Mannose Receptor-Mediated Regulation of Serum Glycoprotein Homeostasis

Lee, Sena J.; Evers, Stefan; Roeder, Daniel; Parlow, Albert F.; Risteli, Juha; Risteli, Leila; Lee, Y. C.; Feizi, Ten; Langen, Hanno; Nussenzweig, Michel C.

doi:10.1126/science.1069540

Cited by 441 publications

(367 citation statements)

References 24 publications

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“…The role of Man in liver localization was further determined by investigating the difference in liver localization between N-DG and N-DG-Man. Man-specific receptors for macromolecules are known to play an important role in glycoprotein distribution (14), and a smaller (28%) increase in liver localization was observed for N-DG-Man, compared with N-DG-Gal (see below).…”

Section: Gamma Scintigraphic Determination Of In Vivo Organ Distributmentioning

confidence: 99%

“…However, several highly specific and potent binding mechanisms are already present in nature and may be exploited in drug delivery (12). Among these mechanisms, the interaction of carbohydratebinding protein lectins with carbohydrates is one of potential utility (2) that has been particularly highlighted by serum-clearance studies of glycoproteins by the asialoglycoprotein receptor (ASGPR) (13) and the mannose receptor (14). The ASGPR protein is a membrane-bound, endocytic lectin found in abundance on the surface of hepatocytes in the liver (15).…”

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confidence: 99%

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LEAPT: Lectin-directed enzyme-activated prodrug therapy

Robinson

Charlton

Garnier

et al. 2004

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

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. We describe a bipartite drug-delivery system that exploits (i) endogenous carbohydrate-to-lectin binding to localize glycosylated enzyme conjugates to specific, predetermined cell types followed by (ii) administration of a prodrug activated by that predelivered enzyme at the desired site. The carbohydrate structure of an ␣-L-rhamnopyranosidase enzyme was specifically engineered through enzymatic deglycosylation and chemical reglycosylation. Combined in vivo and in vitro techniques (gamma scintigraphy, microautoradiography and confocal microscopy) determined organ and cellular localization and demonstrated successful activation of ␣-L-rhamnopyranoside prodrug. Ligand competition experiments revealed enhanced, specific localization by endocytosis and a strongly carbohydrate-dependent, 60-fold increase in selectivity toward target cell hepatocytes that generated a >30-fold increase (from 0.02 to 0.66 mg) in protein delivered. Furthermore, glycosylation engineering enhanced the serum-uptake rate and enzyme stability. This created enzyme activity (0.2 units in hepatocytes) for prodrug therapy, the target of which was switched simply by sugar-type alteration. The therapeutic effectiveness of lectin-directed enzymeactivated prodrug therapy was shown through the construction of the prodrug of doxorubicin, Rha-DOX, and its application to reduce tumor burden in a hepatocellular carcinoma (HepG2) disease model.

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Section: Gamma Scintigraphic Determination Of In Vivo Organ Distributmentioning

confidence: 99%

mentioning

confidence: 99%

LEAPT: Lectin-directed enzyme-activated prodrug therapy

Robinson

Charlton

Garnier

et al. 2004

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

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“…For MR knockout experiments, BM was provided as a kind gift from Professor Padraic Fallon. BM was from a MR −/− mice on a C57BL/6 background [51] and BMDCs were also generated from background C57BL/6 mice. BM was harvested from the tibia and fibia of a mouse by flushing with ice-cold PBS.…”

Section: Generation Of Bone Marrow-derived Dcsmentioning

confidence: 99%

Fasciola hepatica tegumental antigens induce anergic‐like T cells via dendritic cells in a mannose receptor‐dependent manner

