In Vivo Humoral Immune Responses to Isolated Pneumococcal Polysaccharides Are Dependent on the Presence of Associated TLR Ligands

Sen, Goutam; Khan, Abdul Qayyum; Chen, Quanyi; Snapper, Clifford M.

doi:10.4049/jimmunol.175.5.3084

Cited by 91 publications

(74 citation statements)

References 38 publications

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“…The conjugation of a vaccine Ag to a TLR2 agonist was shown to increase both Ab and T cell responses, and thus, TLR2 agonists can clearly function as adjuvants (21). In addition, vaccines against yellow fever and against Pneumococcus have been shown to be efficient partly due to associated TLR2 agonists (17,22). In line with these results, our observations on human and mouse APCs strongly suggest an adjuvant function for ZPS, and we are currently investigating this in in vivo experiments.…”

Section: Discussionsupporting

confidence: 75%

“…1A, scheme c), the carboxyl group was reduced to alcoholic group by treatment with 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide (Sigma-Aldrich) and sodium borohydride (NaBH 4 ; Sigma-Aldrich). Where indicated, a phenol extraction of GBS PS was conducted, as described by Sen et al (17).…”

Section: Chemical Modifications Of Gbs Psmentioning

confidence: 99%

“…This result demonstrates that the zwitterionic motif is required for the ability of PS to stimulate APCs. A recent publication shows that the ability of Pneumococcus PS to induce strong immune responses in mice depends on associated TLR2 agonists that can be separated from the PS by phenol extraction (17). To ensure that the APC stimulatory abilities are not due to a lipophilic contamination, we subjected ZPS2 to phenol extraction and tested the residual biological activity.…”

Section: The Stimulatory Activity Of Zps Depends On the Integrity Of mentioning

confidence: 99%

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Introduction of Zwitterionic Motifs into Bacterial Polysaccharides Generates TLR2 Agonists Able to Activate APCs

Gallorini

Parente

Baronio

et al. 2007

The Journal of Immunology

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It was shown previously that bacterial polysaccharides (PS), which naturally contain both positive and negative charges, are able to activate T cells and APCs. However, the vast majority of bacterial PS are anionic and do not have these properties. In this study, we show that chemical introduction of positive charges into naturally anionic bacterial PS confers to the resulting zwitterionic PS (ZPS) the ability to activate pure human monocytes, monocyte-derived dendritic cells, and mouse bone marrow-derived dendritic cells, as do natural bacterial ZPS. Cells are induced to up-regulate MHC class II and costimulatory molecules and to produce cytokines. In mixed monocyte-T cell cocultures, ZPS induce MHC II-dependent T cell proliferation and up-regulation of activation markers. These stimulatory qualities of ZPS disappear when the positive charge is chemically removed from the molecules and thus the zwitterionic motif is destroyed. The ability of natural and chemically derived ZPS to activate APCs can be blocked by anti-TLR2 mAbs, and TLR2 transfectants show reporter gene transcription upon incubation with ZPS. In conclusion, the generation of a zwitterionic motif in bacterial PS confers the ability to activate both APCs and T cells. This finding has important implications for the design of novel polysaccharide vaccines.

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Section: Discussionsupporting

confidence: 75%

Section: Chemical Modifications Of Gbs Psmentioning

confidence: 99%

Section: The Stimulatory Activity Of Zps Depends On the Integrity Of mentioning

confidence: 99%

See 1 more Smart Citation

Introduction of Zwitterionic Motifs into Bacterial Polysaccharides Generates TLR2 Agonists Able to Activate APCs

Gallorini

Parente

Baronio

et al. 2007

The Journal of Immunology

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“…Moreover the Haemophilus influenzae type b-outer membrane protein complex glycoconjugate has an optimal immunogenicity thanks to the TLR2 agonist properties of the carrier protein (18). Other examples of vaccines owing their potency at least in part to the sometimes fortuitous presence of TLR2 agonists are the yellow fever vaccine (27) and PS vaccines against Streptococcus pneumoniae (28). Thus, TLR2 is a receptor implicated in the strong immunogenicity of natural ZPS but also of vaccines based on PS, attenuated virus or glycoconjugates.…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor 2 dependent immunogenicity of glycoconjugate vaccines containing chemically derived zwitterionic polysaccharides

