The Acquired Immune Response to the Mucosal Adjuvant LTK63 Imprints the Mouse Lung with a Protective Signature

Tritto, Elaine; Muzzi, Alessandro; Pesce, Isabella; Monaci, Elisabetta; Nuti, Sandra; Galli, Grazia; Wack, Andreas; Rappuoli, Rino; Hussell, Tracy; Gregorio, Ennio De

doi:10.4049/jimmunol.179.8.5346

Cited by 30 publications

(18 citation statements)

References 45 publications

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“…We show that TNF-a staining colocalizing with FDC-M2 + cells in GCs is increased in mice primed with Pnc1-TT+LT-K63 compared with mice primed with Pnc1-TT with or without CpG1826, and TTinduced TNF-a secretion by spleen cells was also increased. Accordingly, LT-K63 enhances NF-kB translocation in macrophages of adult mice (18) and increases TNF-a production by CD4 + T cells in vivo (46). Although CpG-ODNs are strong TNF-a inducers in adult mice (43), CpG1826 failed to overcome the delayed TNF-a production in our neonatal murine model, in contrast with LT-K63.…”

Section: Discussionmentioning

confidence: 44%

The Adjuvant LT-K63 Can Restore Delayed Maturation of Follicular Dendritic Cells and Poor Persistence of Both Protein- and Polysaccharide-Specific Antibody-Secreting Cells in Neonatal Mice

Bjarnarson

Adarna

Benonisson

et al. 2012

The Journal of Immunology

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Ab responses in early life are low and short-lived; therefore, induction of protective immunity requires repeated vaccinations. One of the major limitations in early-life immunity is delayed maturation of follicular dendritic cells (FDCs), which play a central role in mediating the germinal center (GC) reaction leading to production of Ab-secreting cells (AbSCs). We assessed whether a nontoxic mutant of Escherichia coli heat-labile enterotoxin (LT-K63) and CpG1826 as model adjuvants could accelerate FDC maturation and immune response in neonatal mice, using a pneumococcal polysaccharide of serotype 1 conjugated to tetanus toxoid (Pnc1-TT) as a model vaccine. In neonatal NMRI mice, a single dose of Pnc1-TT coadministered with LT-K63 enhanced Pnc1-TT–induced GC reaction. In contrast, CpG1826 had no effect. Accordingly, LT-K63, but not CpG1826, accelerated the maturation of FDC networks, detected by FDC-M2+ staining, characteristic for adult-like FDCs. This coincided with migration of MOMA-1+ macrophages into the GCs that can enhance GC reaction and B cell activation. The FDC-M2+ FDC networks colocalized with enhanced expression of TNF-α, which is critical for the maintenance of mature FDCs and is poorly expressed in neonates. The accelerated maturation of FDC networks correlated with increased frequency and prolonged persistence of polysaccharide- and protein-specific IgG+ AbSCs in spleen and bone marrow. Our data show for the first time, to our knowledge, that an adjuvant (LT-K63) can overcome delayed maturation of FDCs in neonates, enhance the GC reaction, and prolong the persistence of vaccine-specific AbSCs in the BM. These properties are attractive for parenteral vaccination in early life.

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Section: Discussionmentioning

confidence: 44%

The Adjuvant LT-K63 Can Restore Delayed Maturation of Follicular Dendritic Cells and Poor Persistence of Both Protein- and Polysaccharide-Specific Antibody-Secreting Cells in Neonatal Mice

Bjarnarson

Adarna

Benonisson

et al. 2012

The Journal of Immunology

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“…All dilutions were conducted with endotoxin-free PBS (Sigma). PBS alone or CpG (10 g) in PBS was administered intranasally in a total volume of 50 l (25 l/nostril) to anesthetized BALB/c mice [23] . Anesthesia was induced by intraperitoneal injection of 50 mg/kg ketamine plus 2.6 mg/kg xylazine in a 100-l solution.…”

Section: Formulation Of Oligonucleotides and Immunization Protocolmentioning

confidence: 99%

“…RNA was extracted from the lung as previously described [23] . In brief, lungs were homogenized in 5 ml of TRIzol (Invitrogen Life Technologies, Paisley, UK), and the total RNA was extracted following the manufacturer's protocol and purified using RNeasy RNA purification columns following the manufacturer's protocol (Qiagen, Milan, Italy).…”

Section: Rna Extraction and Purificationmentioning

confidence: 99%

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Intranasal Administration of CpG Induces a Rapid and Transient Cytokine Response Followed by Dendritic and Natural Killer Cell Activation and Recruitment in the Mouse Lung

