Effect of monophosphoryl lipid A on host resistance to bacterial infection

Chase, Jody; Kubey, W.; Dulek, M H; Holmes, C. J.; Salit, M; Pearson, Frederick C.; Ribi, Edgar

doi:10.1128/iai.53.3.711-712.1986

Cited by 46 publications

(23 citation statements)

References 3 publications

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“…Among these bioactive derivatives is monophosphoryl lipid A (MPLA), produced by hydrolysis of the diphosphoryl lipid A found in wild‐type LPS 5 . MPLA has been found to protect mice against sepsis induced by Gram‐negative infection, caecal ligation and puncture and post‐haemorrhagic Staphylococcal infection 6 . The protective effect of MPLA in mice appears to be neutrophil dependent 7 .…”

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confidence: 99%

MPLA inhibits release of cytotoxic mediators from human neutrophils while preserving efficient bacterial killing

et al. 2014

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Monophosphoryl lipid A (MPLA) is a lipopolysaccharides (LPS) derivative associated with neutrophil-dependent anti-inflammatory outcomes in animal models of sepsis. Little is known about the effect of MPLA on neutrophil function. This study sought to test the hypothesis that MPLA would reduce release of cytotoxic mediators from neutrophils without impairing bacterial clearance. Neutrophils were isolated from whole blood of healthy volunteers. The effects of MPLA and LPS on autologous serum-opsonised Pseudomonas aeruginosa killing by neutrophils and phagocytosis of autologous serum-opsonised zymosan were examined. Neutrophil oxidative burst, chemotaxis, enzyme and cytokine release as well as Toll-like receptor 4 (TLR4) expression were assessed following exposure to LPS or MPLA. LPS, but not MPLA, induced significant release of superoxide and myeloperoxidase from neutrophils. However, MPLA did not impair neutrophil capacity to ingest microbial particles and kill P. aeruginosa efficiently. MPLA was directly chemotactic for neutrophils, involving TLR4, p38 mitogen-activated protein kinase and tyrosine and alkaline phosphatases. LPS, but not MPLA, impaired N-formyl-methionyl-leucyl phenylalanine-directed migration of neutrophils, increased surface expression of TLR4, increased interleukin-8 release and strongly activated the myeloid differentiation primary response 88 pathway. Phosphoinositide 3-kinase inhibition significantly augmented IL-8 release from MPLA-treated neutrophils. The addition of MPLA to LPS-preincubated neutrophils led to a significant reduction in LPS-mediated superoxide release and TLR4 surface expression. Collectively, these findings suggest that MPLA directs efficient chemotaxis and bacterial killing in human neutrophils without inducing extracellular release of cytotoxic mediators and suggest that MPLA warrants further attention as a potential therapeutic in human sepsis.

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MPLA inhibits release of cytotoxic mediators from human neutrophils while preserving efficient bacterial killing

et al. 2014

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“…Results from phase I clinical trials demonstrated that the addition of MPL to recombinant herpes simplex virus type 2 and hepatitis B vaccines resulted in higher seroconversion rates and larger antibody (Ab) titers (reviewed in reference 62), illustrating the efficacy of MPL as an adjuvant. The ability of MPL to promote nonspecific resistance to infection and to induce a state of endotoxin tolerance analogous to that produced by LPS (2,10,33,42) has provided the rationale for the development of MPL as a prophylactic agent for septic shock. Pretreatment of experimental animals with MPL promotes improved survival rates following peritonitis, infection with either gram-negative or gram-positive bacteria, and shock induced by LPS, staphylococcal enterotoxin B, and tumor necrosis factor alpha (TNF-␣) (1,3,4,10).…”

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confidence: 99%

“…The ability of MPL to promote nonspecific resistance to infection and to induce a state of endotoxin tolerance analogous to that produced by LPS (2,10,33,42) has provided the rationale for the development of MPL as a prophylactic agent for septic shock. Pretreatment of experimental animals with MPL promotes improved survival rates following peritonitis, infection with either gram-negative or gram-positive bacteria, and shock induced by LPS, staphylococcal enterotoxin B, and tumor necrosis factor alpha (TNF-␣) (1,3,4,10). These protective effects have been largely attributed to the ability of MPL to induce a state of tolerance to subsequent endotoxin challenge that results in an attenuated systemic response to LPS (chills, fever, and tachycardia), ameliorated production of proinflammatory cytokines (TNF-␣, interleukin-6 , and IL-8), and inhibited development of disseminated intravascular coagulation (2-4, 30, 33, 66).…”

