Toll‐like receptor 2 agonist Pam3CSK4 enhances the induction of antigen‐specific tolerance via the sublingual route

Lombardi, Vincent; Overtvelt, Laurence Van; Horiot, S.; Moussu, Hélène; Chabre, Henri; Louise, Anne; Balazuc, Anne-Marie; Mascarell, Laurent; Moingeon, Philippe

doi:10.1111/j.1365-2222.2008.03056.x

Cited by 94 publications

(72 citation statements)

References 45 publications

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“…Pam3CSK4 reverses established OVA-induced airway inflammation by a mechanism that is critically dependent on IL-12 but not IL-10 or TGF-b (5,6). In a murine model of asthma, Pam3CSK4 was shown to be a valid candidate adjuvant for sublingual allergy vaccines that mediated Th1/Treg cell responses (30). In the present study, we first demonstrated in humans that Pam3CSK4 activates CD8 +…”

Section: Discussionmentioning

confidence: 86%

“…Recent studies suggested that the induction of CD4 + Treg cells might be associated with suppression of allergic responses in patients after successful IT (25). It was demonstrated that the TLR2 synthetic agonist Pam3CSK4 has therapeutic potential to decrease the mite allergen-induced Th2 immune response (28,29); thus, it may be useful as an adjuvant in immunotherapy for allergic disease (30). Our study investigated whether Dermatophagoides pteronyssinusspecific IT can enhance CD8 + Treg populations, as well as whether Pam3CSK4 increases CD8 +…”

Section: Cd25mentioning

confidence: 99%

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TLR2 Agonists Enhance CD8+Foxp3+ Regulatory T Cells and Suppress Th2 Immune Responses during Allergen Immunotherapy

Tsai

Yang

Niu

et al. 2010

The Journal of Immunology

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Pam3CSK4, a synthetic TLR2 ligand, has been shown to expand CD4+ regulatory T cells (Treg cells). Less is known about the function of CD8+ Treg cells than about the function of CD4+ Treg cells generated during allergen-specific immunotherapy (IT). This study investigated whether Dermatophagoides pteronyssinus-specific IT could expand the CD8+CD25+Foxp3+ Treg population and whether Pam3CSK4 could enhance the Treg population. PBMCs were isolated from healthy control subjects and from mite-sensitive asthmatic patients during IT at three specific times: before IT and 6 mo and 1 y after the maximum-tolerated dose. This study was performed without a placebo-controlled group. D. pteronyssinus-specific IT induced a significant increase in CD8+Foxp3+ Treg cells expressing intracellular IL-10 and granzyme B. Costimulation of PBMCs with Pam3CSK4 and D. pteronyssinus 2 expanded the CD8+CD25+Foxp3+ Treg population and inhibited D. pteronyssinus 2-induced IL-4 production. Pam3CSK4-treated CD8+CD25+ Treg cells directly suppressed CD4+ T cell proliferation by cell-contact inhibition. TUNEL revealed that CD8+CD25+ Treg cells, but not CD4+CD25+ Treg cells, directly induced CD4+CD45ROhi+ apoptosis. Our results provide direct evidence that Pam3CSK4 induces an immunomodulatory effect by inducing CD8+ Treg cells; therefore, it may be a good adjuvant for the treatment of mite allergies.

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Section: Discussionmentioning

confidence: 86%

Section: Cd25mentioning

confidence: 99%

TLR2 Agonists Enhance CD8+Foxp3+ Regulatory T Cells and Suppress Th2 Immune Responses during Allergen Immunotherapy

Tsai

Yang

Niu

et al. 2010

The Journal of Immunology

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“…By exploiting a human in vitro allergy model, we tried to predict the potential of BPPcysMPEG to modulate antigen presenting cells and a subsequent allergen-specific immune response. Antigen presenting cells play a decisive role in the induction of immune responses and modulation of this cell population might influence T cell polarization (Lombardi et al, 2008). The stimulation of iDC with BPPcysMPEG with or without the presence of the allergen caused maturation of these cells, as indicated by the upregulation of co-stimulatory molecules and the secretion of proinflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

Local treatment with BPPcysMPEG reduces allergic airway inflammation in sensitized mice

et al. 2011

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According to the hygiene hypothesis, triggering the immune system with microbial components during childhood balances the inherent Th2 bias. In contrast, specific immunotherapy involves exposure of the patient to the allergen in order to achieve desensitization to subsequent contact. In a human in vitro allergy model the potential of the TLR2/6 agonist BPPcysMPEG to modulate antigen presenting cells and allergen-specific immune responses was evaluated. Specific immunomodulation via co-administration of the allergen and BPPcysMPEG enhanced expression of co-stimulatory molecules on DC and increased secretion of the proinflammatory cytokine TNF-?. Acting as an adjuvant, BPPcysMPEG elevated allergen-specific immune responses in co-culture with autologous lymphocytes. Although administration of BPPcysMPEG alone enhanced expression of co-stimulatory molecules on DC, proliferation of autologous lymphocytes was not induced. Based on this finding, the potential of BPPcysMPEG to reduce allergic airway inflammation by preventive modulation of the innate immune system via TLR2/6 agonization was investigated in mice. Local administration of BPPcysMPEG altered cellular influx and cell composition in BAL fluid. Furthermore, the Th2-associated cytokines IL-4 and IL-5 were diminished. Allergen-specific restimulation of cells from mediastinal lymph nodes and splenocytes suggested an alteration of immune responses. The treatment with BPPcysMPEG induced a Th1-dominated cytokine milieu in mediastinal lymph nodes, while allergen-specific immune responses in splenocytes were diminished. The co-administration of allergen and BPPcysMPEG reduced cytokine secretion upon restimulation in mediastinal lymph nodes and splenocytes. From these data we conclude that BPPcysMPEG was able to influence the immune system with regard to subsequent allergen contact by TLR2/6 agonization

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“…Inhibition of allergic asthma by immunomodulation or regulation of the adaptive immune system via manipulation of innate immune processes is an attractive therapeutic strategy. Ligands of the TLR family, such as the synthetic lipoprotein PAM3CSK4 (2,3), LPS (4-6), resiquimod (7,8), and CpG oligodeoxynucleotides (9,10), which activate TLR2, TLR4, TLR7/8, and TLR9, respectively, are capable of inhibiting experimental allergic asthma in animal models. In this context, we examined the immunomodulatory potential of Protollin, a mucosal vaccine adjuvant composed of TLR2 and TLR4 ligands, in a murine model of experimental allergic asthma (11).…”

mentioning

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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Toll‐like receptor 2 agonist Pam3CSK4 enhances the induction of antigen‐specific tolerance via the sublingual route

Abstract: Pam3CSK4 induces Th1/regulatory T cell responses, and as such, is a valid candidate adjuvant for sublingual allergy vaccines.

Cited by 94 publications

References 45 publications

TLR2 Agonists Enhance CD8+Foxp3+ Regulatory T Cells and Suppress Th2 Immune Responses during Allergen Immunotherapy

TLR2 Agonists Enhance CD8+Foxp3+ Regulatory T Cells and Suppress Th2 Immune Responses during Allergen Immunotherapy

Local treatment with BPPcysMPEG reduces allergic airway inflammation in sensitized mice

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

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