The efficiency of antigen delivery from macrophage phagosomes into cytoplasm for MHC class I-restricted antigen presentation

Oh, Yu‐Kyoung; Harding, Clifford V.; Swanson, Joel A.

doi:10.1016/s0264-410x(97)00221-1

Cited by 42 publications

(33 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Macrophages and dendritic cells can present exogenous antigen on MHC class I molecules. Different mechanisms for such alternative MHC class I loading, such as transfer of particulate structures from the lysosomal compartment to the cytoplasm for further antigen degradation by the proteasome, have been described (46). However, professional antigen-presenting cells such as LCL appear to take up DB much more efficiently than sfDB, correlating with the differences in the immunogenicity of these particles.…”

Section: Discussionmentioning

confidence: 99%

Dense Bodies of Human Cytomegalovirus Induce both Humoral and Cellular Immune Responses in the Absence of Viral Gene Expression

Pepperl

Münster

Mach

et al. 2000

J Virol

View full text Add to dashboard Cite

Infection of fibroblast cell cultures with human cytomegalovirus (HCMV) leads to the production of significant amounts of defective enveloped particles, termed dense bodies (DB). These noninfectious structures contain major antigenic determinants which are responsible for induction of both the humoral and the cellular immune response against HCMV. We tested the hypothesis that, by virtue of their unique antigenic and structural properties, DB could induce a significant immune response in the absence of infectious virus. Mice were immunized with gradient-purified DB, which were either left untreated or subjected to sequential rounds of sonication and freeze-thawing to prevent cellular entry. Titers of neutralizing antibodies induced by DB were in a range comparable to levels present in convalescent human sera. The virus-neutralizing antibody response was surprisingly durable, with neutralizing antibodies detected 12 months following primary immunization. The HCMV-specific major histocompatibility complex class I-restricted cytolytic T-cell (CTL) response was assayed using mice transgenic for the human HLA-A2 molecule. Immunization with DB led to high levels of HCMV-specific CTL in the absence of de novo viral protein synthesis. Maximal total cytolytic activity in mice immunized with DB was nearly as efficient as the cytolytic activity induced by a standard immunization with murine cytomegalovirus. Furthermore, DB induced a typical T-helper 1 (Th1)-dominated immune response in mice, as determined by cytokine and immunoglobulin G isotype analysis. Induction of humoral and cellular immune responses was achieved without the concomitant use of adjuvant. We thus propose that DB can serve as a basis for the future development of a recombinant nonreplicating vaccine against HCMV. Finally, such particles could be engineered for efficient delivery of antigens from other pathogens to the immune system.

show abstract

Section: Discussionmentioning

confidence: 99%

Dense Bodies of Human Cytomegalovirus Induce both Humoral and Cellular Immune Responses in the Absence of Viral Gene Expression

Pepperl

Münster

Mach

et al. 2000

J Virol

View full text Add to dashboard Cite

show abstract

“…The second uses microparticles to deliver protein antigens to phagolysosomal compartments that contain MHC I receptors that are being recycled from the plasma membrane. Once delivered these proteins are subsequently degraded by phagolysosomal enzymes into antigenic peptides that complex MHC I receptors and are then trafficked to the cell surface for antigen presentation (5)(6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

“…The microparticles investigated previously as delivery vehicles for protein-based vaccines have been composed of materials such as polycaprolactone, poly(lactic-co-glycolic acid), and polystyrene (5,9,10). Some of these materials degrade via basecatalyzed hydrolysis whereas others cannot be degraded.…”

mentioning

confidence: 99%

A macromolecular delivery vehicle for protein-based vaccines: Acid-degradable protein-loaded microgels

