Abstract:Dendritic cells (DCs) are paramount in initiating and guiding immunity towards a state of activation or tolerance. This bidirectional capacity of DCs sets them at the center stage for treatment of cancer and autoimmune or allergic conditions. Accordingly, many clinical studies use ex vivo DC vaccination as a strategy to boost anti-tumor immunity or to suppress immunity by including vitamin D3, NF-κB inhibitors or retinoic acid to create tolerogenic DCs. As harvesting DCs from patients and differentiating these… Show more
“…Furthermore, after in vitro incubation with BMDCs, we saw striking differences between hPG-FAM that was given freely to these cells and hPG-FAM encapsulated in liposomes (Figures 3 and 4). The liposomal delivery of the antigen reduced the % of cells which had taken up antigens from 69 ± 5% to 8 ± 1% (p < 0.0001), which was possibly due to the cationic charge of the antigen (isoelectric point 10.88) compared to the anionic charge of the liposomes [38]. Even without the addition of RA, the hPG-containing liposomes themselves can induce antigen-specific tolDCs and Tregs (Figure 5).…”
The current treatment of autoimmune and chronic inflammatory diseases entails systemic immune suppression, which is associated with increased susceptibility to infections. To restore immune tolerance and reduce systemic side effects, a targeted approach using tolerogenic dendritic cells (tolDCs) is being explored. tolDCs are characterized by the expression of CD11c, the major histocompatibility complex (MHC)II and low levels of co-stimulatory molecules CD40 and CD86. In this study, tolDCs were generated using a human-proteoglycan-derived peptide (hPG) and all-trans retinoic acid (RA). RA-tolDCs not only display a tolerogenic phenotype but also can induce an antigen-specific regulatory T cell (Treg) response in vitro. However, further analysis showed that RA-tolDCs make up a heterogeneous population of DCs, with only a small proportion being antigen-associated tolDCs. To increase the homogeneity of this population, 1,2-distearoyl-sn-glycero-3-phosphoglycerol (DSPG)-containing liposomes were used to encapsulate the relevant antigen together with RA. These liposomes greatly enhanced the proportion of antigen-associated tolDCs in culture. In addition, in mice, we showed that the liposomal co-delivery of antigen and RA can be a more targeted approach to induce antigen-specific tolerance compared to the injection of RA-tolDCs, and that these liposomes can stimulate the generation of antigen-specific Tregs. This work highlights the importance of the co-delivery of an antigen and immunomodulator to minimize off-target effects and systemic side effects and provides new insights in the use of RA for antigen-specific immunotherapy for autoimmune and chronic inflammatory diseases.
“…Furthermore, after in vitro incubation with BMDCs, we saw striking differences between hPG-FAM that was given freely to these cells and hPG-FAM encapsulated in liposomes (Figures 3 and 4). The liposomal delivery of the antigen reduced the % of cells which had taken up antigens from 69 ± 5% to 8 ± 1% (p < 0.0001), which was possibly due to the cationic charge of the antigen (isoelectric point 10.88) compared to the anionic charge of the liposomes [38]. Even without the addition of RA, the hPG-containing liposomes themselves can induce antigen-specific tolDCs and Tregs (Figure 5).…”
The current treatment of autoimmune and chronic inflammatory diseases entails systemic immune suppression, which is associated with increased susceptibility to infections. To restore immune tolerance and reduce systemic side effects, a targeted approach using tolerogenic dendritic cells (tolDCs) is being explored. tolDCs are characterized by the expression of CD11c, the major histocompatibility complex (MHC)II and low levels of co-stimulatory molecules CD40 and CD86. In this study, tolDCs were generated using a human-proteoglycan-derived peptide (hPG) and all-trans retinoic acid (RA). RA-tolDCs not only display a tolerogenic phenotype but also can induce an antigen-specific regulatory T cell (Treg) response in vitro. However, further analysis showed that RA-tolDCs make up a heterogeneous population of DCs, with only a small proportion being antigen-associated tolDCs. To increase the homogeneity of this population, 1,2-distearoyl-sn-glycero-3-phosphoglycerol (DSPG)-containing liposomes were used to encapsulate the relevant antigen together with RA. These liposomes greatly enhanced the proportion of antigen-associated tolDCs in culture. In addition, in mice, we showed that the liposomal co-delivery of antigen and RA can be a more targeted approach to induce antigen-specific tolerance compared to the injection of RA-tolDCs, and that these liposomes can stimulate the generation of antigen-specific Tregs. This work highlights the importance of the co-delivery of an antigen and immunomodulator to minimize off-target effects and systemic side effects and provides new insights in the use of RA for antigen-specific immunotherapy for autoimmune and chronic inflammatory diseases.
“…The population of DCs, which comprises heterogeneous subgroups, performs a pivotal role in guiding the immunity towards activation or tolerance 138 . Since the mucosal environment is constantly exposed to diverse commensal and foreign antigens, it is important for the immune system to distinguish between harmless and harmful antigens.…”
Section: Basic Mechanism Of Mucosal Immunity and Mucosal Vaccinesmentioning
confidence: 99%
“…11 ) 222 , 223 , 224 . In liposomes, cationic lipids such as 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 3 β -[ N -( N ′, N ′-dimethylaminoethane)-carbamoyl]cholesterol (DC-Chol) exhibited DC-activating effects by inducing the expression of DC maturation markers and production of proinflammatory cytokines 138 . By contrast, negatively charged nanoparticles containing phosphatidyl serine (PS) showed an immunotolerant effect by mimicking the apoptotic cells 225 , 226 .…”
“… 46 Hence, nanovaccines are presented to DCs is the prime step to induce an antitumor immune response. 47 , 48 Once recognized as antigens, DCs shift to secondary lymphoid organs and uptake, process and present antigens to T cells, thus, the CD8+ T cells are activated to boost adaptive antitumor immunity, 49–51 meantime, γδT cells are stimulated by the nanovaccines to induce innate antitumor immunity ( Figure 1 ). 51 Figure 1.…”
Section: Effect Of the Nanovaccines On Dcsmentioning
An attractive type of cancer immunotherapy is cancer therapeutic vaccines that induce antitumor immunity effectively. Although supportive results in the recent vaccine studies, there are still numerous drawbacks, such as poor stability, weak immunogenicity and strong toxicity, to be tackled for promoting the potency and durability of antitumor efficacy. NPs (Nanoparticles)-based vaccines offer unique opportunities to breakthrough the current bottleneck. As a rule, nanovaccines are new the generations of vaccines that use NPs as carriers and/or adjuvants. Several advantages of nanovaccines are constantly explored, including optimal nanometer size, high stability, plenty of antigen loading, enhanced immunogenicity, tunable antigen presentation, more retention in lymph nodes and promote patient compliance by a lower frequency of dosing. Here, we summarized the merits and highlight the diverse role nanovaccines play in improving antitumor responses.
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