Clinical Grade OK432-activated Dendritic Cells
Emma WestRuth MorganKaren J. ScottAlison MerrickA. LubenkoDavid PawsonPeter J. SelbyPaul HatfieldR. PrestwichSheila FraserDavid EvesAlan AnthoneyChris TwelvesDebbie BeirnePoulam M. PatelDearbhaile O’DonnellSuzanne M. WattMichael WallerAllan B. DietzPhilip RobinsonAlan Melcher
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Abstract:
Dendritic cells (DC) are under intense preclinical and early clinical evaluation for the immunotherapy of cancer. However, the optimal culture conditions and route of delivery for DC vaccination have not been established. Here we describe the first human application of DC matured with the bacterial agent OK432 (OK-DC), using a short-term serum-free culture protocol, which generates mature DC from CD14+ precursors after 5 days. These cells were prepared within the framework of a National Blood Service facility, demonstrating that DC represent a product which is potentially deliverable alongside current standardized cell therapies within the UK National Health Service. In vitro analysis confirmed that OK-DC were mature, secreted tumor necrosis factor-α, interleukin-6, and interleukin-12, and stimulated both T cell and natural killer cell function. To explore effective delivery of OK-DC to lymph nodes, we performed an initial clinical tracking study of radioactively labeled, unpulsed OK-DC after intralymphatic injection into the dorsum of the foot. We showed that injected DC rapidly localized to ipsilateral pelvic lymph nodes, but did not disseminate to more distant nodes over a 48-hour period. There was no significant toxicity associated with OK-DC delivery. These results show that OK-DC are suitable for clinical use, and that intralymphatic delivery is feasible for localizing cells to sites where optimal priming of innate and adaptive antitumor immunity is likely to occur.Keywords:
Priming (agriculture)
Adjuvants are a critical component for vaccines, especially for a poorly immunogenic antigen, such as nicotine. However, the impact of adjuvant release rate from a vaccine formulation on its immunogenicity has not been well illustrated. In this study, we fabricated a series of hybrid-nanoparticle-based nicotine vaccines to study the impact of adjuvant release rate on their immunological efficacy. It was found that the nanovaccine with a medium or slow adjuvant release rate induced a significantly higher anti-nicotine antibody titer than that with a fast release rate. Furthermore, the medium and slow adjuvant release rates resulted in a significantly lower brain nicotine concentration than the fast release rate after nicotine challenge. All findings suggest that adjuvant release rate affects the immunological efficacy of nanoparticle-based nicotine vaccines, providing a potential strategy to rationally designing vaccine formulations against psychoactive drugs or even other antigens. The hybrid-nanoparticle-based nicotine vaccine with an optimized adjuvant release rate can be a promising next-generation immunotherapeutic candidate against nicotine.
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Objective To observe the significance of expressions of CD14+CD16+ on peripheral monocytes in children with Kawasaki di-sease (KD).Methods The expression of CD14+ and CD14+CD16+ monocytes in 16 children with KD (1-11 years old) were analyzed by flow cytomety both pre-treatment and post-treatment.And the percentages of CD14+CD16+ monocytes among CD14+ monocytes were calculated.Sixteen healthy children (10 months -10 years old) were served as normal control group.Statistical analysis was performed using t test.Results The levels of CD14+ monocytes,percentage of CD14+CD16+ monocytes among CD14+ monocytes and CD14+CD16+ monocytes in children with KD during acute phase (n=16) were (1.03±0.58)×109 L-1,(12.53±5.31)% and(1.20±0.79)×108 L-1.They were significantly higher than those in the normal controls[(0.57±0.21)×109 L-1,(3.86±1.84)% and (0.21±0.10)×108 L-1](Pa0.05).Followed by the patients' condition improved(n=15), the increased expressive levels[(1.03±0.60) ×109 L-1,( 12.83±6.51)%,(1.22±0.82)×108 L-1] decreased [(0.49±0.21)×109 L-1,(5.07±4.77)%,(0.24±0.20)×108 L-1)(Pa0.01)].The expressive levels of CD14+CD16+ monocytes were no significant differences between the post-treatment and the normal controls(Pa0.05).And the expressive levels remained high when the patient recurred.Conclusions The expressive levels of CD14+CD16+ monocytes increase in children with KD.And they change when the patient's clinical condition change.