Pesce¹,

Monaci²,

Muzzi³

et al. 2009

J Innate Immun

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CpG-containing oligodeoxynucleotides are potent mucosal adjuvants and effective as stand-alone treatment of respiratory infections in mice. Although CpG is also used as a type 1 helper immunomodulator in the treatment of asthma and allergic disease, immune modulation following intranasal application has not been fully characterized yet. Using a B-type CpG, we monitored RNA expression profiles, cytokine production and cellular activation in lung tissue and bronchoalveolar lavages ex vivo and cytokine production of purified cell populations in vitro. CpG triggered the upregulation of many transcripts, including interferon response genes and proinflammatory cytokine genes, between 3 h and 4 days. Overlapping subsets of these cytokine proteins were induced in vitro in purified CD11c+ cells, B cells and alveolar macrophages from the lung, thus identifying these cells as direct targets of CpG. While lung B cells strongly respond to CpG in vitro, less activation is found ex vivo, suggesting efficient CpG sequestering or rapid B cell migration after activation. In contrast, a type II alveolar epithelial cell line did not respond to CpG in vitro. We noted selective recruitment of plasmacytoid dendritic cells (DCs) into the lung tissue, and of conventional DCs and natural killer (NK) cells into the lung tissue and bronchoalveolar space. Furthermore, CpG induced activation of intrapulmonary DCs, NK and T cells. We hypothesize that CpG-linked adjuvanticity and clearance of respiratory pathogens are mediated by two major mechanisms: transient induction of the interferon pathway limiting microbial survival and selective recruitment of DCs and NK cells, which allows for better adaptive responses.

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“…For comparison, mice were given i.n. immunizations with CpG ODN, an adjuvant known to depend on TLR9 and MyD88 signalling, and LTK63, a detoxified mutant of the LT holotoxin with well documented mucosal adjuvant functions (Tritto et al, 2007). Following three i.n.…”

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confidence: 99%

CTA1-DD adjuvant promotes strong immunity against human immunodeficiency virus type 1 envelope glycoproteins following mucosal immunization

Sundling

Schön

Mörner

et al. 2008

Journal of General Virology

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Strategies to induce potent and broad antibody responses against the human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Env) at both systemic and mucosal sites represent a central goal for HIV-1 vaccine development. Here, we show that the non-toxic CTA1-DD adjuvant promoted mucosal and systemic humoral and cell-mediated immune responses following intranasal (i.n.) immunizations with trimeric or monomeric forms of HIV-1 Env in mice and in nonhuman primates. Env-specific IgG subclasses in the serum of immunized mice reflected a balanced Th1/Th2 type of response. Strikingly, i.n. immunizations with Env and the CTA1-DD adjuvant induced substantial levels of mucosal anti-Env IgA in bronchial alveolar lavage and also detectable levels in vaginal secretions. By contrast, parenteral immunizations of Env formulated in Ribi did not stimulate mucosal IgA responses, while the two adjuvants induced a similar distribution of Env-specific IgG-subclasses in serum. A single parenteral boost with Env in Ribi adjuvant into mice previously primed i.n. with Env and CTA1-DD, augmented the serum anti-Env IgG levels to similar magnitudes as those observed after three intraperitoneal immunizations with Env in Ribi. The augmenting potency of CTA1-DD was similar to that of LTK63 or CpG oligodeoxynucleotides (ODN). However, in contrast to CpG ODN, the effect of CTA1-DD and LTK63 appeared to be independent of MyD88 and toll-like receptor signalling. This is the first demonstration that CTA1-DD augments specific immune responses also in non-human primates, suggesting that this adjuvant could be explored further as a clinically safe mucosal vaccine adjuvant for humoral and cell-mediated immunity against HIV-1 Env. INTRODUCTIONBecause the majority of natural human immunodeficiency virus type 1 (HIV-1) transmissions occur via mucosal membranes an effective prophylactic vaccine should stimulate immune responses that are active at the portal site for viral entry (Gupta & Klasse, 2006;Mestecky et al., 2005). Vaccine-induced neutralizing antibodies (NAbs) that interfere with viral entry have been found to be the protective correlates of many other prophylactic antiviral vaccines (Parren et al., 2001;Wicker et al., 2007;Zignol et al., 2004). An HIV-1 vaccine that prevents or limits virus replication in the mucosa should reduce the risk of systemic viral dissemination (Haase, 2005;Maher et al., 2005;Mazanec et al., 1992) and may reduce the risk of human-to-human transmission (Kozlowski & Neutra, 2003;Mascola, 2003;Neutra & Kozlowski, 2006). However, the development of mucosal vaccines has been slow, owing mainly to the lack of safe and effective mucosal adjuvants. Furthermore, there is insufficient knowledge as to the best route for immunization of the genital tract: i.n., local vaginal, rectal or parenteral. Also, combinations of regimens, such as mucosal priming followed by systemic boost, or, systemic priming followed by mucosal boost, have not been exhaustively investigated (Vajdy et al., 2004). Finally, an overriding problem to ...

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The Acquired Immune Response to the Mucosal Adjuvant LTK63 Imprints the Mouse Lung with a Protective Signature

Cited by 30 publications

References 45 publications

The Adjuvant LT-K63 Can Restore Delayed Maturation of Follicular Dendritic Cells and Poor Persistence of Both Protein- and Polysaccharide-Specific Antibody-Secreting Cells in Neonatal Mice

The Adjuvant LT-K63 Can Restore Delayed Maturation of Follicular Dendritic Cells and Poor Persistence of Both Protein- and Polysaccharide-Specific Antibody-Secreting Cells in Neonatal Mice

Intranasal Administration of CpG Induces a Rapid and Transient Cytokine Response Followed by Dendritic and Natural Killer Cell Activation and Recruitment in the Mouse Lung

CTA1-DD adjuvant promotes strong immunity against human immunodeficiency virus type 1 envelope glycoproteins following mucosal immunization

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