Liposomal delivery of lipoarabinomannan triggers Mycobacterium tuberculosis specific T-cells

Kallert, Stephanie; Zenk, Sebastian F.; Walther, Paul; Grieshober, Mark; Weil, Tanja; Stenger, Steffen

doi:10.1016/j.tube.2015.04.001

Cited by 18 publications

(13 citation statements)

References 52 publications

(24 reference statements)

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“…PBMCs were isolated from anonymized buffy coat preparations obtained from purified protein derivative (PPD)‐ positive healthy blood donors by density gradient centrifugation. Monocytes were isolated by adherence on plastic and differentiated into CD1 + APCs by incubation with GM‐CSF (10 ng/mL) and IL‐4 (10 ng/mL) for 3–4 days and γ‐irraditated (30 Gy) after being detached with EDTA (1 mM; Sigma‐Aldrich).…”

Section: Methodsmentioning

confidence: 99%

The tyrosine kinase inhibitor dasatinib reduces the growth of intracellular Mycobacterium tuberculosis despite impairing T‐cell function

et al. 2018

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Tyrosine kinases are checkpoints for multiple cellular pathways and dysregulation induces malignancies, most notably chronic myeloid leukemia (CML). Inhibition of Abltyrosine kinases has evolved as a new concept for the treatment of CML and other malignant diseases. Due to the multiple immune-modulatory pathways controlled by tyrosine kinases, treatment with tyrosine kinase inhibitors (TKIs) will not only affect the biology of malignant cells but also modulate physiological immune functions. To understand the effects of TKIs on host defense against intracellular bacteria, we investigated the immunological impact of the dual Abl/Src TKI dasatinib on the cellular immune response to Mycobacterium tuberculosis (Mtb). Our results demonstrate that dasatinib impaired proliferation, cytokine release (IFN-γ, TNF-α, GM-CSF), expression of granulysin and degranulation of cytotoxic effector molecules of human Mtb-specific T-lymphocytes by inhibition of lymphocyte-specific protein tyrosine kinase (Lck) phosphorylation. Despite this profound inhibition of T-cell function, dasatinib suppressed growth of virulent Mtb in human macrophages co-cultured with autologous Mtb-specific T-cells (49±15%). Functional analysis suggested that growth inhibition is due to dasatinib-triggered lysosomal acidification inMtb-infected macrophages. These results highlight the significance of innate immune responses, i.e. acidification of lysosomes, which control the multiplication of intracellular bacteria despite the lack of efficient T-cell support. Keywords: Human primary cells r infection immunology r infection immunology r tuberculosis r T-cells r Tyrosine kinase inhibitorAdditional supporting information may be found online in the Supporting Information section at the end of the article.

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Section: Methodsmentioning

confidence: 99%

The tyrosine kinase inhibitor dasatinib reduces the growth of intracellular Mycobacterium tuberculosis despite impairing T‐cell function

et al. 2018

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“…Liposomes are versatile tool to encapsulate and deliver a wide range of molecules, not only proteins but also glycolipid antigens. Kallert et al demonstrated that purified mycobacterial LAM can be efficiently delivered into CD1 + APC via liposomes and this delivery system induces robust LAM-specific Th1-biased CD1-restricted T-cell responses in primary human cells ( 202 ). The authors used liposomes consisted of egg-PC, Chol, and stearylated octaarginine and proved that octaarginine, a cell-penetrating peptide consisting of eight positively charged arginines, increases the glycolipid antigen accumulation into lipid-APCs.…”

Section: Liposomes As Antigen Carrier In Innovative Vaccine Preparatimentioning

confidence: 99%

“…The authors used liposomes consisted of egg-PC, Chol, and stearylated octaarginine and proved that octaarginine, a cell-penetrating peptide consisting of eight positively charged arginines, increases the glycolipid antigen accumulation into lipid-APCs. The efficacy of octaarginine-containing liposomes was also tested in in vivo models of immunization using both BCG primed guinea pigs ( 203 ), where these liposomes induced a delayed type hypersensitivity reaction in the skin and in rhesus macaques, using glucose monomycolate (GMM) as antigen, where a CD1-restricted Th1-skewed immune response was observed ( 202 , 204 ). In a recent study, GMM-containing liposomes were decorated with a high-affinity glycan ligand of the sialic acid-binding Ig-like lectin-7, a siglec receptor expressed on DC that mediates rapid endocytosis and transport of its cargo to LYs ( 205 ).…”

