Lipid-based Self-Adjuvanting Vaccines

Brown, Lorena E.; Jackson, David C.

doi:10.2174/156720105774370258

Cited by 41 publications

(38 citation statements)

References 102 publications

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“…While Cop-1-induced neuroprotection could be obtained by passive T cell transfer, later studies demonstrated that more significant neuroprotection is achieved by subcutaneous injection of naked Cop-1 (without adjuvant) [17]. The T cell-mediated immune response elicited by this latter type of immunization is weak [46][47][48]. These results questioned the role of T cells in Cop-1-mediated neuroprotection, and led us to postulate additional mechanisms mediating Cop-1-induced neuroprotection.…”

Section: Discussionmentioning

confidence: 99%

T cell independent mechanism for copolymer‐1‐induced neuroprotection

et al. 2007

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Despite active investigation of copolymer-1 (Cop-1) for nearly 40 years the mechanisms underlying its neuroprotective properties remain contentious. Nonetheless, current dogma for Cop-1 neuroprotective activities in autoimmune and neurodegenerative diseases include bystander suppression of autoimmune T cells and attenuation of microglial responses. In this report, we demonstrate that Cop-1 interacts directly with primary human neurons and decreases neuronal cell death induced by staurosporine or oxidative stress. This neuroprotection is mediated through protein kinase Ca and brainderived neurotrophic factor. Dendritic cells (DC) uptake Cop-1, deliver it to the injury site, and release it in an active form. Interactions between Cop-1 and DC enhance DC blood brain barrier migration. In a rat model with optic nerve crush injury, Cop-1-primed DC induce T cell independent neuroprotection. These findings may facilitate the development of neuroprotective approaches using DC-mediated Cop-1 delivery to diseased nervous tissue. IntroductionCopolymer-1 (Cop-1) was developed to mimic the encephalitogenic epitope of myelin basic protein (MBP). However, when administered in complete Freund's adjuvant it failed to induce experimental autoimmune encephalitis (EAE). Surprisingly, Cop-1 suppressed EAE when administered with MBP [1][2][3][4]. These observations led to the development of Cop-1 as a treatment for relapsing-remitting multiple sclerosis [5][6][7][8]. Over the past three decades, scientists have tried to determine how Cop-1 exerts its therapeutic effects [2,4,9,10]. Cop-1-specific T cells partially cross-react with MBP, leading to the secretion of neurotrophic and antiinflammatory factors such as brain derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor, [11][12][13]. [17], and experimentally induced encephalitis [18]. The mechanism(s) underlying Cop-1-induced neuroprotection were attributed to T cells. T cells modulate microglial and astrocyte responses and as such attenuate toxic inflammatory activities and neurodegeneration [11,12,19]. Indeed, the mechanism underlying T cellinduced neuroprotection is linked to modulation of microglial function [20] and increased production of neurotrophins at the site of injury [11,12]. After central nervous system (CNS) injury microglia commonly display a neurotoxic phenotype with local production of glutamate and increased expression of nitric oxide synthase (iNOS), pro-inflammatory cytokines, quinolinic acid and arachidonic acid and its metabolites [21,22]. T cells can induce a neuroprotective microglial phenotype [20].Under certain conditions with progressive neurodegeneration the Cop-1 neuroprotective response is seen before an adaptive immune response is generated [15,17,23], suggesting that Cop-1 induced neuroprotection may be, at least in part, T cell independent. We now demonstrate that Cop-1 treatment of primary human neurons intoxicated with staurosporine or reactiveoxygen species significantly decreases cell death. This neuroprotection is associ...

