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Sample records for adjuvant cfa induced

  1. Models of Inflammation: Carrageenan- or Complete Freund's Adjuvant (CFA)-Induced Edema and Hypersensitivity in the Rat.

    PubMed

    McCarson, Kenneth E

    2015-01-01

    Animal models of inflammation are used to assess the production of inflammatory mediators at sites of inflammation, the processing of pain sensation at CNS sites, the anti-inflammatory properties of agents such as nonsteroidal anti-inflammatory drugs (NSAIDs), and the efficacy of putative analgesic compounds in reversing cutaneous hypersensitivity. Detailed in this unit are methods to elicit and measure carrageenan- and complete Freund's adjuvant (CFA)-induced cutaneous inflammation. Due to possible differences between the dorsal root sensory system and the trigeminal sensory system, injections into either the footpad or vibrissal pad are described. In this manner, cutaneous inflammation can be assessed in tissue innervated by the lumbar dorsal root ganglion neurons (footpad) or by the trigeminal ganglion neurons (vibrissal pad). PMID:26331888

  2. A time-dependent degeneration manner of condyle in rat CFA-induced inflamed TMJ.

    PubMed

    Xu, Liqin; Guo, Huilin; Li, Cheng; Xu, Jie; Fang, Wei; Long, Xing

    2016-01-01

    Temporomandibular joint (TMJ) inflammation is a potential risk factor of osteoarthritis (OA) but the detailed degenerative changes in the inflamed TMJ remain unclear. In this study, we evaluated the changes of condylar cartilage and subchondral bone in rat inflamed TMJ induced by Freund's complete adjuvant (CFA). Articular cavity was injected with CFA and the TMJ samples were collected 1, 2, 3, and 4-week post-injection. Hematoxylin & Eosin (H&E) staining, toluidine blue (TB) staining, Safranin O (S.O) staining, Masson trichrome staining and micro-CT were used to assess TMJ degeneration during inflammation. Osteoclast and osteoblast activities were analyzed by tartrate-resistant acid phosphatase (TRAP) staining and osteocalcin (OCN) immunohistochemistry staining respectively. The expression of receptor activator of NF-kB ligand (RANKL) and osteoprotegerin (OPG) in condylar cartilage and subchondral bone was also evaluated through immunohistochemistry and RANKL/OPG ratio was evaluated. Reduced cartilage thickness, decreased number of chondrocytes, and down-regulated proteoglycan expression were observed in the condylar cartilage in the inflamed TMJ. Enhanced osteoclast activity, and expanded bone marrow cavity were reached the peak in the 2-week after CFA-injection. Meanwhile the RANKL/OPG ratio in the cartilage and subchondral bone also increased in the 2-week CFA-injection. Immature, unmineralized new bones with irregular trabecular bone structure, atypical condylar shape, up-regulated OCN expression, and decreased bone mineral density (BMD) were found in the inflamed TMJ. The time-dependent degeneration manner of TMJ cartilage and subchondral bone was found in CFA-induced arthritis rat model. The degeneration in the TMJ with inflammation might be a risk factor and should be concerned. PMID:27158347

  3. Multiepitope fusion antigen induces broadly protective antibodies that prevent adherence of Escherichia coli strains expressing colonization factor antigen I (CFA/I), CFA/II, and CFA/IV.

    PubMed

    Ruan, Xiaosai; Knudsen, David E; Wollenberg, Katie M; Sack, David A; Zhang, Weiping

    2014-02-01

    Diarrhea is the second leading cause of death in children younger than 5 years and continues to be a major threat to global health. Enterotoxigenic Escherichia coli (ETEC) strains are the most common bacteria causing diarrhea in developing countries. ETEC strains are able to attach to host small intestinal epithelial cells by using bacterial colonization factor antigen (CFA) adhesins. This attachment helps to initiate the diarrheal disease. Vaccines that induce antiadhesin immunity to block adherence of ETEC strains that express immunologically heterogeneous CFA adhesins are expected to protect against ETEC diarrhea. In this study, we created a CFA multiepitope fusion antigen (MEFA) carrying representative epitopes of CFA/I, CFA/II (CS1, CS2, and CS3), and CFA/IV (CS4, CS5, and CS6), examined its immunogenicity in mice, and assessed the potential of this MEFA as an antiadhesin vaccine against ETEC. Mice intraperitoneally immunized with this CFA MEFA exhibited no adverse effects and developed immune responses to CFA/I, CFA/II, and CFA/IV adhesins. Moreover, after incubation with serum of the immunized mice, ETEC or E. coli strains expressing CFA/I, CFA/II, or CFA/IV adhesins were significantly inhibited in adherence to Caco-2 cells. Our results indicated this CFA MEFA elicited antibodies that not only cross-reacted to CFA/I, CFA/II and CFA/IV adhesins but also broadly inhibited adherence of E. coli strains expressing these seven adhesins and suggested that this CFA MEFA could be a candidate to induce broad-spectrum antiadhesin protection against ETEC diarrhea. Additionally, this antigen construction approach (creating an MEFA) may be generally used in vaccine development against heterogenic pathogens. PMID:24351757