Murthy

Schuck

et al. 2003

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

388

361

View full text Add to dashboard Cite

The development of protein-based vaccines remains a major challenge in the fields of immunology and drug delivery. Although numerous protein antigens have been identified that can generate immunity to infectious pathogens, the development of vaccines based on protein antigens has had limited success because of delivery issues. In this article, an acid-sensitive microgel material is synthesized for the development of protein-based vaccines. The chemical design of these microgels is such that they degrade under the mildly acidic conditions found in the phagosomes of antigenpresenting cells (APCs). The rapid cleavage of the microgels leads to phagosomal disruption through a colloid osmotic mechanism, releasing protein antigens into the APC cytoplasm for class I antigen presentation. Ovalbumin was encapsulated in microgel particles, 200 -500 nm in diameter, prepared by inverse emulsion polymerization with a synthesized acid-degradable crosslinker. Ovalbumin is released from the acid-degradable microgels in a pH-dependent manner; for example, microgels containing ovalbumin release 80% of their encapsulated proteins after 5 h at pH 5.0, but release only 10% at pH 7.4. APCs that phagocytosed the acid-degradable microgels containing ovalbumin were capable of activating ovalbumin-specific cytoxic T lymphocytes. The aciddegradable microgels developed in this article should therefore find applications as delivery vehicles for vaccines targeted against viruses and tumors, where the activation of cytoxic T lymphocytes is required for the development of immunity.polymer ͉ crosslinker ͉ encapsulation ͉ vaccination ͉ cytotoxic T lymphocyte

show abstract

“…However, the efficiency of this process is dramatically increased when they are linked to a 'particulated' support such as microparticles [4,139]. Indeed, the use of PLGA and polystyrene particles resulted in enhanced antigen delivery into the cytoplasm and promotion of strong MHC class I-restricted responses [140]. Initially, it was proposed that the endocytic compartments were disrupted by the use of microparticles, thereby favoring antigen release into the cytosol.…”

Section: Vaccination Strategies To Deliver Exogenous Antigens Into Thmentioning

confidence: 99%

Rational Design of Vaccination Strategies to Promote Antigen Entry into the MHC Class I-Restricted Presentation Pathway

Becker¹,

Guzmán²

2004

Transfus Med Hemother

View full text Add to dashboard Cite

Cytotoxic CD8+ T lymphocytes (CTLs) constitute one of the main effector mechanisms against tumors and viral infections. CTLs specifically recognize short peptides (8-10 residues long) displayed on the surface of ‘target’ cells, which result from the processing of foreign or abnormal proteins (e.g. virus and tumor proteins) and are bound to major histocompatibility complex (MHC) class I molecules. Virtually all nucleated cells display on their surface fragments of intracellularly produced polypeptides. When there are signs of invasion or transformation, CTLs take control of the situation by destroying these ‘labeled’ target cells. This is an extremely efficient mechanism. However, the efficient differentiation of naïve CD8+ T cells into CTLs is a limiting prerequisite. To achieve this differentiation, dendritic cells (DCs) are critical since only these professional antigen-presenting cells (APCs) can provide not only the peptide presented onto the MHC class I molecules but also the costimulatory signals required for this activation. To this end, DCs take up antigens and degrade them into peptides which are loaded on MHC class I and presented onto the surface to prime specific T lymphocytes. In this review, we summarize the current knowledge on the mechanisms used by professional APCs in the processing and presentation of endogenous and exogenous antigens in the context of MHC class I molecules (i.e. priming and cross-priming). We will also discuss new vaccination strategies that take advantage of these physiological mechanisms in order to improve the elicitation of cytotoxic responses to eliminate intracellular pathogens and tumors.

show abstract

The efficiency of antigen delivery from macrophage phagosomes into cytoplasm for MHC class I-restricted antigen presentation

Cited by 42 publications

References 25 publications

Dense Bodies of Human Cytomegalovirus Induce both Humoral and Cellular Immune Responses in the Absence of Viral Gene Expression

Dense Bodies of Human Cytomegalovirus Induce both Humoral and Cellular Immune Responses in the Absence of Viral Gene Expression

A macromolecular delivery vehicle for protein-based vaccines: Acid-degradable protein-loaded microgels

Rational Design of Vaccination Strategies to Promote Antigen Entry into the MHC Class I-Restricted Presentation Pathway

Contact Info

Product

Resources

About