Targeting Antigens to Dendritic Cell Receptors for Vaccine Development

Apostolopoulos, Vasso; Thalhammer, Theresia; Tzakos, Andreas G.; Stojanovska, Lily

doi:10.1155/2013/869718

Cited by 140 publications

(127 citation statements)

References 219 publications

(273 reference statements)

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“…DC in particular are proficient in processing exogenous antigens for presentation by class I molecules via the cross-presentation pathway [58]. Most adjuvants have properties or are designed to access one or both of these pathways using a number of mechanisms such as the nature of the particulate (microparticles, VLP, ISCOM) [59][60][61][62], having membrane fuseogenic properties (liposomes, ISCOM) [63,64] or cell surface receptor binding (mannan or recombinant antibody) [3,4,6,8].…”

Section: Efficient Generation Of Cd8mentioning

confidence: 99%

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Vaccine delivery by penetratin: mechanism of antigen presentation by dendritic cells

et al. 2016

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Cell penetrating peptides (CPP) or membrane translocating peptides such as, penetratin from Antennapedia homeodomain or TAT from human immunodeficiency virus are useful vectors for the delivery of protein antigens or their cytotoxic (Tc) or helper (Th) T cell epitopes to antigen presenting cells. Mice immunized with CPP containing immunogens elicit antigen-specific Tc and/or Th responses and could be protected from tumor challenges. In the present paper, we investigate the mechanism of class I and class II antigen presentation of ovalbumin covalently linked to penetratin (AntpOVA) by bone marrow-derived dendritic cells (BMDC) with the use of biochemical inhibitors of various pathways of antigen processing and presentation. Results from our study suggested that uptake of AntpOVA is via a combination of energy independent (membrane fusion) and energy dependent pathways (endocytosis). Once internalized by either mechanism, multiple tap-dependent or independent antigen presentation pathways are accessed whilst not completely dependent on proteasomal processing but involving proteolytic trimming in the ER and Golgi compartments. Our study provides an understanding on the mechanism of antigen presentation mediated by CPP and leads to greater insights into future development of vaccine formulations.

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Section: Efficient Generation Of Cd8mentioning

confidence: 99%

“…Studies have identified receptors on various DC subtypes that are efficient in generating immune responses [3,4]. There are also multiple approaches reported for the targeted delivery of antigens to some of these receptors expressed on DC and few vaccines are currently in clinical trials [4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Vaccine delivery by penetratin: mechanism of antigen presentation by dendritic cells

et al. 2016

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“…114-121 Alternatively, TAAs can be specifically conveyed to DCs in vivo by (1) fusing them to monoclonal antibodies, polypeptides or carbohydrates that specifically target DC-specific receptors (e.g., mannose receptor, C type 1 (MRC1), CD209 (also known as DC-SIGN), and lymphocyte antigen 75 (LY75, also known as DEC-205)), [122][123][124][125][126][127][128]130,131,133,153 or DC-associated glycolipids (e.g., glycosphingolipid globotriaosylceramide (Gb 3 )); 154,155 (2) encapsulating them in immunoliposomes that target DCs, [156][157][158] or (3) encoding them in vectors targeting DCs. [159][160][161][162] In the latter case, to overcome the tolerogenic activity of iDCs, 123,124 strategies aiming to target DCs in vivo also need to simultaneously integrate DC-activating stimuli such as TLR agonists and/or pro-inflammatory cytokines.…”

Section: Introductionmentioning

confidence: 99%

Trial watch: Dendritic cell-based anticancer immunotherapy

et al. 2017

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Dendritic cell (DC)-based vaccines against cancer have been extensively developed over the past two decades. Typically DC-based cancer immunotherapy entails loading patient-derived DCs with an appropriate source of tumor-associated antigens (TAAs) and efficient DC stimulation through a so-called "maturation cocktail" (typically a combination of pro-inflammatory cytokines and Toll-like receptor agonists), followed by DC reintroduction into patients. DC vaccines have been documented to (re)activate tumor-specific T cells in both preclinical and clinical settings. There is considerable clinical interest in combining DC-based anticancer vaccines with T cell-targeting immunotherapies. This reflects the established capacity of DC-based vaccines to generate a pool of TAA-specific effector T cells and facilitate their infiltration into the tumor bed. In this Trial Watch, we survey the latest trends in the preclinical and clinical development of DC-based anticancer therapeutics. We also highlight how the emergence of immune checkpoint blockers and adoptive T-cell transfer-based approaches has modified the clinical niche for DC-based vaccines within the wide cancer immunotherapy landscape.

