Monophosphoryl lipid A: In vitro effects on human T cells proliferation and cytokines production

Monophosphoryl lipid A (MPLA) is a detoxified derivative of LPS that induces tolerance to LPS and augments host resistance to bacterial infections. Previously, we demonstrated that LPS inhibits [Formula: see text] absorption in the medullary thick ascending limb (MTAL) through a basolateral Toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-ERK pathway. Here we examined whether pretreatment with MPLA would attenuate LPS inhibition. MTALs from rats were perfused in vitro with MPLA (1 µg/ml) in bath and lumen or bath alone for 2 h, and then LPS was added to (and MPLA removed from) the bath solution. Pretreatment with MPLA eliminated LPS-induced inhibition of [Formula: see text] absorption. In MTALs pretreated with MPLA plus a phosphatidylinositol 3-kinase (PI3K) or Akt inhibitor, LPS decreased [Formula: see text] absorption. MPLA increased Akt phosphorylation in dissected MTALs. The Akt activation was eliminated by a PI3K inhibitor and in MTALs from TLR4−/−or Toll/IL-1 receptor domain-containing adaptor-inducing IFN-β (TRIF)−/−mice. The effect of MPLA to prevent LPS inhibition of [Formula: see text] absorption also was TRIF dependent. Pretreatment with MPLA prevented LPS-induced ERK activation; this effect was dependent on PI3K. MPLA alone had no effect on [Formula: see text] absorption, and MPLA pretreatment did not prevent ERK-mediated inhibition of [Formula: see text] absorption by aldosterone, consistent with MPLA's low toxicity profile. These results demonstrate that pretreatment with MPLA prevents the effect of LPS to inhibit [Formula: see text] absorption in the MTAL. This protective effect is mediated directly through MPLA stimulation of a TLR4-TRIF-PI3K-Akt pathway that prevents LPS-induced ERK activation. These studies identify detoxified TLR4-based immunomodulators as novel potential therapeutic agents to prevent or treat renal tubule dysfunction in response to bacterial infections.

Download Full-text

The Combinations Chitosan-Pam3CSK4 and Chitosan-Monophosphoryl Lipid A: Promising Immune-Enhancing Adjuvants for Anticaries Vaccine PAc

Infection and Immunity ◽

10.1128/iai.00651-19 ◽

2019 ◽

Vol 87 (12) ◽

Author(s):

Yongli Bi ◽

Qingan Xu ◽

Lingkai Su ◽

Jiantao Xu ◽

Zhongfang Liu ◽

...

Keyword(s):

Lipid A ◽

Vaccine Development ◽

Protection Effect ◽

Content Type ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

Tooth Surfaces ◽

Antibody Titers

ABSTRACT We previously demonstrated that recombinant protein PAc could be administered as an anticaries vaccine. However, the relatively weak immunogenicity of PAc limits its application. In the present study, we investigated the effect of two adjuvant combinations of chitosan plus Pam3CSK4 (chitosan-Pam3CSK4) and of chitosan plus monophosphoryl lipid A (chitosan-MPL) in the immune responses to the PAc protein in vivo and in vitro. PAc-chitosan-Pam3CSK4 or PAc-chitosan-MPL promoted significantly higher PAc-specific antibody titers in serum and saliva, inhibited Streptococcus mutans colonization onto the tooth surfaces, and endowed better protection effect with significantly less caries activities than PAc alone. Chitosan-Pam3CSK4 and chitosan-MPL showed no statistically significant differences. In conclusion, our study demonstrated that the chitosan-Pam3CSK4 and chitosan-MPL combinations are promising for anticaries vaccine development.

