The immune response of mice and cynomolgus monkeys to macaque mucin 1-mannan

Vaughan, Hilary A; Ho, Deborah W.M; Karanikas, Vaios; Sandrin, Mauro S.; Pietersz, Geoffrey A.

doi:10.1016/s0264-410x(00)00143-2

Cited by 17 publications

(8 citation statements)

References 33 publications

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“…Previously, mannan was shown to enhance both humoral and cellular immunity against various immunogens conjugated to mannan. Multiple mechanisms likely contribute to the adjuvant properties of mannan conjugates, including activation of complement, enhancing uptake and presentation of the conjugated antigen, as well as by providing a stronger signal to antigen-specific B cells by simultaneous triggering of B-cell receptors and CD21/CD35 molecules [ 26 - 28 , 31 - 35 , 70 - 75 ]. Notably, under certain conditions mannan was shown to induce predominantly Th2 polarized anti-inflammatory immune responses to a conjugated non-self peptides [ 33 , 34 , 37 , 38 ], a response which would presumably be beneficial to an anti-Aβ vaccine.…”

Section: Discussionmentioning

confidence: 99%

Mannan-Abeta28conjugate prevents Abeta-plaque deposition, but increases microhemorrhages in the brains of vaccinated Tg2576 (APPsw) mice

Petrushina

Ghochikyan

Mkrtichyan

et al. 2008

J Neuroinflammation

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Background: New pre-clinical trials in AD mouse models may help to develop novel immunogenadjuvant configurations with the potential to avoid the adverse responses that occurred during the clinical trials with AN-1792 vaccine formulation. Recently, we have pursued an alternative immunization strategy that replaces QS21 the Th1 type adjuvant used in the AN-1792 clinical trial with a molecular adjuvant, mannan that can promote a Th2-polarized immune response through interactions with mannose-binding and CD35/CD21 receptors of the innate immune system. Previously we established that immunization of wild-type mice with mannan-Aβ 28 conjugate promoted Th2-mediated humoral and cellular immune responses. In the current study, we tested the efficacy of this vaccine configuration in amyloid precursor protein (APP) transgenic mice (Tg2576).

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Section: Discussionmentioning

confidence: 99%

Mannan-Abeta28conjugate prevents Abeta-plaque deposition, but increases microhemorrhages in the brains of vaccinated Tg2576 (APPsw) mice

Petrushina

Ghochikyan

Mkrtichyan

et al. 2008

J Neuroinflammation

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“…As mentioned previously, mannosylated Ags, such as BSA and Mycobacterium leprae HSP65 protein, have been shown to increase MHC class II-restricted T cell responses by 100-to 200-fold over their nonmannosylated counterparts (3, 7). In contrast, mice immunized with mucin 1 conjugated to oxidized mannan induced CTL responses and tumor protection (8,(22)(23)(24)(25). Furthermore, mannan-coated liposomes containing DNA or protein have been shown to elicit CTL responses and hallmarks of Th1-mediated immunity, such as delayed-type hypersensitivity responses and the secretion of cytokines (IL-12 and IFN-␥) (4,5,9,26,27).…”

Section: Discussionmentioning

confidence: 99%

“…Mannosylation of Ags has been reported to enhance MHC class I-and MHC class II-restricted Ag presentation and T cell stimulation by up to 200-fold compared with nonmannosylated proteins (3)(4)(5)(6)(7). Furthermore, in vivo induction of Th1 cytokines and Ag-specific CTL responses were observed in mice upon immunization with mannosylated vaccines (6,8,9). Thus, Ag mannosylation is an attractive strategy for boosting cell-mediated immune responses.…”

mentioning

confidence: 99%

A Model Vaccine Exploiting Fungal Mannosylation to Increase Antigen Immunogenicity

Lam

Mansour

Specht

et al. 2005

The Journal of Immunology

100

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Ag mannosylation represents a promising strategy to augment vaccine immunogenicity by targeting Ag to mannose receptors (MRs) on dendritic cells. Because fungi naturally mannosylate proteins, we hypothesized that Ags engineered in fungi would have an enhanced capacity to stimulate T cell responses. Using the model Ag OVA, we generated proteins that differentially expressed N- and O-linked mannosylation in the yeast Pichia pastoris and compared them to their unglycosylated counterparts produced in Escherichia coli. We found that yeast-derived OVA proteins containing N-linkages, extensive O-linkages, or both were more potent than the unmannosylated Ags at inducing OVA-specific CD4+ T cell proliferation. This elevated response to fungal Ags was inhibited by mannan, suggesting involvement of MRs. However, the macrophage MR (CD206) was not essential, because macrophage MR-deficient dendritic cells were fully competent in presenting yeast-derived OVA Ags. Thus, the use of fungal glycosylation to provide N-linked and/or extensive O-linked mannosylation increased the capacity of the model Ag OVA to stimulate Ag-specific T cell responses in an MR-dependent manner. These data have implications for vaccine design by providing proof of principle that yeast-derived mannosylation can enhance immunogenicity.