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“…DLS and TEM confirmed particle formation where a smaller particle size was observed for the control library (16-18) due to their smaller molecular weights. strategies for many decades [128]. The presence of the large numbers of the MRs on the surface of macrophages and DCs is known to be evidence for their significant role in antigen presentation [192,267].…”

Section: Resultsmentioning

confidence: 99%

“…Further, Apostolopoulos et al showed that immunisation with MUC1 attached to reduced mannan provided poor protection despite induction of tumour-specific CD8 T cell responses [71]. Studies such as that of Napper and Taylor showed this anomaly in protection versus antibody titre [123], and examples of successful mannosylated versus unmannosyled-vaccines, whereby protection was obtained, can be found in various articles [128,129].…”

Section: Mannosylated Proteinsmentioning

confidence: 99%

Mannosylated lipopetides as model vaccines for targeting the mannose receptor

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The mannose receptor (MR) is an important component of the immune system and understanding the structural and conformational characteristics of this receptor is a key aspect of targeted vaccine design. Improved understanding of the role of carbohydrate recognition domains (CRDs) 4-7 in recognising glycosylated ligands present on the surface of pathogens such as C. albicans, P. carinii, L. donovani, and M. tuberculosis has given new insight into MR vaccine development. Initial studies identified mannan and its derivatives to be important ligands in MR targeting, providing essential knowledge about structural properties of the MR. During the last decade many attempts have been made to target this receptor for applications including vaccine and drug development.In the present study, a library of vaccine constructs comprising fluorescently-labelled mannosylated lipid dendrimers that contained the ovalbumin CD4 + epitope, OVA323-339, as the model peptide antigen were synthesised using fluorenylmethyloxycarbonyl (Fmoc) solid phase peptide synthesis (SPPS). The vaccine constructs were designed with an alanine spacer between the O-linked mannose moieties to investigate the impact of distance between the mannose units on receptor-mediated uptake and/or binding in antigen presenting cells.Mannosylated building blocks were prepared with a Lewis acid reaction and the reaction was successfully modified and monitored for a better yield. This was followed by solid phase synthesis of mannosylated peptides with an azide functional group and a fluorescent tag. Considering the presence of multi-components on the designed mannosylated peptide, different methods of preparation was used and a high yield of the final mannosylated peptides with an azide functional group and a fluorescent tag were prepared. Further, OVA323-339 lipopeptides with an alkyne functional group were prepared using microwave assisted peptide synthesis. Final vaccine structures were prepared by attaching azide and alkyne functional groups using click chemistry. The same methods were applied for the preparation of a library of control vaccine structures.In vitro uptake studies performed on macrophage (F4/80 + ) and dendritic (CD11c + ) cells showed significant uptake and/or binding for vaccine constructs containing mannose and lipid, and also for the lipopeptide vaccine construct without mannose when compared to the controls (containing no lipid, no mannose and no mannose or lipid). Further, in vitro mannan competition assays demonstrated that uptake of the mannosylated and lipidated vaccine constructs was MR mediated. To address the specificity of receptor uptake, surface plasmon resonance (SPR) was performed usingBiacore technology which confirmed a high affinity of the mannosylated and lipidated vaccine constructs towards the human recombinant MR in vitro when compared with vaccine constructs without mannose. These studies also confirmed that both mannose and lipid moieties play significant II roles in receptor-mediated uptake on APCs, potentially faci...

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Targeting Antigens to Dendritic Cell Receptors for Vaccine Development

Cited by 140 publications

References 219 publications

Vaccine delivery by penetratin: mechanism of antigen presentation by dendritic cells

Vaccine delivery by penetratin: mechanism of antigen presentation by dendritic cells

Trial watch: Dendritic cell-based anticancer immunotherapy

Mannosylated lipopetides as model vaccines for targeting the mannose receptor

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