Download Full-text

Dexamethasone and Monophosphoryl Lipid A-Modulated Dendritic Cells Promote Antigen-Specific Tolerogenic Properties on Naive and Memory CD4+ T Cells

Frontiers in Immunology ◽

10.3389/fimmu.2016.00359 ◽

2016 ◽

Vol 7 ◽

Cited By ~ 13

Author(s):

Jaxaira Maggi ◽

Katina Schinnerling ◽

Bárbara Pesce ◽

Catharien M. Hilkens ◽

Diego Catalán ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd4 T Cells ◽

Lipid A ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

Memory Cd4 T Cells

Download Full-text

Increased in vitro migration of human umbilical cord mesenchymal stem cells toward acellular foreskin treated with bacterial derivatives of monophosphoryl lipid A or supernatant of Lactobacillus acidophilus

Human Cell ◽

10.1007/s13577-019-00308-7 ◽

2019 ◽

Vol 33 (1) ◽

pp. 10-22

Author(s):

Ali Shojaeian ◽

Ameneh Mehri-Ghahfarrokhi ◽

Mehdi Banitalebi-Dehkordi

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Umbilical Cord ◽

Lactobacillus Acidophilus ◽

Lipid A ◽

Human Umbilical Cord ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

Derivatives Of

Download Full-text

Monophosphoryl lipid A prevents impairment of medullary thick ascending limb HCO3− absorption and improves plasma HCO3− concentration in septic mice

AJP Renal Physiology ◽

10.1152/ajprenal.00033.2018 ◽

2018 ◽

Vol 315 (3) ◽

pp. F711-F725 ◽

Cited By ~ 3

Author(s):

Bruns A. Watts ◽

Thampi George ◽

Edward R. Sherwood ◽

David W. Good

Keyword(s):

Metabolic Acidosis ◽

Lipid A ◽

Cecal Ligation ◽

Thick Ascending Limb ◽

Erk Activation ◽

Medullary Thick Ascending Limb ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

Base Disorder

Metabolic acidosis is the most common acid-base disorder in septic patients and is associated with increased mortality. Previously, we demonstrated that sepsis induced by cecal ligation and puncture (CLP) impairs [Formula: see text] absorption in the medullary thick ascending limb (MTAL) by 1) decreasing the intrinsic [Formula: see text] absorptive capacity and 2) enhancing inhibition of [Formula: see text] absorption by LPS through upregulation of Toll-like receptor (TLR) 4 signaling. Both effects depend on ERK activation. Monophosphoryl lipid A (MPLA) is a detoxified TLR4 agonist that enhances innate antimicrobial immunity and improves survival following sepsis. Pretreatment of MTALs with MPLA in vitro prevents LPS inhibition of [Formula: see text] absorption. Here we examined whether pretreatment with MPLA would protect the MTAL against sepsis. Vehicle or MPLA was administered to mice 48 h before sham or CLP surgery, and MTALs were studied in vitro 18 h postsurgery. Pretreatment with MPLA prevented the effects of sepsis to decrease the basal [Formula: see text] absorption rate and enhance inhibition by LPS. These protective effects were mediated through MPLA stimulation of a Toll/IL-1 receptor domain-containing adaptor-inducing IFN-β-(TRIF)-dependent phosphatidylinositol 3-kinase-Akt pathway that prevents sepsis- and LPS-induced ERK activation. The effects of MPLA to improve MTAL [Formula: see text] absorption were associated with marked improvement in plasma [Formula: see text] concentration, supporting a role for the kidneys in the pathogenesis of sepsis-induced metabolic acidosis. These studies support detoxified TLR4-based immunomodulators, such as MPLA, that enhance antimicrobial responses as a safe and effective approach to prevent or treat sepsis-induced renal tubule dysfunction and identify cell signaling pathways that can be targeted to preserve MTAL [Formula: see text] absorption and attenuate metabolic acidosis during sepsis.

Download Full-text

Monophosphoryl Lipid a as an adjuvant for immune therapy? A detailed in vitro comparison to LPS

Clinical and Translational Allergy ◽

10.1186/2045-7022-4-s2-o21 ◽

2014 ◽

Vol 4 (S2) ◽

Author(s):

Stefan Schülke ◽

Lothar Vogel ◽

Adam Flaczyk ◽

Sonja Wolfheimer ◽

Stefan Vieths ◽

...