  4. Shp-1 dephosphorylates TRPV1 in dorsal root ganglion neurons and alleviates CFA-induced inflammatory pain in rats.

    PubMed

    Xiao, Xing; Zhao, Xiao-Tao; Xu, Ling-Chi; Yue, Lu-Peng; Liu, Feng-Yu; Cai, Jie; Liao, Fei-Fei; Kong, Jin-Ge; Xing, Guo-Gang; Yi, Ming; Wan, You

    2015-04-01

    Transient receptor potential vanilloid 1 (TRPV1) receptors are expressed in nociceptive neurons of rat dorsal root ganglions (DRGs) and mediate inflammatory pain. Nonspecific inhibition of protein-tyrosine phosphatases (PTPs) increases the tyrosine phosphorylation of TRPV1 and sensitizes TRPV1. However, less is known about tyrosine phosphorylation's implication in inflammatory pain, compared with that of serine/threonine phosphorylation. Src homology 2 domain-containing tyrosine phosphatase 1 (Shp-1) is a key phosphatase dephosphorylating TRPV1. In this study, we reported that Shp-1 colocalized with and bound to TRPV1 in nociceptive DRG neurons. Shp-1 inhibitors, including sodium stibogluconate and PTP inhibitor III, sensitized TRPV1 in cultured DRG neurons. In naive rats, intrathecal injection of Shp-1 inhibitors increased both TRPV1 and tyrosine-phosphorylated TRPV1 in DRGs and induced thermal hyperalgesia, which was abolished by pretreatment with TRPV1 antagonists capsazepine, BCTC, or AMG9810. Complete Freund's adjuvant (CFA)-induced inflammatory pain in rats significantly increased the expression of Shp-1, TRPV1, and tyrosine-phosphorylated TRPV1, as well as the colocalization of Shp-1 and TRPV1 in DRGs. Intrathecal injection of sodium stibogluconate aggravated CFA-induced inflammatory pain, whereas Shp-1 overexpression in DRG neurons alleviated it. These results suggested that Shp-1 dephosphorylated and inhibited TRPV1 in DRG neurons, contributing to maintain thermal nociceptive thresholds in normal rats, and as a compensatory mechanism, Shp-1 increased in DRGs of rats with CFA-induced inflammatory pain, which was involved in protecting against excessive thermal hyperalgesia. PMID:25790452

  5. Probing the Effects and Mechanisms of Electroacupuncture at Ipsilateral or Contralateral ST36-ST37 Acupoints on CFA-induced Inflammatory Pain.

    PubMed

    Lu, Kung-Wen; Hsu, Chao-Kuei; Hsieh, Ching-Liang; Yang, Jun; Lin, Yi-Wen

    2016-01-01

    Transient receptor potential vanilloid 1 (TRPV1) and associated signaling pathways have been reported to be increased in inflammatory pain signaling. There are accumulating evidences surrounding the therapeutic effect of electroacupuncture (EA). EA can reliably attenuate the increase of TRPV1 in mouse inflammatory pain models with unclear signaling mechanisms. Moreover, the difference in the clinical therapeutic effects between using the contralateral and ipsilateral acupoints has been rarely studied. We found that inflammatory pain, which was induced by injecting the complete Freund's adjuvant (CFA), (2.14 ± 0.1, p < 0.05, n = 8) can be alleviated after EA treatment at either ipsilateral (3.91 ± 0.21, p < 0.05, n = 8) or contralateral acupoints (3.79 ± 0.25, p < 0.05, n = 8). EA may also reduce nociceptive Nav sodium currents in dorsal root ganglion (DRG) neurons. The expression of TRPV1 and associated signaling pathways notably increased after the CFA injection; this expression can be further attenuated significantly in EA treatment. TRPV1 and associated signaling pathways can be prevented in TRPV1 knockout mice, suggesting that TRPV1 knockout mice are resistant to inflammatory pain. Through this study, we have increased the understanding of the mechanism that both ipsilateral and contralateral EA might alter TRPV1 and associated signaling pathways to reduce inflammatory pain. PMID:26906464