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“…16 Results of studies in macaques have consistently predicted clinical outcomes in humans after gene transfer with adenoviral and retroviral vectors. [17][18][19][20][21][22][23][24] In addition, macaques have a considerably longer lifespan than the commonly used laboratory animals, an important asset for evaluating long-term safety and durability of expression after rAAV-mediated gene transfer. However, difficulties in distinguishing native rhesus FIX from the highly homologous human cognate 25 have impeded use of macaques for preclinical evaluation of rAAV vector-mediated expression of FIX.…”

Section: Introductionmentioning

confidence: 99%

Sustained high-level expression of human factor IX (hFIX) after liver-targeted delivery of recombinant adeno-associated virus encoding the hFIX gene in rhesus macaques

Nathwani

Davidoff

Hanawa

et al. 2002

Blood

160

159

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The feasibility, safety, and efficacy of liverdirected gene transfer was evaluated in 5 male macaques (aged 2.5 to 6.5 years) by using a recombinant adeno-associated viral (rAAV) vector (rAAV-2 CAGG-hFIX) that had previously mediated persistent therapeutic expression of human factor IX (hFIX; 6%-10% of physiologic levels) in murine models. A dose of 4 ؋ 10 12 vector genomes (vgs)/kg of body weight was administered through the hepatic artery or portal vein. Persistence of the rAAV vgs as circular monomers and dimers and high-molecularweight concatamers was documented in liver tissue by Southern blot analysis for periods of up to 1 year. Vector particles were present in plasma, urine, or saliva for several days after infusion (as shown by polymerase chain reaction analysis), and the vgs were detected in spleen tissue at low copy numbers. An enzyme-linked immunosorption assay capable of detecting between 1% and 25% of normal levels of hFIX in rhesus plasma was developed by using hyperimmune serum from a rhesus monkey that had received an adenoviral vector encoding hFIX. Two macaques having 3 and 40 rAAV genome equivalents/cell, respectively, in liver tissue had 4% and 8% of normal physiologic plasma levels of hFIX, respectively. A level of hFIX that was 3% of normal levels was transiently detected in one other macaque, which had a genome copy number of 25 before abrogation by a neutralizing antibody (inhibitor) to hFIX. This nonhuman-primate model will be useful in further evaluation and development of rAAV vectors for gene therapy of hemophilia B. IntroductionRecombinant adeno-associated viral vectors (rAAVs) hold great promise for the treatment of hemophilia B. Preclinical studies in murine and canine models of hemophilia B have demonstrated persistent therapeutic expression of factor IX (FIX) leading to correction of the bleeding phenotype after intramuscular or portal vein administration of rAAV. 1-7 Liver-targeted delivery of rAAV resulted in significantly higher levels of FIX than observed after intramuscular administration of an equivalent dose of vector in immunodeficient mice. 8 More important, the development of neutralizing antibodies (NAbs) to human FIX (hFIX) is more common after intramuscular injection of rAAV than after intraportal administration of the same dose of vector. [8][9][10][11] Mice with persistent hFIX expression after liver-targeted delivery of rAAV could not mount a substantial antibody (Ab) response when challenged repeatedly with hFIX antigen in Freund adjuvant, a result suggesting that the liver has a unique ability to induce immune tolerance to neoantigens. 12 Endothelial cells of the liver, which can efficiently process and cross-present exogenous soluble antigens to CD8 ϩ T cells, are intimately involved in antigenspecific immune tolerance after liver-targeted gene transfer with rAAV vectors. 13 The findings of sustained expression of hFIX at therapeutic levels after a single bolus injection of rAAV vector into the portal vein of mice [3][4][5][6]8 and the absence of toxicity aft...

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The immune response of mice and cynomolgus monkeys to macaque mucin 1-mannan

Cited by 17 publications

References 33 publications

Mannan-Abeta28conjugate prevents Abeta-plaque deposition, but increases microhemorrhages in the brains of vaccinated Tg2576 (APPsw) mice

Mannan-Abeta28conjugate prevents Abeta-plaque deposition, but increases microhemorrhages in the brains of vaccinated Tg2576 (APPsw) mice

A Model Vaccine Exploiting Fungal Mannosylation to Increase Antigen Immunogenicity

Sustained high-level expression of human factor IX (hFIX) after liver-targeted delivery of recombinant adeno-associated virus encoding the hFIX gene in rhesus macaques

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