Aldridge

O’Neill

2016

Eur J Immunol

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FoxP3 + Treg cells and anergic T cells are the two regulatory phenotypes of T-cell responses associated with helminth infection. Here, we examine the T-cell responses in mice duringKeywords: Anergy r C-type lectin receptors r Dendritic cells r Helminth infection r Host-pathogen interactions r Mannose receptor r T-cell responses Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionHelminth parasites can survive within their hosts for many years by suppressing T-cell driven protective immune responses and Th1/Th2-mediated pathology through the induction of regulatory networks that suppress inflammatory responses [1][2][3][4]. These regulatory networks include regulatory T cells (Treg) that in the context of helminth infection is widely understood. Treg cells supCorrespondence: Dr. Sandra M. O'Neill e-mail: sandra.oneill@dcu.ie press the immune response to helminth-driven Th1/Th2 immune pathology through the induction of IL-10 and TGF-β. Brugia malayi, infection induces a regulatory response with enhanced FoxP3 expression and increased cell surface expression of CTLA4, a negative regulator of T-cell function [5] while Schistosoma haematobium infection in humans has also been associated with FoxP3 + Treg cells with the highest percentage of this cell population observed in younger patients [6]. However, less is currently known about the regulatory response termed in vivo anergy or adaptive tolerance.Few studies have examined the role of anergenic T cells during helminth infection. The induction of this cell population is thought C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 1180-1192 Immunity to infection 1181 to be the result of the persistent contact of parasite antigen with immune cells during chronic helminth infection [7]. Anergenic T cells differ from Treg cells in that they do not express FoxP3 or produce IL-10 or TGF-β. Instead anergy is a hyporesponsive state with the failure of T cells to proliferate or produce cytokines when restimulated with antigens in vitro [8]. Anergic T cells do not secrete IL-2, a factor important for T-cell proliferation and effector responses. However, the addition of IL-2 can overcome this hyporesponsiveness, restoring helminth-driven T-cell responses. Gene analysis studies have identified a number of genes including Rnf128 (Grail), Itch, Egr2 and Egr3, and CblB that are involved in the induction and maintenance of T-cell anergy [9,10]. A number of helminth infections have shown T-cell anergy or Tcell hyporesponsiveness to be involved in immune suppression. Studies involving S. mansoni show the enhanced expression of GRAIL is linked to the suppression of Th2 cells and also using a filarial nematode, CD4 + T cells become functionally unresponsive [11,12]. Other studies indicate that anergenic-like T cells are the result of helminth infections, with an increase in anergenic markers and T-cell suppression [13][14][15][16]. Fasciola hepatica causes chronic liver d...

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“…Glycoproteins with terminal sialic acids on their glycans persist longer in the blood than glycoproteins with terminal galactose, N-acetylglycosamine, or mannose residues because the latter compounds are cleared rapidly via receptors in the liver and on reticuloendothelial cells (e.g., the asialoglycoprotein receptor and the mannose receptor) (10,20,30,31). In addition, glycan structures produced in nonhuman cells can cause immune reactions, as exemplified by the reaction against xenografts of porcine origin; these reactions are primarily caused by the presence of ␣-galactose on the glycoproteins (7).…”

mentioning

confidence: 99%

In Vivo Synthesis of Mammalian-Like, Hybrid-Type N-Glycans inPichia pastoris

Vervecken

Kaǐgorodov

Callewaert

et al. 2004

Appl Environ Microbiol

167

122

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The Pichia pastoris N-glycosylation pathway is only partially homologous to the pathway in human cells. In the Golgi apparatus, human cells synthesize complex oligosaccharides, whereas Pichia cells form mannose structures that can contain up to 40 mannose residues. This hypermannosylation of secreted glycoproteins hampers the downstream processing of heterologously expressed glycoproteins and leads to the production of protein-based therapeutic agents that are rapidly cleared from the blood because of the presence of terminal mannose residues. Here, we describe engineering of the P. pastoris N-glycosylation pathway to produce nonhyperglycosylated hybrid glycans. This was accomplished by inactivation of OCH1 and overexpression of an ␣-1,2-mannosidase retained in the endoplasmic reticulum and N-acetylglucosaminyltransferase I and ␤-1,4-galactosyltransferase retained in the Golgi apparatus. The engineered strain synthesized a nonsialylated hybrid-type N-linked oligosaccharide structure on its glycoproteins. The procedures which we developed allow glycan engineering of any P. pastoris expression strain and can yield up to 90% homogeneous protein-linked oligosaccharides.Most protein-based therapeutic agents produced in heterologous expression systems are glycosylated, a modification that is crucial for correct folding, stability, and bioactivity of the protein and influences its pharmacokinetic properties, such as tissue distribution and blood clearance. Glycoproteins with terminal sialic acids on their glycans persist longer in the blood than glycoproteins with terminal galactose, N-acetylglycosamine, or mannose residues because the latter compounds are cleared rapidly via receptors in the liver and on reticuloendothelial cells (e.g., the asialoglycoprotein receptor and the mannose receptor) (10,20,30,31). In addition, glycan structures produced in nonhuman cells can cause immune reactions, as exemplified by the reaction against xenografts of porcine origin; these reactions are primarily caused by the presence of ␣-galactose on the glycoproteins (7). Another example is the immune reaction against glycoproteins from yeast, which results from the presence of ␣-1,3-mannose, ␤-linked mannose, and/or phosphate residues in either a phosphomonoester or phosphodiester linkage (1, 32). Consequently, recombinant glycoproteins produced for therapeutic applications should be expressed in heterologous hosts that produce protein-linked oligosaccharides that closely resemble those of humans.

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Mannose Receptor-Mediated Regulation of Serum Glycoprotein Homeostasis

Cited by 441 publications

References 24 publications

LEAPT: Lectin-directed enzyme-activated prodrug therapy

LEAPT: Lectin-directed enzyme-activated prodrug therapy

Fasciola hepatica tegumental antigens induce anergic‐like T cells via dendritic cells in a mannose receptor‐dependent manner

In Vivo Synthesis of Mammalian-Like, Hybrid-Type N-Glycans inPichia pastoris

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