| 1. |
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| 2. |
- Berenjian, Saideh, et al.
(författare)
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The nanoparticulate Quillaja saponin KGI exerts anti-proliferative eff ects by down-regulation of cell cycle molecules in U937 and HL-60 human leukemia cells
- 2014
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Ingår i: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 55:7, s. 1618-1624
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Tidskriftsartikel (refereegranskat)abstract
- Cancer cells are characterized by uncontrolled replication involving loss of control of cyclin dependent kinases (CDKs) and cyclins, and by abolished differentiation. In this study we introduce KGI, which is a nanoparticle with a Quillaja saponin as an active molecule. By the use of RNA array analysis and confirmation at the protein level, we show that KGI affects myeloid leukemia cells (in particular, the U937 monoblast cancer cell) by the following mechanisms: (A) ceasing cell replication via proteasome degradation, (B) down-regulation of key molecules at check points between G1/S and G2/M phases, (C) reduction of thymidine kinase activity, followed by (D) exit to differentiation and production of interleukin-8 (IL-8), eventually leading to apoptosis. Leukemia cell lines (U937 and HL-60 cells) were exposed to KGI for 8 h, after which the drug was removed. The cancer cells did not revert to replication over the following 10 days. Thus our findings suggest that the nanoparticle KGI inhibits proliferation and promotes differentiation in leukemic cells by interfering with the cell cycle process.
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| 3. |
- Camussone, C. M., et al.
(författare)
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Immune response and functional role of antibodies raised in heifers against a Staphylococcus aureus CP5 lysate and recombinant antigens vaccine formulated with Iscom Matrix adjuvant
- 2014
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Ingår i: Veterinary Immunology and Immunopathology. - : Elsevier BV. - 0165-2427 .- 1873-2534. ; 162:3-4, s. 96-107
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Tidskriftsartikel (refereegranskat)abstract
- Staphylococcus aureus is the most frequently isolated pathogen from bovine intramammary infections worldwide. Commercially available vaccines for mastitis control are composed either of S. aureus lysates or inactivated whole-cells formulated with traditional adjuvants. We recently showed the ability of a S. aureus CP5 lysate vaccine adjuvanted with Iscom Matrix to generate a longer lasting specific antibody response in blood and milk with improved opsonic capacity compared with a S. aureus CP5 whole-cell formulation. The aim of the present study was to obtain an experimental immunogen composed of lysed cells of a CP5 S. aureus strain supplemented with recombinant clumping factor A fibronectin binding protein A and beta-toxin formulated with Iscom Matrix characterize the immune response generated when immunizing pregnant heifers and assess the functional role of antibodies raised against this immunogen in experimental models. Both a lysate vaccine and a lysate + recombinant antigens vaccine elicited antibodies that promoted neutrophil phagocytosis and inhibited internalization into mammary epithelial cells in vitro. Incorporation of defined antigenic molecules to the lysate formulation elicited a strong specific humoral immune response against both lysate and recombinant antigens and was associated with higher expression of regulatory and pro-inflammatory cytokines. In addition antibodies were efficient for blocking S. aureus binding to bovine fibrinogen and fibronectin and neutralizing beta-toxin effect in vitro placing these antigens as candidates to be included in a formulation directed to prevent staphylococcal bovine mastitis. (C) 2014 Elsevier B.V. All rights reserved.
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| 4. |
- Camussone, Cecilia M., et al.
