TLR2 activation by proteosomes promotes uptake of particulate vaccines at mucosal surfaces

Chabot, Sophie; Chernin, Tyler S.; Shawi, M.; Wagner, Jessica; Farrant, Stephanie; Burt, David S.; Cyr, Sonya; Neutra, Marian R.

doi:10.1016/j.vaccine.2007.05.029

Cited by 42 publications

(30 citation statements)

References 59 publications

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“…5), but there are no afferent lymphatics [50]. Exogenous stimuli therefore come directly from the mucosal surfaces via a follicle-associated epithelium containing specialized SIgA is dimeric ⁄ polymeric, therefore exerting efficient microbial agglutination and virus neutralization SIgA performs non-inflammatory extracellular and intracellular immune exclusion by inhibiting epithelial adherence and invasion SIgA exhibits cross-reactive ('innate-like') activity and provides cross-protection in the herd SIgA (particularly SIgA2) is quite stable (bound SC stabilizes both isotypes of IgA) SIgA is endowed with mucophilic and lectin-binding properties (via bound SC in both isotypes and mannose in IgA2) epithelial M cells [53], probably aided by DC which are activated by bacterial components and may penetrate the epithelium with their processes [54,55].…”

Section: Inductive Sitesmentioning

confidence: 99%

Mucosal Immunity: Induction, Dissemination, and Effector Functions

2009

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Prevention of infections by vaccination remains a compelling goal to improve public health. Most infections involve the mucosae, but the development of vaccines against many of these pathogens has yet to be successful. Mucosal vaccines would make immunization procedures easier, be better suited for mass administration, and most efficiently induce immune exclusion – a term coined for non‐inflammatory antibody shielding of internal body surfaces – mediated principally by secretory immunoglobulin A (SIgA). The exported antibodies are polymeric, mainly IgA dimers (pIgA) – produced by local plasma cells stimulated by antigens that target the mucosae. SIgA was early shown to be complexed with an epithelial glycoprotein – the secretory component (SC). In 1974, a common SC‐dependent transport of pIgA and pentameric IgM was proposed. From the basolateral surface, pIg‐SC complexes are taken up by endocytosis and finally extruded into the lumen. Membrane SC is now referred to as polymeric Ig receptor (pIgR). In 1980, it was shown to be synthesized as a larger transmembrane protein – first cloned from rabbit and then from human. Mice deficient for pIgR showed that this is the only receptor responsible for epithelial transport of IgA and IgM. In the gut, induction of B cells occurs in gut‐associated lymphoid tissue, particularly the Peyer’s patches, but also in mesenteric lymph nodes. Plasma cell differentiation is accomplished in the lamina propria to which the memory/effector cells home. The airways also receive such cells from nasopharynx‐associated lymphoid tissue – but by different homing receptors. Such compartmentalization is a challenge for development of mucosal vaccines.

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Section: Inductive Sitesmentioning

confidence: 99%

Mucosal Immunity: Induction, Dissemination, and Effector Functions

2009

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“…Injection of TLR2 ligands into the gut lumen has been shown to induce migration of subepithelial DCs and promote antigen capture by follicle-associated epithelium. 38 As outlined above,TLR2-mediated IL-10 production in LPMNC represents an additional key homeostatic mechanism that critically serves to limit proinflammatory cytokine production and tissue damage in the intestinal mucosa. In fact, it has recently been demonstrated that oral administration of LcrV-secreting Lactococcus lactis induces IL-10 via TLR2, thus preventing immune-mediated 2,4,6-trinitrobenzene sulfonic acid colitis, 39 yet the major cellular target of TLR2 remains to be identified .…”