CD16
Monocyte
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CD14 has been reported to be the lipopolysaccharide (LPS)-LPS binding protein receptor. The effects of interferon-γ (IFN-γ) on CD14 expression have not been clearly established. The purpose of this investigation was to examine the effects of IFN-γ alone and IFN-γ followed by bacterial LPS on CD14 expression. Human peripheral blood monocytes were isolated by counterflow centrifugal elutriation (CCE). Monocytes were cultured for 48 h with IFN-γ alone or for 24 h with IFN-γ followed by LPS for a second 24 h. IFN-γ alone caused a down-regulation of CD14 expression, as assessed by flow cytometry, relative to CD14 expression in untreated monocytes. In addition, CD14 expression was even more significantly down-regulated after IFN-γ pretreatment followed by either Prevotella intermedia or Salmonella typhimurium LPS. Likewise, the percentage of CD14+ monocytes decreased after IFN-γ alone and even more dramatically after IFN-γ treatment followed by either LPS. This study clearly demonstrated that IFN-γ down-regulates CD14 expression and that LPS following IFN-γ pretreatment potentiates this effect.
Monocyte
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ObjectiveTo investigate whether immune adjuvant can enhance the immunity of dendritic cell vaccine against murine breast cancer. Methods4 groups of mice with tumor are injected saline, immume adjuvant, dendritic cell (DC) vaccine and DC vaccine coupled with immune vaccine, respectively. Tumor volume and weight are measured 21 d later.ResultsThe tumor size in the DC vaccine coupled with immune vaccine group was significantly small compared with control group (P=0.001) and the DC vaccine group (P=0.047).ConclusionImmune adjuvant can enhance the immunity of dendritic cell vaccine against murine breast cancer.
Cancer vaccine
Vaccine adjuvant
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Electrostatic interactions and phosphate exchange are the most important mechanisms for the adsorption of antigens onto aluminum-containing adjuvant. But the immunogenicity of the final vaccine is not proportional to the amount and the adsorption strength of antigens onto aluminum-containing adjuvant. The stability of aluminum adjuvant would be decreased while it is stored in room temperature. However, it does not affect immune enhancement activity. Usually, aluminum adjuvant should avoid exposure to elevated temperature in long time, and buffer salts such as phosphate could be used to protect vaccines containing aluminum adjuvant. Now the new formulation of aluminum-adjuvanted vaccine dry powder can increase the stability of vaccines. This review describes recent studies on the interaction between aluminum adjuvant and antigens, the stability of vaccines containing aluminum adjuvant and the development tendency of aluminum adjuvant.
Vaccine adjuvant
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An adjuvant (immunopotentiator), when added to a vaccine, will enhance the immunogenicity of the antigen with the stimulation of an elevated humoral immune response. Some adjuvants may also stimulate a cell-mediated response against the antigen. One advantage of including an adjuvant in the vaccine mixture is that smaller quantities of the antigen are usually required to stimulate a good response. New synthetic experimental vaccines may require the presence of an adjuvant to achieve an immunogenic response. There is no single universal adjuvant, but numerous adjuvants are available alone (e.g., muramyl dipeptide and Quil A derivatives), or conjugated to the antigen (e.g., Immune-stimulating complexes [ISCOMs]), or in mixtures (e.g., Montanides, Guildhay or MF-59 adjuvants). The adjuvant selected will be based on experimental data produced with a variety of antigen preparations, taking into consideration the nature and dose to be administered, the route of vaccine administration, and any contraindications. For human vaccines, it should be remembered that aluminum salt adjuvants have been the only licensed preparations for the past sixty yr.