(författare)
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Immune response of heifers against a Staphylococcus aureus CP5 whole cell and lysate vaccine formulated with ISCOM Matrix adjuvant
- 2014
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Ingår i: Research in Veterinary Science. - : Elsevier BV. - 0034-5288 .- 1532-2661. ; 96:1, s. 86-94
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Tidskriftsartikel (refereegranskat)abstract
- Staphylococcus aureus is the most frequently isolated pathogen from bovine intramammary infections worldwide. Commercially available vaccines for mastitis control are composed either of S. aureus lysates or whole-cells formulated with traditional adjuvants. We recently showed the ability of a S. aureus CP5 whole-cell vaccine adjuvanted with ISCOM Matrix to increase specific antibodies production in blood and milk, improving opsonic capacity, compared with the same vaccine formulated with Al(OH)(3). However, there is no information about the use of ISCOM Matrix for the formulation of bacterial lysates. The aim of this study was to characterize the innate and humoral immune responses induced by a S. aureus CP5 whole-cell or lysate vaccine, formulated with ISCOM Matrix after immunization of pregnant heifers. Both immunogens stimulated strong humoral immune responses in blood and milk, raising antibodies that increased opsonic capacity. Lysate formulation generated a higher and longer lasting antibody titer and stimulated a higher expression of regulatory and pro-inflammatory cytokines compared with the whole-cell vaccine. (C) 2013 Elsevier Ltd. All rights reserved.
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| 5. |
- Camussone, C. M., et al.
(författare)
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Immune response of heifers against a Staphylococcus aureus CP5 whole cell vaccine formulated with ISCOMATRIX™ adjuvant
- 2013
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Ingår i: Journal of dairy research (Print). - 0022-0299 .- 1469-7629. ; 80:1, s. 72-80
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Tidskriftsartikel (refereegranskat)abstract
- The shortcomings of Staphylococcus aureus vaccines to control bovine mastitis have been attributed to insufficient capacity of the vaccines to induce opsonizing antibodies and to stimulate cellular immune responses. Types of antigen, administration route and adjuvant used in a vaccine formulation have been identified as critical factors for the development of opsonic antibodies. Current commercially available vaccines for Staph. aureus bovine mastitis control are formulated with Al(OH)3 and oil-based adjuvants. The aim of this study was to evaluate the immune response of heifers immunized with a Staph. aureus CP5 whole cell vaccine formulated either with Al(OH)3 or ISCOMATRIX ™. Twenty primigravid Holstein dairy heifers in the last trimester of gestation were immunized either with a vaccine formulated with ISCOMATRIX™ (n = 6), Al(OH)3 (n = 7), or saline solution (placebo) (n = 7). Immunization was carried out 38 and 10 d before calving. Heifers vaccinated with Staph. aureus adjuvanted with ISCOMATRIX™ responded with significantly higher levels of anti-bacterin and anti-CP5 IgG and IgG2 in sera than animals in the Al(OH)3 or control groups. Animals in the ISCOMATRIX™ group responded with significantly higher anti-bacterin specific IgG in whey than animals in the Al(OH)3 and control groups, detected from the first week post calving until 60 d of lactation. Sera from animals inoculated with Staph. aureus in ISCOMATRIX™, obtained 7 d post partum, significantly increased both the number of neutrophils ingesting bacteria and the number of bacteria being ingested by the neutrophils, compared with sera obtained from heifers vaccinated with Al(OH)3 or non-vaccinated controls. These features coupled to safety of the ISCOMATRIX™ formulation, warrant additional studies.
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| 6. |
- de Sandt, Carolien E. van, et al.
(författare)
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Novel G3/DT adjuvant promotes the induction of protective T cells responses after vaccination with a seasonal trivalent inactivated split-virion influenza vaccine
- 2014
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 32:43, s. 5614-5623
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Tidskriftsartikel (refereegranskat)abstract
- Vaccines used against seasonal influenza are poorly effective against influenza A viruses of novel subtypes that may have pandemic potential. Furthermore, pre(pandemic) influenza vaccines are poorly immunogenic, which can be overcome by the use of adjuvants. A limited number of adjuvants has been approved for use in humans, however there is a need for alternative safe and effective adjuvants that can enhance the immunogenicity of influenza vaccines and that promote the induction of broad-protective T cell responses. Here we evaluated a novel nanoparticle, G3, as an adjuvant for a seasonal trivalent inactivated influenza vaccine in a mouse model. The G3 adjuvant was formulated with or without steviol glycosides (DT, for diterpenoid). The use of both formulations enhanced the virus-specific antibody response to all three vaccine strains considerably. The adjuvants were well tolerated without any signs of discomfort. To assess the protective potential of the vaccine-induced immune responses, an antigenically distinct influenza virus strain, A/Puerto Rico/8/34 (A/PR/8/34), was used for challenge infection. The vaccine-induced antibodies did not cross-react with strain A/PR/8/34 in HI and VN assays. However, mice immunized with the G3/DT-adjuvanted vaccine were partially protected against A/PR/8/34 infection, which correlated with the induction of anamnestic virus-specific CD8(+) T cell responses that were not observed with the use of G3 without DT. Both formulations induced maturation of human dendritic cells and promoted antigen presentation to a similar extent. In conclusion, G3/DT is a promising adjuvant formulation that not only potentiates the antibody response induced by influenza vaccines, but also induces T cell immunity which could afford broader protection against antigenically distinct influenza viruses.