Section: S64mentioning

confidence: 99%

Barrier-protective function of intestinal epithelial Toll-like receptor 2

2008

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The intestinal epithelial cell (IEC) barrier plays an important role in maintaining mucosal immune homeostasis. Dysregulated IEC barrier function appears to trigger and perpetuate inflammation in inflammatory bowel diseases (IBD). Novel risk variants in the Toll-like receptor 2 (TLR2) gene have previously been associated with a more severe disease phenotype in a subgroup of IBD patients. Recent studies have provided important insights of the commensal and host defense mechanisms to maintain functional barrier integrity of the intestinal epithelium through TLR2. Deficient TLR2 signaling may imbalance commensal-dependent intestinal epithelial barrier defense, facilitating mucosal injury and leading to increased susceptibility of colitis. Treatment with a synthetic TLR2 ligand significantly suppresses mucosal inflammation by efficiently protecting tight junction-associated integrity of the intestinal epithelium in vivo. These beneficial effects may be supplemented by TLR2-induced anti-inflammatory immune responses (such as interleukin-10 production) in lamina propria mononuclear cells. Thus, cell-specific TLR2 targeting may offer a novel therapeutic approach to human IBD therapy by protecting IEC barrier function.

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“…Protollin was determined to be safe and well-tolerated up to a dose of 1.5 mg LPS when administered via the intranasal route in phase I (12) and II (13) human clinical trials, and has been tested as an intranasal vaccine adjuvant in animal models of influenza (14), respiratory syncytial virus (15), severe acute respiratory syndrome (16), plague (Yersinia pestis) (17), and measles (18) infection, as well as in models of Alzheimer's disease (19). Protollin consists of LPS molecules (TLR4 ligand) from Shigella flexneri, a Gram-negative bacterium, noncovalently incorporated in nanomolecular vesicles formed by proteosomes, consisting of purified hydrophobic outer-membrane proteins from Neisseria meningitidis (shown to signal via a TLR2/1 heterodimer complex) (20,21).…”

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confidence: 99%

ICOS-Expressing CD4 T Cells Induced via TLR4 in the Nasal Mucosa Are Capable of Inhibiting Experimental Allergic Asthma

Shalaby

Nakada

et al. 2012

The Journal of Immunology

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Modulation of adaptive immune responses via the innate immune pattern recognition receptors, such as the TLRs, is an emerging strategy for vaccine development. We investigated whether nasal rather than intrapulmonary application of Protollin, a mucosal adjuvant composed of TLR2 and TLR4 ligands, is sufficient to elicit protection against murine allergic lower airway disease. Wild-type, Tlr2−/−, or Tlr4−/− BALB/c mice were sensitized to a birch pollen allergen extract (BPEx), then received either intranasal or intrapulmonary administrations of Protollin or Protollin admixed with BPEx, followed by consecutive daily BPEx challenges. Nasal application of Protollin or Protollin admixed with BPEx was sufficient to inhibit allergic lower airway disease with minimal collateral lung inflammation. Inhibition was dependent on TLR4 and was associated with the induction of ICOS in cells of the nasal mucosa and on both CD4+Foxp3+ and CD4+Foxp3− T cells of the draining lymph nodes (LNs), as well as their recruitment to the lungs. Adoptive transfer of cervical LN CD4+ICOS+, but not CD4+ICOS−, cells inhibited BPEx-induced airway hyperresponsiveness and bronchoalveolar lavage eosinophilia. Thus, our data indicate that expansion of resident ICOS-expressing CD4+ T cells of the cervical LNs by nasal mucosal TLR4 stimulation may inhibit the development of allergic lower airway disease in mice.

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TLR2 activation by proteosomes promotes uptake of particulate vaccines at mucosal surfaces

Cited by 42 publications

References 59 publications

Mucosal Immunity: Induction, Dissemination, and Effector Functions

Mucosal Immunity: Induction, Dissemination, and Effector Functions

Barrier-protective function of intestinal epithelial Toll-like receptor 2

ICOS-Expressing CD4 T Cells Induced via TLR4 in the Nasal Mucosa Are Capable of Inhibiting Experimental Allergic Asthma

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