  6. Probing the Effects and Mechanisms of Electroacupuncture at Ipsilateral or Contralateral ST36–ST37 Acupoints on CFA-induced Inflammatory Pain

    PubMed Central

    Lu, Kung-Wen; Hsu, Chao-Kuei; Hsieh, Ching-Liang; Yang, Jun; Lin, Yi-Wen

    2016-01-01

    Transient receptor potential vanilloid 1 (TRPV1) and associated signaling pathways have been reported to be increased in inflammatory pain signaling. There are accumulating evidences surrounding the therapeutic effect of electroacupuncture (EA). EA can reliably attenuate the increase of TRPV1 in mouse inflammatory pain models with unclear signaling mechanisms. Moreover, the difference in the clinical therapeutic effects between using the contralateral and ipsilateral acupoints has been rarely studied. We found that inflammatory pain, which was induced by injecting the complete Freund’s adjuvant (CFA), (2.14 ± 0.1, p < 0.05, n = 8) can be alleviated after EA treatment at either ipsilateral (3.91 ± 0.21, p < 0.05, n = 8) or contralateral acupoints (3.79 ± 0.25, p < 0.05, n = 8). EA may also reduce nociceptive Nav sodium currents in dorsal root ganglion (DRG) neurons. The expression of TRPV1 and associated signaling pathways notably increased after the CFA injection; this expression can be further attenuated significantly in EA treatment. TRPV1 and associated signaling pathways can be prevented in TRPV1 knockout mice, suggesting that TRPV1 knockout mice are resistant to inflammatory pain. Through this study, we have increased the understanding of the mechanism that both ipsilateral and contralateral EA might alter TRPV1 and associated signaling pathways to reduce inflammatory pain. PMID:26906464

  7. Pulmonary gallium uptake in rats with granulomatosis induced by complete Freund adjuvant

    SciTech Connect

    Stanislas-Leguern, G.; Masse, R.; Jaubert, F.; Chretien, J.; Huchon, G.

    1988-01-01

    To investigate the mechanism of gallium-67 uptake in lung granulomatosis, we studied 13 rats in which lung granulomatosis was induced by injection of complete Freund adjuvant (CFA) and 14 controls. Gallium uptake was assessed in bronchoalveolar lavage fluid and lavaged lung. The cells responsible for gallium uptake were identified by latent image activation autoradiography. Gallium activity in both lavaged lungs and bronchoalveolar cells (BAC) was higher in CFA-treated animals than in controls (172,205 +/- 134,783 DPM versus 44,456 +/- 14,486 DPM +/- SD (p less than 0.05) and 40,083 +/- 16,350 DPM versus 9100 +/- 4114 DPM (p less than 0.05), respectively). In control rats, about two-thirds of total lung gallium was located in the interstitium, whereas in CFA-treated rats it was found in the mononuclear cells of lung granulomas. Gallium tracks were more numerous in the alveolar macrophages (AM) of CFA-treated rats than in control AM (28.4 +/- 10.0/field versus 8.4 +/- 3.8/field, p less than 0.001) but the number of tracks was proportional to the number of AM (52.4 +/- 18.7 versus 12.2 +/- 4.3, respectively; p less than 0.001). It is concluded that in rats with CFA-induced lung granulomatosis 1) pulmonary gallium uptake increases, 2) mononuclear cells are responsible for this uptake in both granulomas and AM, and 3) the increased uptake is due to the increased number of mononuclear cells.

  8. Systemic immunotoxicity reactions induced by adjuvanted vaccines.

    PubMed

    Batista-Duharte, Alexander; Portuondo, Deivys; Pérez, O; Carlos, Iracilda Zeppone

    2014-05-01

    Vaccine safety is a topic of concern for the treated individual, the family, the health care personnel, and the others involved in vaccination programs as recipients or providers. Adjuvants are necessary components to warrant the efficacy of vaccines, however the overstimulation of the immune system is also associated with adverse effects. Local reactions are the most frequent manifestation of toxicity induced by adjuvanted vaccines and, with the exception of the acute phase response (APR), much less is known about the systemic reactions that follow vaccination. Their low frequency or subclinical expression meant that this matter has been neglected. In this review, various systemic reactions associated with immune stimulation will be addressed, including: APR, hypersensitivity, induction or worsening of autoimmune diseases, modification of hepatic metabolism and vascular leak syndrome (VLS), with an emphasis on the mechanism involved. Finally, the authors analyze the current focus of discussion about vaccine safety and opportunities to improve the design of new adjuvanted vaccines in the future. PMID:24607449