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| 7. |
- Hassan, Saadia Bashir, et al.
(författare)
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The Nanoparticulate Quillaja Saponin BBE Is Selectively Active Towards Renal Cell Carcinoma
- 2013
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 33:1, s. 143-151
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To characterize the cytotoxic effect of BBE, the particulate of desacyl-saponin, in model systems of solid tumours. Materials and Methods: Cytotoxic activity of BBE was investigated in solid human tumour cell lines, in tumour cells from patients with renal cell carcinoma, in normal human renal cells and in peripheral blood mononuclear cells. The BBE mode of cell death was assessed in vitro. In vivo effect of BBE was evaluated in xenograft-bearing mice. Results: BBE was selectively active against renal cell carcinoma, with no or little effect on normal cells. BBE induced caspase activity and apoptosis. An inhibitory activity of BBE on xenograft tumour growth, with no apparent signs of haematological toxicity was shown. In the non-proliferative model of patient tumour cells, BBE was active on only 1/5 patient samples, suggesting association of BBE effect with cell proliferation. Conclusion: BBE has interesting activities against renal cell carcinoma and should be further explored as a drug against this resistant tumour type.
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| 8. |
- Hecker, Yanina P., et al.
(författare)
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A Neospora caninum vaccine using recombinant proteins fails to prevent foetal infection in pregnant cattle after experimental intravenous challenge
- 2014
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Ingår i: Veterinary Immunology and Immunopathology. - : Elsevier BV. - 0165-2427 .- 1873-2534. ; 162:3-4, s. 142-153
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to evaluate the immunogenicity and protective efficacy of rNcSAG1, rNcHSP20 and rNcGRA7 recombinant proteins formulated with immune stimulating complexes (ISCOMs) in pregnant heifers against vertical transmission of Neospora caninum. Twelve pregnant heifers were divided into 3 groups of 4 heifers each, receiving different formulations before mating. Immunogens were administered twice subcutaneously: group A animals were inoculated with three recombinant proteins (rNcSAG1, rNcHSP20, rNcGRA7) formulated with ISCOMs; group B animals received ISCOM-MATRIX (without antigen) and group C received sterile phosphate-buffered saline (PBS) only. The recombinant proteins were expressed in Escherichia coil and purified nickel resin. All groups were intravenously challenged with the NC-1 strain of N. caninum at Day 70 of gestation and dams slaughtered at week 17 of the experiment. Heifers from group A developed specific antibodies against rNcSAG1, rNcHSP20 and rNcGRA7 prior to the challenge. Following immunization, an statistically significant increase of antibodies against rNcSAG1 and rNcHSP20 in all animals of group A was detected compared to animals in groups B and C at weeks 5, 13 and 16 (P< 0.001). Levels of antibodies against rNcGRA7 were statistical higher in group A animals when compared with groups B and Cat weeks 5 and 16 (P> 0.001). There were no differences in IFN-gamma production among the experimental groups at any time point (P> 0.05). Transplacental transmission was determined in all foetuses of groups A, B and C by Western blot, immunohistochemistry and nested PCR. This work showed that rNcSAG1, rNcHSP20 and rNcGRA7 proteins while immunogenic in cattle failed to prevent the foetal infection in pregnant cattle challenged at Day 70 of gestation.