Muramyl dipeptide
Immunoadjuvant
Immunopotentiator
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The aim of the study was to analyze the relationship between monocyte subpopulations and phenotype/ functions of monocyte-derived dendritic cells (DCs), as well as DC sensitivity to the tolerogenic effect of dexamethasone. Materials and methods. The study included 15 healthy donors. DCs were generated by cultivating enriched fractions of CD14+ monocytes with or without CD16+cell depletion (CD16-Mo-DCs or CD16+Mo-DCs, respectively) in the presence of interferon alpha (IFNα) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Monocyte subpopulations were obtained by immunomagnetic negative selection. Results. CD16+Mo-DCs were characterized by higher percentage of mature (CD83+CD14-) and lower number of semi-mature (CD14+CD83+) cells, but were similar to CD16-Mo-DCs by HLA-DR and CD86 expression, involved in the presentation of antigens and activation of naive T-cells. and also to co-inhibitory/ tolerogenic molecules B7-H1 and TLR-2. CD16+Mo-DCs displayed higher allostimulatory activity, which was positively correlated with CD86 expression ( rS = 0.69; p = 0.027) and negatively – with TLR-2 expression ( rS = -0.72; p = 0.1). Allostimulatory activity of CD16-Mo-DCs was positively correlated with the number of mature CD14-CD83+DCs and semi-mature CD14+CD83+DCs. Addition of dexamethasone (10-6 M) into CD16-Mo-DCs and CD16+Mo-DCs cultures led to the delay of DC maturation, the decrease of CD86 and the increase of TLR-2 expression, as well as the increase of cells with co-inhibitory CD86- B7-H1+ phenotype that was positively correlated with the reduction of DC allostimulatory activity. The decrease of CD86+/TLR-2+ index in CD16+Mo-DC population was due to the reduction of CD86+DCs and in CD16-Mo-DC population – to the increase of TLR-2+cells. Dexamethasone possessed higher inhibitory effect on DC maturation in the CD16+Mo-DC cultures. Conclusion. CD14+ monocytes, both contained and depleted by CD16+ cells, can differentiate into DCs when cultured with IFNα. The presence of CD16+ cells in whole blood monocyte pool is associated with generation of DCs showed a more mature phenotype and higher allostimulatory activity. Both CD16- and CD16+ monocyte-derived DCs are sensitive to suppressive effect of dexamethasone. However, dexamethasone tolerogenic effect involves different mechanisms in CD16-Mo-DCs and CD16+Mo-DCs.
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CD86
Monocyte
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Abstract Increased percentage of monocytes with low CD14 expression and that co‐express CD16 (CD14+/CD16+) have been reported in hemodialysis (HD) patients. We sought to determine whether CD14+/CD16+ monocytes in HD therapy are sensibilized cells to a proinflammatory activity. Cells from 32 HD patients, and from 9 Systemic Lupus Erythematosus (SLE), 9 individuals with human immunodeficiency virus (HIV)‐1‐ and 15 healthy controls were studied. Cells were analyzed by means of flow cytometry for CD14/CD16 expression and immune function (cytokine, chemokines, and sialoadhesin expression), and phagocytosis. Increased percentage of CD14+/CD16+ monocytes was observed in HD patients. Compared with CD14++ monocytes, the CD14+/CD16+ monocytes exhibited increased expression of proinflammatory cytokines and markers of differentiated cells. In addition, these monocytes showed an increased phagocytic activity. Similarly, CD14+/CD16+ monocytes from SLE and HIV patients showed increased inflammatory activity as compared with CD14++ cells. These results support that CD14+/CD16+ monocytes from HD patients evidence characteristics of primed prestimulated proinflammatory cells, similar to data observed in SLE and HIV.
CD16
Proinflammatory cytokine
Monocyte
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The adjuvant effects of CFNCpG on the humoral immune response of rabbits were investigated on the CFNCpG,Freund's complete adjuvant and aluminium hydroxide.An inactivated BVDV-1 was served as antigen.The neutralizing antibody titers were tested every 7 days after immunization to evaluate the immune adjuvant effects of CFNCpG on antigen of inactivated BVDV-1.The results showed that the antibody titer was 4.4(log_2SN_)(50))7 days and more than 7.0 14 days after CFNCpG was used as adjuvant alone. When CFNCpG combined with aluminium hydroxide was used as adjuvants,the antibody titer was higher than 7.0 after 21 days which was equal to the adjuvant effects of Freund's complete adjuvant.The CFNCpG is a useful adjuvant component in BVDV-1 inactivated vaccine in further research.
Antibody titer
Aluminium hydroxide
Antibody response
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Vaccine adjuvant
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