Gallorini

Mancuso

Cozzi

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Group B Streptococcus (GBS) causes serious infection in neonates and is an important target of vaccine development. Zwitterionic polysaccharides (ZPS), obtained through chemical introduction of positive charges into anionic polysaccharides (PS) from GBS, have the ability to activate human and mouse antigen presenting cells (APCs) through toll-like receptor 2 (TLR2).To generate a polysaccharide vaccine with antigen (Ag) and adjuvant properties in one molecule, we have conjugated ZPS with a carrier protein. ZPS-glycoconjugates induce higher T-cell and Ab responses to carrier and PS, respectively, compared to control PS-glycoconjugates made with the native polysaccharide form. The increased immunogenicity of ZPS-conjugates correlates with their ability to activate dendritic cells (DCs). Moreover, protection of mothers or neonate offspring from lethal GBS challenge is better when mothers are immunized with ZPS-conjugates compared to immunization with PS-conjugates. In TLR2 knockout mice, ZPS-conjugates lose both their increased immunogenicity and protective effect after vaccination. When ZPS are coadministered as adjuvants with unconjugated tetanus toxoid (TT), they have the ability to increase the TT-specific antibody titer. In conclusion, glycoconjugates containing ZPS are potent vaccines. They target Ag to TLR2-expressing APCs and activate these APCs, leading to better T-cell priming and ultimately to higher protective Ab titers. Thus, rational chemical design can generate potent PS-adjuvants with wide application, including glycoconjugates and coadministration with unrelated protein Ags.adjuvant ͉ dendritic cell ͉ Group B Streptococcus C lassically, capsular polysaccharides (PS) from bacteria are considered to be T-independent Ags (1) able to activate B cells directly, without a contribution of help by CD4 ϩ T cells. Therefore, the immune response to PS fails to induce significant and prolonged titers of antibody with high avidity in infants and persistent Agspecific memory B cells in adults. For this reason, in vaccines, PS are mostly used conjugated with a carrier protein that provides T-cell help and consequently immunological memory (2). Glycoconjugate vaccines against the Gram-positive bacterium Group B Streptococcus (GBS) have been shown to confer serotype specific protection in mice and have been tested in clinical trials (3). In humans, addition of alum to the vaccine formulation did not further increase the immune response induced (4). In contrast, in animal models, adsorption to Al(OH) 3 (alum) enhances the immunogenicity of the glycoconjugate (5, 6) which may be explained by the possibility that animals are more naive to GBS than humans. Moreover, a number of commercially available glycoconjugate vaccines, such as those against Meningococcus C, Haemophilus influenza, and the 7-valent Pneumococcus vaccine, use alum or aluminium phosphate as an adjuvant. Thus, the combination of glycoconjugates with adjuvants likely generates potent vaccines, able to activate APCs and induce strong Ag-specific T and B c...

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“…Phytochemicals such as specific polysaccharides have been shown to boost the innate immune system, especially through interaction with Toll-like receptors (TLRs) in mucosa-associated lymphoid tissue (MALT) [101][102][103] . The TLRs evolved to interact with polysaccharides found in the walls of bacteria; they are an essential part of developing and maintaining a competent immune system 104 .…”

Section: Herbsmentioning

confidence: 99%

Chinese Medicine and Biomodulation in Cancer Patients—Part Two

Sagar

Wong

2008

Current Oncology

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Traditional Chinese Medicine (TCM) is a whole system containing therapeutic interventions that individually induce biomodulation at the physiologic, chemical, and molecular levels. The theory of TCM proposes a synergy between specific interventions selected as part of a care plan based on TCM diagnostic theory. Combining TCM with the modern practice of oncology seems, in conjunction with biomedical interventions (surgery, radiotherapy, chemotherapy, and pharmaceuticals), to have potential advantages through the synergy of biomodulation. Biomodulation approaches are broadly categorized as modification of tumour response and reduction of adverse effects; modulation of immunity; prevention of cancer progression; and enhancement of symptom control. Although the database of preclinical studies is rapidly expanding, good-quality clinical trials are notably scarce.Laboratory studies suggest that some herbs increase the effectiveness of conventional chemotherapy without increasing toxicity. A healthy immune system is necessary for control of malignant disease, and the immune suppression associated with cancer contributes to its progression. Many Chinese herbs contain glycoproteins and polysaccharides (among them, constituents of Coriolus versicolor, Ganoderma lucidum, Grifola frondosa, Astragalus membranaceus, Panax ginseng, and various other medicinal mushrooms) that can modulate metastatic potential and the innate immune system. Phytochemicals such as specific polysaccharides have been shown to boost the innate immune system, especially through interaction with Tolllike receptors in mucosa-associated lymphoid tissue. This intervention can potentially improve the effectiveness of new anticancer vaccines. An increase in virusassociated cancers presents a major public health problem that requires novel therapeutic strategies. A number of herbal therapies have both antiviral activity and the ability to promote immunity, possibly inhibiting the initiation and promotion of virus-associated cancers.The mechanisms learned from basic science should be applied to clinical trials both of specific interventions and of whole-system care plans that safely combine the TCM approach with the conventional biomedical model. In Western medicine, the combination of TCM herbs with drug therapies is controversial, given lack of knowledge concerning whether a drug is favourably enhanced or whether adverse effects occur. Using initial data from the preclinical studies, future clinical research needs to evaluate the combinations, some of which are showing favourable synergy.

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In Vivo Humoral Immune Responses to Isolated Pneumococcal Polysaccharides Are Dependent on the Presence of Associated TLR Ligands

Cited by 91 publications

References 38 publications

Introduction of Zwitterionic Motifs into Bacterial Polysaccharides Generates TLR2 Agonists Able to Activate APCs

Introduction of Zwitterionic Motifs into Bacterial Polysaccharides Generates TLR2 Agonists Able to Activate APCs

Toll-like receptor 2 dependent immunogenicity of glycoconjugate vaccines containing chemically derived zwitterionic polysaccharides

Chinese Medicine and Biomodulation in Cancer Patients—Part Two

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