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| 9. |
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| 10. |
- Hellman, Stina, et al.
(författare)
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Cytokine responses to various larval stages of equine strongyles and modulatory effects of the adjuvant G3 in vitro
- 2020
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Ingår i: Parasite Immunology. - : Wiley. - 0141-9838 .- 1365-3024. ; 43
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Tidskriftsartikel (refereegranskat)abstract
- Aims To generate different larval stages ofStrongylus vulgarisand to study cytokine responses in cultures of eqPBMC exposed to defined larval stages ofS. vulgarisand cyathostomins with the aim to understand the early immune reaction to these parasites. Methods and results EqPBMC were exposed toS. vulgarislarvae (L3, exsheated L3 and L4) and cyathostomin L3 and analysed for cytokine gene expression. Procedures for decontamination, culturing and attenuation of larvae were established. Transcription of IL-4, IL-5 and IL-13 was induced by bothS. vulgarisand cyathostomin L3. Moulting ofS. vulgarisfrom L3 to L4 stage was accompanied by a shift to high expression of IL-5 and IL-9 (exsheated L3 and L4) and IFN-gamma (L4 only). In parallel, the adjuvant G3 modified the cytokine profile induced by both parasites by reducing the expression of IL-4, IL-5 and IL-10 while concomitantly enhancing the expression of IFN-gamma. Conclusion The L4 stage ofS. vulgarisgenerated a cytokine profile different from that induced by the earlier L3 stage ofS. vulgarisand cyathostomins. This diversity depending on the life cycle stage will have implications for the choice of antigen and adjuvant in future vaccine design.
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| 11. |
- Hellman, Stina, et al.
(författare)
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The adjuvant G3 promotes a Th1 polarizing innate immune response in equine PBMC
- 2018
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Ingår i: Veterinary Research. - : Springer Science and Business Media LLC. - 0928-4249 .- 1297-9716. ; 49
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Tidskriftsartikel (refereegranskat)abstract
- The immunomodulatory effect of a new particulate adjuvant, G3, alone or in combination with agonists to TLR2/1 or TLR5 was evaluated in cultures of equine PBMC. Exposure to the G3 adjuvant up-regulated genes encoding IFN-, IL-1, IL-6, IL-8, IL-12p40 and IL-23p19 in the majority of the horses tested, indicating that the G3 adjuvant induced a pro-inflammatory and Th1 dominated profile. In accordance, genes encoding IL-13, IL-4, IL-10 and TGF- remained unaffected and genes encoding IFN-, IL-17A and TNF- were only occasionally and weakly induced. The two TLR agonists Pam3CSK4 (TLR2/1) and FliC (TLR5) induced cytokine profiles characterized by a clear induction of IL-10 as well as up-regulation of the genes encoding IL-1, IL-6 and IL-8. The presence of G3 modified this response, in particular by reducing the FliC and Pam3CSK4 induced production of IL-10. Furthermore, G3 acted in synergy with Pam3CSK4 in enhancing the production of IFN- whereas G3 combined with FliC increased the gene expression of IL-8. Thus, the G3 adjuvant seems to have the capacity to promote a Th1 polarizing innate immune response in eqPBMC, both by favouring IFN- production and by reducing production of IL-10 induced by co-delivered molecules. These features make G3 an interesting candidate to further evaluate for its potential as an adjuvant in equine vaccines.
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| 12. |
- Hjertner, Bernt, et al.