  9. Adjuvant-induced Human Monocyte Secretome Profiles Reveal Adjuvant- and Age-specific Protein Signatures.

    PubMed

    Oh, Djin-Ye; Dowling, David J; Ahmed, Saima; Choi, Hyungwon; Brightman, Spencer; Bergelson, Ilana; Berger, Sebastian T; Sauld, John F; Pettengill, Matthew; Kho, Alvin T; Pollack, Henry J; Steen, Hanno; Levy, Ofer

    2016-06-01

    Adjuvants boost vaccine responses, enhancing protective immunity against infections that are most common among the very young. Many adjuvants activate innate immunity, some via Toll-Like Receptors (TLRs), whose activities varies with age. Accordingly, characterization of age-specific adjuvant-induced immune responses may inform rational adjuvant design targeting vulnerable populations. In this study, we employed proteomics to characterize the adjuvant-induced changes of secretomes from human newborn and adult monocytes in response to Alum, the most commonly used adjuvant in licensed vaccines; Monophosphoryl Lipid A (MPLA), a TLR4-activating adjuvant component of a licensed Human Papilloma Virus vaccine; and R848 an imidazoquinoline TLR7/8 agonist that is a candidate adjuvant for early life vaccines. Monocytes were incubated in vitro for 24 h with vehicle, Alum, MPLA, or R848 and supernatants collected for proteomic analysis employing liquid chromatography-mass spectrometry (LC-MS) (data available via ProteomeXchange, ID PXD003534). 1894 non-redundant proteins were identified, of which ∼30 - 40% were common to all treatment conditions and ∼5% were treatment-specific. Adjuvant-stimulated secretome profiles, as identified by cluster analyses of over-represented proteins, varied with age and adjuvant type. Adjuvants, especially Alum, activated multiple innate immune pathways as assessed by functional enrichment analyses. Release of lactoferrin, pentraxin 3, and matrix metalloproteinase-9 was confirmed in newborn and adult whole blood and blood monocytes stimulated with adjuvants alone or adjuvanted licensed vaccines with distinct clinical reactogenicity profiles. MPLA-induced adult monocyte secretome profiles correlated in silico with transcriptome profiles induced in adults immunized with the MPLA-adjuvanted RTS,S malaria vaccine (Mosquirix™). Overall, adjuvants such as Alum, MPLA and R848 give rise to distinct and age-specific monocyte secretome profiles

  10. Development and preclinical evaluation of safety and immunogenicity of an oral ETEC vaccine containing inactivated E. coli bacteria overexpressing colonization factors CFA/I, CS3, CS5 and CS6 combined with a hybrid LT/CT B subunit antigen, administered alone and together with dmLT adjuvant.

    PubMed

    Holmgren, J; Bourgeois, L; Carlin, N; Clements, J; Gustafsson, B; Lundgren, A; Nygren, E; Tobias, J; Walker, R; Svennerholm, A-M

    2013-05-01

    A first-generation oral inactivated whole-cell enterotoxigenic Escherichia coli (ETEC) vaccine, comprising formalin-killed ETEC bacteria expressing different colonization factor (CF) antigens combined with cholera toxin B subunit (CTB), when tested in phase III studies did not significantly reduce overall (generally mild) ETEC diarrhea in travelers or children although it reduced more severe ETEC diarrhea in travelers by almost 80%. We have now developed a novel more immunogenic ETEC vaccine based on recombinant non-toxigenic E. coli strains engineered to express increased amounts of CF antigens, including CS6 as well as an ETEC-based B subunit protein (LCTBA), and the optional combination with a nontoxic double-mutant heat-labile toxin (LT) molecule (dmLT) as an adjuvant. Two test vaccines were prepared under GMP: (1) A prototype E. coli CFA/I-only formalin-killed whole-cell+LCTBA vaccine, and (2) A "complete" inactivated multivalent ETEC-CF (CFA/I, CS3, CS5 and CS6 antigens) whole-cell+LCTBA vaccine. These vaccines, when given intragastrically alone or together with dmLT in mice, were well tolerated and induced strong intestinal-mucosal IgA antibody responses as well as serum IgG and IgA responses to each of the vaccine CF antigens as well as to LT B subunit (LTB). Both mucosal and serum responses were further enhanced (adjuvanted) when the vaccines were co-administered with dmLT. We conclude that the new multivalent oral ETEC vaccine, both alone and especially in combination with the dmLT adjuvant, shows great promise for further testing in humans. PMID:23541621