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Section: Discussionmentioning

confidence: 99%

T cell independent mechanism for copolymer‐1‐induced neuroprotection

et al. 2007

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“…The mechanism for the immune-enhancing effect studied with other bacterial lipopeptides and lipoproteins suggests lipoprotein recognition of TLR receptors on cells of the innate immune system (20)(21)(22)(23). In this study, the interactions of rLP2086 with TLR2 and/or TLR2/TLR1 complexes on cell surfaces, and the subsequent cell activation, were confirmed using HEK293 hTLR2 cells that express human TLR2 and TLR1.…”

Section: Interactions Of Nmb Lipoproteins With Htlr2-expressing Cellsmentioning

confidence: 99%

“…This effect was enabled by induction of neutralizing antibodies (28,29) and by in vivo priming of epitope-specific cytotoxic T cells and memory T cells (30)(31)(32). Since antibodies to the lipid moieties are not generated in vivo, the immune-enhancing effect of the lipids is believed to be similar to that of a conventional adjuvant, and thus, bacterial lipoprotein/lipopeptidecontaining vaccines are recognized as one category of selfadjuvanting vaccines (21)(22)(23)33). Other categories include lipid-core peptides, single-chain palmitoylated peptides, and glycolipid analogues of bacterial lipopolysaccharides (21).…”

Section: Immune-enhancing Effects Of the N-terminal Lipids Of Rlp2086mentioning

confidence: 99%

“…It was perceived in early days that the lipids simply anchor the lipoproteins/lipopeptides to the surface membrane of immune cells to facilitate the internalization. Recent research suggested that the lipid moieties interact with various TLRs, a type of membranebound pattern recognition receptors (PRRs), to drive the endocytosis of the lipoproteins by antigen-presenting cells (34) and induce various immune responses (21,22,32). PRR is a key component of the innate immune system to identify pathogen-associated molecular patterns (PAMPs) (35).…”

Section: Immune-enhancing Effects Of the N-terminal Lipids Of Rlp2086mentioning

confidence: 99%

“…In DC, the dimerization of the intracellular domains of TLR2 and TLR1 or TLR6 triggers a cascade of intracellular signal transductions and kinase activations that result in the de-inhibition of NFkB, a nuclear factor that controls the transcription of DNA. The free NFkB can translocate to the nucleus, where it binds to the enhancer or promoter regions of target genes and regulates their transcription (22). The target genes of NFkB control all the functions associated with DC maturation, and thus the chain of events leading to the priming of the immune responses, which likely include (1) activation of antigen-specific CD4 + T cells that can secrete cytokines and induce B cells to produce antigen-specific antibodies against the internalized, processed, and presented peptide epitopes; (2) activation of cytotoxic CD8 + T cell that can lyse infected cells and differentiate to long-lived memory T cells; and (3) secretion of cytokines that activate other immune cells, e.g., NK cells and phagocytes, to attack the infected cells (22).…”

Section: Immune-enhancing Effects Of the N-terminal Lipids Of Rlp2086mentioning

confidence: 99%

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The Dual Role of Lipids of the Lipoproteins in Trumenba, a Self-Adjuvanting Vaccine Against Meningococcal Meningitis B Disease

Luo

Friese

Runnels

et al. 2016

AAPS J

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ABSTRACT.Trumenba (bivalent rLP2086) is a vaccine licensed for the prevention of meningococcal meningitis disease caused by Neisseria meningitidis serogroup B (NmB) in individuals 10-25 years of age in the USA. The vaccine is composed of two factor H binding protein (fHbp) variants that were recombinantly expressed in Escherichia coli as native lipoproteins: rLP2086-A05 and rLP2086-B01. The vaccine was shown to induce potent bactericidal antibodies against a broad range of NmB isolates expressing fHbp that were different in sequence from the fHbp vaccine antigens. Here, we describe the characterization of the vaccine antigens including the elucidation of their structure which is characterized by two distinct motifs, the polypeptide domain and the N-terminal lipid moiety. In the vaccine formulation, the lipoproteins self-associate to form micelles driven by the hydrophobicity of the lipids and limited by the size of the folded polypeptides. The micelles help to increase the structural stability of the lipoproteins in the absence of bacterial cell walls. Analysis of the lipoproteins in Toll-like receptor (TLR) activation assays revealed their TLR2 agonist activity. This activity was lost with removal of the O-linked fatty acids, similar to removal of all lipids, demonstrating that this moiety plays an adjuvant role in immune activation. The thorough understanding of the structure and function of each moiety of the lipoproteins, as well as their relationship, lays the foundation for identifying critical parameters to guide vaccine development and manufacture.

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