(författare)
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A novel adjuvant G3 induces both Th1 and Th2 related immune responses in mice after immunization with a trivalent inactivated split-virion influenza vaccine
- 2018
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1358-8745. ; 36, s. 3340-3344
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Tidskriftsartikel (refereegranskat)abstract
- A preferred adjuvant should promote both Th1 and Th2 responses. However, most adjuvants in common use are biased towards a Th2-driven response. Therefore, the ability of a novel saponin-based adjuvant G3 to inducing balanced Thl and Th2 responses in BALB/c mice immunized with a split trivalent seasonal influenza vaccine was evaluated in comparison to that of the adjuvant Al(OH) 3 . Clear differences in the IgG profiles induced by G3, Al(OH)(3) or non-adjuvanted vaccine were recorded. Both adjuvants enhanced high and similar levels of the Th2 associated IgG1 subtype compared to mice given vaccine alone. Only G3 enhanced the IgG2a subclass reflecting a Th1 response, whereas Al(OH)(3) even abrogated the IgG2a production. Accordingly, G3 enhanced the production of IL-2 and IFN-gamma and also of IL-2/IFN-gamma double secreting cells, emphasizing the strong Th1 driving effect of G3. Only Al(OH)(3) increased splenocyte production of IL-17. Taken together, the results indicate a strong propensity for G3 to induce both Th1 and Th2 driven immune responses. (C) 2018 The Authors. Published by Elsevier Ltd.
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| 13. |
- Hu, Kefei, et al.
(författare)
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Nanoparticulate Quillaja saponin induces apoptosis in human leukemia cell lines with a high therapeutic index
- 2010
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Ingår i: International Journal of Nanomedicine. - 1176-9114 .- 1178-2013. ; 5:1, s. 51-62
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Tidskriftsartikel (refereegranskat)abstract
- Saponin fractions of Quillaja saponaria Molina (QS) have cytotoxic activity against cancer cells in vitro, but are too toxic to be useful in the clinic. The toxic effect was abolished by converting QS fractions into stable nanoparticles through the binding of QS to cholesterol. Two fractions of QS were selected for particle formation, one with an acyl-chain (ASAP) was used to form killing and growth-inhibiting (KGI) particles, and the other without the acyl-chain (DSAP) was used to formulate blocking and balancing effect (BBE) particles. KGI showed significant growth inhibiting and cancer cell-killing activities in nine of 10 cell lines while BBE showed that on one cell line. The monoblastoid lymphoma cell line U937 was selected for analyzing the mode of action. Low concentrations of KGI (0.5 and 2 microg/mL) induced irreversible exit from the cell cycle, differentiation measured by cytokine production, and eventually programmed cell death (apoptosis). Compared to normal human monocytes, the U937 cells were 30-fold more sensitive to KGI. The nontoxic BBE blocked the cell killing effect of KGI in a concentration-dependent manner. In conclusion, the formulation of QS into nanoparticles has the potential of becoming a new class of anticancer agents.
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| 14. |
- Morein, Bror, et al.
(författare)
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Immune responsiveness in the neonatal period
- 2007
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Ingår i: Journal of Comparative Pathology. - : Elsevier BV. - 0021-9975 .- 1532-3129. ; 137, s. S27-S31
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Tidskriftsartikel (refereegranskat)abstract
- The maintenance of pregnancy requires suppression of the maternal immune system which would naturally recognize the developing fetus as an allograft and seek to destroy it by mounting a Th1 regulated Cytotoxic immune response. During pregnancy a range of soluble factors are produced by the placenta which switch maternal immune regulation towards a protective Th2 phenotype. These factors also influence the developing fetal immune system and all newborns initially have an immunological milieu skewed towards Th2 immunity. Vaccination during the neonatal period must therefore overcome the dual challenge of the inhibitory effect of maternally derived antibody and this natural Th2 regulatory environment. One means of overcoming these obstacles is by the use of adjuvant systems that can redirect the neonatal immune response towards an appropriate Th1 regulated reaction that affords protection from infectious disease. In this overview, experiments are described in which viral antigens incorporated into immune stimulatory complexes (ISCOMs) are able to induce immune responses with balanced Th1 and Th2 regulation in neonatal mice, as evidenced by the nature of the IgG subclass response and cytokine profile, and the induction of cytotoxic lymphocytes. ISCOM adjuvanted vaccines are able to induce similar protective immunity in the newborn of larger animal species including cattle, horses and dogs.
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