Section: Liposomes As Antigen Carrier In Innovative Vaccine Preparatimentioning

confidence: 99%

The Multirole of Liposomes in Therapy and Prevention of Infectious Diseases

et al. 2018

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Liposomes are closed bilayer structures spontaneously formed by hydrated phospholipids that are widely used as efficient delivery systems for drugs or antigens, due to their capability to encapsulate bioactive hydrophilic, amphipathic, and lipophilic molecules into inner water phase or within lipid leaflets. The efficacy of liposomes as drug or antigen carriers has been improved in the last years to ameliorate pharmacokinetics and capacity to release their cargo in selected target organs or cells. Moreover, different formulations and variations in liposome composition have been often proposed to include immunostimulatory molecules, ligands for specific receptors, or stimuli responsive compounds. Intriguingly, independent research has unveiled the capacity of several phospholipids to play critical roles as intracellular messengers in modulating both innate and adaptive immune responses through various mechanisms, including (i) activation of different antimicrobial enzymatic pathways, (ii) driving the fusion–fission events between endosomes with direct consequences to phagosome maturation and/or to antigen presentation pathway, and (iii) modulation of the inflammatory response. These features can be exploited by including selected bioactive phospholipids in the bilayer scaffold of liposomes. This would represent an important step forward since drug or antigen carrying liposomes could be engineered to simultaneously activate different signal transduction pathways and target specific cells or tissues to induce antigen-specific T and/or B cell response. This lipid-based host-directed strategy can provide a focused antimicrobial innate and adaptive immune response against specific pathogens and offer a novel prophylactic or therapeutic option against chronic, recurrent, or drug-resistant infections.

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“…The identification and evaluation of lipid antigens is another key objective of WP1. Using protease cleavable CD1b-molecules, formulation of lipid-containing liposomes ( 13 ) or inclusion of α-galactosyl ceramide (α-GalCer) ( 14 ) to activate iNKT cells the potential of lipid antigens as vaccines is being evaluated. Liposomes are a particularly attractive delivery system, because they offer a simple and flexible platform to combine antigens and adjuvants, including immune modulators triggering the toll-like receptor (TLR) pathways ( 15 ).…”

Section: Wp1 Discovery Of Novel Tb Vaccine Strategiesmentioning

confidence: 99%

TBVAC2020: Advancing Tuberculosis Vaccines from Discovery to Clinical Development

et al. 2017

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TBVAC2020 is a research project supported by the Horizon 2020 program of the European Commission (EC). It aims at the discovery and development of novel tuberculosis (TB) vaccines from preclinical research projects to early clinical assessment. The project builds on previous collaborations from 1998 onwards funded through the EC framework programs FP5, FP6, and FP7. It has succeeded in attracting new partners from outstanding laboratories from all over the world, now totaling 40 institutions. Next to the development of novel vaccines, TB biomarker development is also considered an important asset to facilitate rational vaccine selection and development. In addition, TBVAC2020 offers portfolio management that provides selection criteria for entry, gating, and priority settings of novel vaccines at an early developmental stage. The TBVAC2020 consortium coordinated by TBVI facilitates collaboration and early data sharing between partners with the common aim of working toward the development of an effective TB vaccine. Close links with funders and other consortia with shared interests further contribute to this goal.

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Liposomal delivery of lipoarabinomannan triggers Mycobacterium tuberculosis specific T-cells

Cited by 18 publications

References 52 publications

The tyrosine kinase inhibitor dasatinib reduces the growth of intracellular Mycobacterium tuberculosis despite impairing T‐cell function

The tyrosine kinase inhibitor dasatinib reduces the growth of intracellular Mycobacterium tuberculosis despite impairing T‐cell function

The Multirole of Liposomes in Therapy and Prevention of Infectious Diseases

TBVAC2020: Advancing Tuberculosis Vaccines from Discovery to Clinical Development

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