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Lipopolysaccharide and monophosphoryl lipid A differentially regulate interleukin-12, gamma interferon, and interleukin-10 mRNA production in murine macrophages

1997

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Monophosphoryl lipid A (MPL) is a nontoxic derivative of the lipid A region of lipopolysaccharide (LPS) that is being developed as both an adjuvant and prophylactic drug for septic shock. We compared the ability of LPS and MPL to induce interleukin-10 (IL-10), IL-12 p35, IL-12 p40, gamma interferon (IFN-␥), glucocorticoid receptor (GR), IL-1 receptor antagonist (IL-1ra), and inducible nitric oxide synthase mRNA expression in murine peritoneal macrophages. These genes were chosen for their ability to positively or negatively regulate the host immune response and thus for their potential involvement in MPL-induced adjuvanticity or in its ability to protect against sepsis. LPS was a more potent inducer of IL-12 p35, IL-12 p40, and IFN-␥ mRNA, as well as of IL-12 protein, than MPL. In contrast, MPL induced higher levels of IL-10 mRNA than did LPS from 1 to 1,000 ng/ml. In general, MPL was not a more potent inducer of negative regulatory genes, since MPL and LPS induced similar levels of GR and IL-1ra mRNA. Addition of anti-IL-10 antibody to cultures increased the induction of MPL-induced IL-12 p35, IL-12 p40, and IFN-␥ mRNA, suggesting that the enhanced production of IL-10 by MPL-stimulated macrophages contributes to decreased production of mRNA for IL-12 (p35 and p40) and IFN-␥. Conversely, the addition of exogenous IL-10 to LPS-treated macrophages reduced the mRNA expression of these cytokine genes. These studies suggest that enhanced production of IL-10 by MPL-stimulated macrophages may contribute to the reduced toxicity of MPL through its negative action on induction of cytokines shown to enhance endotoxicity.

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“…Monophosphoryl lipid A (MPL or MPLA) is an effective and exceedingly safe and non-toxic adjuvant vaccine adjuvant (98)(99)(100)(101)(102)(103)(104)(105)(106)(107). It is a highly specific TLR4 agonist.…”

Section: Vaccine Adjuvant: Monophosphoryl Lipid Amentioning

confidence: 99%

Twelve immunotherapy drugs that could cure cancers

Cheever

2008

Immunological Reviews

307

218

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Immune T cells can kill cancer cells. Cancer vaccines function by increasing the number of immune T cells. There are exceedingly strict biologic limits imposed on the immune system to prevent excessive T-cell activation and expansion. The same biological restrictions limit cancer vaccines. Immunotherapeutic agents that circumvent the biological restrictions have been invented and formulated, including (i) dendritic cell activators and growth factors, (ii) vaccine adjuvants, (iii) T-cell stimulators and growth factors, (iv) immune checkpoint inhibitors, and (v) agents to neutralize or inhibit suppressive cells, cytokines, and enzymes. Few of these agents are broadly available for the development of effective multiple component regimens. The major problem facing immunotherapy today is a lack of broad availability of agents already in existence. The National Cancer Institute has developed a well-vetted ranked list of agents with high potential to serve as immunotherapeutic drugs. This review focuses on 12 of the agents, all with proven ability to augment T-cell responses. Alone, each has little chance of making substantial inroads into cancer therapy. In combinations dictated by biology, the agents are overwhelmingly likely to have an impact. Future availability of these agents for development of innovative combination cancer therapy regimens will provide a benchmark for the resolve of the national cancer therapy translational research enterprise.

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Effect of monophosphoryl lipid A on host resistance to bacterial infection

Cited by 46 publications

References 3 publications

MPLA inhibits release of cytotoxic mediators from human neutrophils while preserving efficient bacterial killing

MPLA inhibits release of cytotoxic mediators from human neutrophils while preserving efficient bacterial killing

Lipopolysaccharide and monophosphoryl lipid A differentially regulate interleukin-12, gamma interferon, and interleukin-10 mRNA production in murine macrophages

Twelve immunotherapy drugs that could cure cancers

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