Keyword(s):

Lipid A ◽

Immune Therapy ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

In Vitro Comparison

Download Full-text

Monophosphoryl-Lipid A (MPLA) is an Efficacious Adjuvant for Inactivated Rabies Vaccines

Viruses ◽

10.3390/v11121118 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1118 ◽

Cited By ~ 1

Author(s):

Chen Chen ◽

Chengguang Zhang ◽

Ruiming Li ◽

Zongmei Wang ◽

Yueming Yuan ◽

...

Keyword(s):

Immune Responses ◽

Neutralizing Antibodies ◽

Lipid A ◽

Survival Ratio ◽

Effective Measure ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid

Rabies, as one of the most threatening zoonoses in the world, causes a fatal central nervous system (CNS) disease. So far, vaccination with rabies vaccines has been the most effective measure to prevent and control this disease. At present, inactivated rabies vaccines are widely used in humans and domestic animals. However, humoral immune responses induced by inactivated rabies vaccines are relatively low and multiple shots are required to achieve protective immunity. Supplementation with an adjuvant is a practical way to improve the immunogenicity of inactivated rabies vaccines. In this study, we found that monophosphoryl-lipid A (MPLA), a well-known TLR4 agonist, could significantly promote the maturation of bone marrow-derived dendritic cells (BMDC) through a TLR4-dependent pathway in vitro and the maturation of conventional DCs (cDCs) in vivo. We also found that MPLA, serving as an adjuvant for inactivated rabies vaccines, could significantly facilitate the generation of T follicular helper (Tfh) cells, germinal center (GC) B cells, and plasma cells (PCs), consequently enhancing the production of RABV-specific total-IgG, IgG2a, IgG2b, and the virus-neutralizing antibodies (VNAs). Furthermore, MPLA could increase the survival ratio of mice challenged with virulent RABV. In conclusion, our results demonstrate that MPLA serving as an adjuvant enhances the intensity of humoral immune responses by activating the cDC–Tfh–GC B axis. Our findings will contribute to the improvement of the efficiency of traditional rabies vaccines.

Download Full-text

Promotion of Cellular and Humoral Immunity against Foot-and-Mouth Disease Virus by Immunization with Virus-Like Particles Encapsulated in Monophosphoryl Lipid A and Liposomes

Vaccines ◽

10.3390/vaccines8040633 ◽

2020 ◽

Vol 8 (4) ◽

pp. 633

Author(s):

Woo Sik Kim ◽

Yong Zhi ◽

Huichen Guo ◽

Eui-Baek Byun ◽

Jae Hyang Lim ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

Lipid A ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Virus Like Particles ◽

Monophosphoryl Lipid A ◽

Monophosphoryl Lipid ◽

Foot And Mouth ◽

Ifn Γ

Virus-like particles (VLPs) have emerged as promising vaccine candidates against foot-and-mouth disease (FMD). However, such vaccines provide a relatively low level of protection against FMD virus (FMDV) because of their poor immunogenicity. Therefore, it is necessary to design effective vaccine strategies that induce more potent immunogenicity. In order to investigate the means to improve FMD VLP vaccine (VLPFMDV) immunogenicity, we encapsulated VLPs (MPL/DDA-VLPFMDV) with cationic liposomes based on dimethyldioctadecylammonium bromide (DDA) and/or monophosphoryl lipid A (MPL, TLR4 agonist) as adjuvants. Unlike inactivated whole-cell vaccines, VLPFMDV were successfully encapsulated in this MPL/DDA system. We found that MPL/DDA-VLPFMDV could induce strong cell-mediated immune responses by inducing not only VLP-specific IFN-γ+CD4+ (Th1), IL-17A+CD4+ (Th17), and IFN-γ+CD8+ (activated CD8 response) T cells, but also the development of VLP-specific multifunctional CD4+ and CD8+ memory T cells co-expressing IFN-γ, TNF-α, and IL-2. In addition, the MPL/DDA-VLPFMDV vaccine markedly induced VLP-specific antibody titers; in particular, the vaccine induced greater Th1-predominant IgG responses than VLPFMDV only and DDA-VLPFMDV. These results are expected to provide important clues for the development of an effective VLPFMDV that can induce cellular and humoral immune responses, and address the limitations seen in current VLP vaccines for various diseases.

Download Full-text