In vivo targeting of dendritic cells for activation of cellular immunity using vaccine carriers based on pH-responsive microparticles

Abstract

Activating the immune system to trigger a specific response is a major challenge in vaccine development. In particular, activating sufficient cytotoxic T lymphocyte-mediated cellular immunity, which is crucial for the treatment of many diseases including cancer and AIDS, has proven to be especially challenging. In this study, antigens were encapsulated in acid-degradable polymeric particle carriers to cascade cytotoxic T lymphocyte activation. To target dendritic cells, the most potent antigen-presenting cells, the particle carriers, were further conjugated with monoclonal antibodies. A series of ex vivo and in vivo studies have shown increased receptor-mediated uptake of antibody-conjugated particles by dendritic cells as well as migration of particle-carrying dendritic cells to lymph nodes and stimulation of naïve T cells leading to enhanced cellular immune response as confirmed by specific cell lysis and IFN-␥ secretion.acid-degradable particle ͉ drug delivery ͉ targeted vaccine

Materials engineering for immunomodulation

“…With regard to recognition, some subclasses of dendritic cell possess an endocytic receptor, DEC205 (ref. 20), which has been successfully used to enhance dendritic-cell uptake, for example with an antigen or a biomaterial particle conjugated to anti-DEC205 antibodies 21,22 . Recruitment involves chemoattracting other APCs to the delivery site, and strategies include the use, variously, Complement-activating, nucleophile-containing polymeric nanoparticles 28 Induced antigen-specific monoclonal antibody; induced IFN-γ-producing antigenspecific CD8 + T cells 28 Recombinant C3d 72,95 Recombinant, trimeric C3d protein conjugated to protein antigen through an avidin bridge 18 Induced a more robust and protective response to antigen when administered with IFA than when protein antigen administered in IFA or with alum 18 Recombinant, trimeric C3d-antigen fusion DNA vaccine 95 Generated higher-binding, early-appearing and neutralizing antibody responses; increased the number of IFN-γ-producing antigen-specific CD8 + T cells 95 The responses shown are related to engineering approaches to triggering these pathways or types of immunity using biomaterials.…”

Exploiting lymphatic transport and complement activation in nanoparticle vaccines

“…Antigen targeting [1][2][3][4][5] and adjuvancy schemes 6,7 that respectively facilitate delivery of antigen to dendritic cells and elicit their activation have been explored in vaccine development. Here we investigate whether nanoparticles can be used as a vaccine platform by targeting lymph noderesiding dendritic cells via interstitial flow and activating these cells by in situ complement activation.…”

“…Strategies for antigen delivery have recently focused on in vivo targeting of dendritic cells through the use of monoclonal antibodies either fused with protein 1,2,4 or grafted to the surface of microparticles 3 . Such strategies often target peripheral dendritic cells in skin.…”

“…For example, molecular danger signals that mimic the effect of the endotoxin lipopolysaccharide (LPS), such as monophosphoryl lipid A, have been explored 7 , as well as the cytokines CD40 ligand and interferon (IFN)-g 1,2,16 . Delivery of danger signals with antigen by co-encapsulation in liposomes 3,16 , packaging into virus-like particles 14 or co-injection with dendritic cell-targeting antibody fusion proteins 1,4,22 have been successful at producing adaptive immune responses, but despite such promising results, many complexities remain including toxicity, physiological transport and economic feasibility. As an alternative adjuvant strategy, we explored the possibility of using the complement cascade as a danger signal of innate immunity, designing our nanoparticles with a surface chemistry that spontaneously induces complement activation in situ.…”

Multifunctional nanoparticles for cancer immunotherapy

“…For example, Kwon et al conjugated anti-DEC205 on microparticles and showed that these particles are taken up by DCs three times higher than non-targeted counterparts in vivo. 44 It has been shown that human and murine DCs and macrophages express mannose receptor (MR) on their surface. Several studies have confirmed the feasibility of using mannose or mannan to target protein antigens, liposomes, and other micro and NPs to APCs.…”