Dendritic Cell-Derived Exosomes Express a
            <i>Streptococcus pneumoniae</i>
            Capsular Polysaccharide Type 14 Cross-Reactive Antigen That Induces Protective Immunoglobulin Responses against Pneumococcal Infection in Mice

Colino, Jesus; Snapper, Clifford M.

doi:10.1128/iai.01217-06

Cited by 56 publications

(47 citation statements)

References 46 publications

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“…Protection against S. pneumoniae relies not only on innate immune responses, but also requires an intact adaptive response (36). To determine if mTOR plays a role in mediating infection and to assess whether impaired antibody responses in the mTOR KI mice might be biologically relevant, mice were challenged with a low dose (10 6 CFU) of live, encapsulated Pn14 and were re-challenged after 14d with a high dose (10 8 CFU) and followed for 15 days.…”

Section: Resultsmentioning

confidence: 99%

B Cell–Specific Deficiencies in mTOR Limit Humoral Immune Responses

Zhang

Pruitt

Tran

et al. 2013

The Journal of Immunology

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Generation of high-affinity Abs in response to Ags/infectious agents is essential for developing long-lasting immune responses. B cell maturation and Ab responses to Ag stimulation require Ig somatic hypermutation (SHM) and class-switch recombination (CSR) for high-affinity responses. Upon immunization with either the model Ag 4-hydroxy-3-nitrophenylacetyl hapten (NP) conjugated to chicken γ globulin lysine (NP-CGG) or heat-killed Streptococcus pneumoniae capsular type 14 protein (Pn14), knock-in (KI) mice hypomorphic for mTOR function had a decreased ability to form germinal centers, develop high-affinity anti-NP–specific or anti-Pn14–specific Abs, and perform SHM/CSR. Hypomorphic mTOR mice also had a high mortality (40%) compared with wild-type (WT) (0%) littermates and had lower pneumococcal surface protein A–specific Ab titers when immunized and challenged with live S. pneumoniae infection. Mice with mTOR deleted in their B cell lineage (knockout [KO]) also produced fewer splenic germinal centers and decreased high-affinity Ab responses to NP-CGG than did their WT littermates. CSR rates were lower in mTOR KI and KO mice, and pharmacologic inhibition of mTOR in WT B cells resulted in decreased rates of ex vivo CSR. RNA and protein levels of activation-induced cytidine deaminase (AID), a protein essential for SHM and CSR, were lower in B cells from both KI and B cell–specific KO mice, concomitant with increases in phosphorylated AKT and FOXO1. Rescue experiments increasing AID expression in KI B cells restored CSR levels to those in WT B cells. Thus, mTOR plays an important immunoregulatory role in the germinal center, at least partially through AID signaling, in generating high-affinity Abs.

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Section: Resultsmentioning

confidence: 99%

B Cell–Specific Deficiencies in mTOR Limit Humoral Immune Responses

Zhang

Pruitt

Tran

et al. 2013

The Journal of Immunology

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“…The IgG1κ 44.1 mAb is highly specific for PPS14, and shows no cross-reactivity with cell wall and other Pn polysaccharides or host tissues, with the exception of a cross-reactive PPS14 glycoconjugate constitutively expressed by murine dendritic cell exosomes (37). Analysis of the rearranged sequences of the variable regions of the heavy and light chain genes, using the IgBLAST database (http://www.ncbi.nlm.nih.gov/igblast/), indicates that 44.1 mAb belongs to the V H 1/Vκ21 protein family.…”

Section: Resultsmentioning

confidence: 99%

Differential Idiotype Utilization for the In Vivo Type 14 Capsular Polysaccharide-Specific Ig Responses to Intact Streptococcus pneumoniae versus a Pneumococcal Conjugate Vaccine

Colino

Duke

Arjunaraja

et al. 2012

The Journal of Immunology

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Murine IgG responses specific for the capsular polysaccharide (pneumococcal capsular polysaccharide serotype 14; PPS14) of Streptococcus pneumoniae type 14 (Pn14), induced in response to intact Pn14 or a PPS14–protein conjugate, are both dependent on CD4+ T cell help but appear to use marginal zone versus follicular B cells, respectively. In this study, we identify an idiotype (44.1-Id) that dominates the PPS14-specific IgG, but not IgM, responses to intact Pn14, isolated PPS14, and Group B Streptococcus (strain COH1-11) expressing capsular polysaccharide structurally identical to PPS14. The 44.1-Id, however, is not expressed in the repertoire of natural PPS14-specific Abs. In distinct contrast, PPS14-specific IgG responses to a soluble PPS14–protein conjugate exhibit minimal usage of the 44.1-Id, although significant 44.1-Id expression is elicited in response to conjugate attached to particles. The 44.1-Id elicited in response to intact Pn14 was expressed in similar proportions among all four IgG subclasses during both the primary and secondary responses. The 44.1-Id usage was linked to the Igha, but not Ighb, allotype and was associated with induction of relatively high total PPS14-specific IgG responses. In contrast to PPS14–protein conjugate, avidity maturation of the 44.1-Id–dominant PPS14-specific IgG responses was limited, even during the highly boosted T cell-dependent PPS14-specific secondary responses to COH1-11. These results indicate that different antigenic forms of the same capsular polysaccharide can recruit distinct B cell clones expressing characteristic idiotypes under genetic control and suggest that the 44.1-Id is derived from marginal zone B cells.

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“…Regarding infectious diseases, a successful immunization against diphtheria and Leishmania infections was achieved by use of DC-derived exosomes that were exposed to diphtheria toxin [63] or Leish-mania major [64] antigens, respectively. Furthermore, exosomes found in human breast milk can boost the immune response and alter the T cell balance toward a regulatory phenotype [65,66].…”

Section: Natural Functions Of Exosomes and Their Intrinsic Biologimentioning

confidence: 99%

Using exosomes, naturally-equipped nanocarriers, for drug delivery

Batrakova

Kim

2015

Journal of Controlled Release

843

646

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Exosomes offer distinct advantages that uniquely position them as highly effective drug carriers. Comprised of cellular membranes with multiple adhesive proteins on their surface, exosomes are known to specialize in cell–cell communications and provide an exclusive approach for the delivery of various therapeutic agents to target cells. In addition, exosomes can be amended through their parental cells to express a targeting moiety on their surface, or supplemented with desired biological activity. Development and validation of exosome-based drug delivery systems are the focus of this review. Different techniques of exosome isolation, characterization, drug loading, and applications in experimental disease models and clinic are discussed. Exosome-based drug formulations may be applied to a wide variety of disorders such as cancer, various infectious, cardiovascular, and neuro-degenerative disorders. Overall, exosomes combine benefits of both synthetic nanocarriers and cell-mediated drug delivery systems while avoiding their limitations.

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Dendritic Cell-Derived Exosomes Express a Streptococcus pneumoniae Capsular Polysaccharide Type 14 Cross-Reactive Antigen That Induces Protective Immunoglobulin Responses against Pneumococcal Infection in Mice

Cited by 56 publications

References 46 publications

B Cell–Specific Deficiencies in mTOR Limit Humoral Immune Responses

B Cell–Specific Deficiencies in mTOR Limit Humoral Immune Responses

Differential Idiotype Utilization for the In Vivo Type 14 Capsular Polysaccharide-Specific Ig Responses to Intact Streptococcus pneumoniae versus a Pneumococcal Conjugate Vaccine

Using exosomes, naturally-equipped nanocarriers, for drug delivery

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