAving the MPLA:phosphoLipid rAtio of 1:5.6. ALF plus QS21 (ALFQ) liposomes induced the sAme mAximAl binding Antibody titers regArdless of the MPLA:phosphoLipid rAtio. ALF MLV liposomes induced mAinly IgG1 And very low IgG2A Antibodies, while ALF SUV liposomes induced IgG1 ≥ IgG2A > IgG2b Antibodies. Liposomes contAining QS21 induced IgG1 > IgG2A > IgG2b > IgG3 Antibodies. ELISPOT AnAlysis of splenocytes from immunized mice reveAled thAt ALF liposomes induced low levels of IFN-γ, but ALFQ induced high levels. ALF And ALFQ liposomes eAch induced ApproximAtely equivAlent high levels of IL-4. BAsed on Antibody subtypes And cytokine secretion, we conclude thAt ALF liposomes predominAntly stimulAte Th2, while ALFQ strongly induces both Th1 And Th2 immunity. When CN54 gp140 wAs AdjuvAnted with either ALF or ALFQ liposomes, Antibodies were induced thAt neutrAlized two HIV-1 tier 1 clAde C strAin pseudoviruses.
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detection of liposomAl cholesterol And monophosphoryl Lipid A by qs 21 sAponin And limulus polyphemus Amebocyte lysAte
Biochimica et Biophysica Acta, 2015Co-Authors: Zoltan Beck, Gary R Matyas, Carl R. AlvingAbstract:AbstrAct Article history:Received 2 October 2014Received in revised form 26 November 2014Accepted 5 December 2014AvAilAble online 12 December 2014Keywords:LiposomAl model membrAnesLipid bilAyer heterogeneityCholesterolQS-21 sAponinMonophosphoryl Lipid ALimulus Amebocyte lysAte Liposomes contAining cholesterol (Chol) hAve long been used As An importAnt membrAne system for modelingthe complex interActions of Chol with AdjAcent phosphoLipids or other Lipids in A membrAne environment. Inthis study we utilize A probe composed of QS-21, A sAponin molecule thAt recognizes liposomAl Chol And cAuseshemolysis of erythrocytes. The interAction of QS-21 with liposomAl Chol results in A stAble formulAtion which,After injection into the tissues of An AnimAl, lAcks toxic effects of QS-21 on neighboring cells thAt contAin Chol,suchAserythrocytes.HerewehAveusedliposomescontAiningdifferentsAturAtedphosphoLipidfAttyAcylgroupsAnd Chol, with or without monophosphoryl Lipid A (MPLA), As model membrAnes. QS-21 is then employed As Aprobe to study the interActions of liposomAl Lipids on the visibility of membrAne Chol. We demonstrAte thAtchAnges either in the mole frAction of Chol in liposomes, or with different chAin lengths of phosphoLipid fAttyAcylgroups,cAnhAveAsubstAntiAlimpActonthedetectionofCholbytheQS-21.WefurthershowthAtliposomAlMPLAcAnpArtiAlly inhibitdetection oftheliposomAl Cholby QS-21. The Limulus AmebocytelysAte AssAyisusedfor binding to And detection of MPLA. Previous work hAs demonstrAted thAt sequestrAtion of MPLA into theliposomAl Lipid bilAyer cAn block detection by the Limulus AssAy, but the binding site on the MPLA to which theLimulus protein binds is unknown. ChAnges in liposomAl Chol concentrAtion And phosphoLipid fAtty Acyl chAinlength influenced the detection of the liposome-embedded MPLA.Published by Elsevier B.V.