  11. Evaluation of Anti-Inflammatory Potential of the New Ganghwaljetongyeum on Adjuvant-Induced Inflammatory Arthritis in Rats

    PubMed Central

    Kim, Wangin; Park, Sangbin; Kim, Youg Ran; Shin, Wook; Lee, Yumi; Choi, Donghee; Kim, Mirae; Lee, Hyunju; Kim, Seonjong; Na, Changsu

    2016-01-01

    Ganghwaljetongyeum (GHJTY) has been used as a standard treatment for arthritis for approximately 15 years at the Korean Medicine Hospital of Dongshin University. GHJTY is composed of 18 medicinal herbs, of which five primary herbs were selected and named new Ganghwaljetongyeum (N-GHJTY). The purpose of the present study was to observe the effect of N-GHJTY on arthritis and to determine its mechanism of action. After confirming arthritis induction using complete Freund's adjuvant (CFA) in rats, N-GHJTY (62.5, 125, and 250 mg/kg/day) was administered once a day for 10 days. In order to determine pathological changes, edema of the paws and weight were measured before and for 10 days after N-GHJTY administration. Cytokine (TNF-α, IL-1β, and IL-6) levels and histopathological lesions in the knee joint were also examined. Edema in the paw and knee joint of N-GHJTY-treated rats was significantly decreased at 6, 8, and 10 days after administration, compared to that in the CFA-control group, while weight consistently increased. Rats in N-GHJTY-treated groups also recovered from the CFA-induced pathological changes and showed a significant decline in cytokine levels. Taken together, our results showed that N-GHJTY administration was effective in inhibiting CFA-induced arthritis via anti-inflammatory effects while promoting cartilage recovery by controlling cytokine levels. PMID:27382402

  12. Paederia foetida Linn. inhibits adjuvant induced arthritis by suppression of PGE(2) and COX-2 expression via nuclear factor-κB.

    PubMed

    Kumar, Vikas; Al-Abbasi, F A; Ahmed, Danish; Verma, Amita; Mujeeb, Mohd; Anwar, Firoz

    2015-05-01

    The current investigation was undertaken to determine the anti-inflammatory and antioxidant effects of Paederia foetida Linn. (PF) along with its mechanism of action when implemented in tissue protection. HPTLC was used in the identification of the compound quercetin, while in vitro analysis confirmed the significance of the antioxidant and anti-inflammatory action of PF. We initially demonstrated the in vivo anti-inflammatory effect of PF, evaluating it against a variety of phlogistic agents as well as turpentine oil, prostaglandin and arachidonic acid. Groups of rats, fasted overnight, were treated as follows: Group I: normal control (vehicle), Group II: PF (100 mg kg(-1)), Group III: arthritic control (CFA only, 0.05 ml), Group IV, V, VI: CFA (0.05 ml) + PF (25, 50 and 100 mg kg(-1)) and Group VII: CFA (0.05 ml) + indomethacin (10 mg per kg b.w.). PF significantly protected against paw edema, arthritic index and body weight alteration induced by Complete Fruend's Adjuvant (CFA). Other observations, like histological and macroscopic changes, were observed in CFA induced inflammation in knee joints. Subcutaneous administration of CFA was accompanied by proinflammatory cytokine status, as appraised by the amplification of interleukin-2 (IL-2), interleukin-1β (IL-1β) and tumor necrosis factor (TNF-α); oxidative stress status was estimated by the enhancement of the level of lipid peroxidation (LPO) and the depletion of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione (GSH). Pre-treatment with PF significantly (P < 0.001) protected against CFA induced oxidative stress and proinflammatory cytokines. More prominently, CFA administration augmented tissue and plasma superoxide (O2) and hydrogen peroxide (H2O2) levels, while the PF pre-treatment significantly (P < 0.001) reversed all CFA induced intracellular interruption. Following CFA induced arthritis, PF was tested for its free radical scavenging activity against the DPPH and ABTS radicals

  13. Bidirectional effects of serum TNF alpha level and spinal p38MAPK phosphorylation on hyperalgesia variation during CFA-induced arthritis

    PubMed Central

    Akhtari, Zeinab; Zaringhalam, Jalal; Eidi, Akram; Manaheji, Homa; Tekieh, Elaheh

    2012-01-01

    Regarding the role of TNFα in the induction of hyperalgesia, the dual suggested roles of the Pp38 MAPK intracellular pathway in the emergence of symptomatic inflammation, we aimed to investigate the bidirectional effects of serum TNFα level and p38 MAPK phosphorylation on hyperalgesia variation during different stages of adjuvant-induced arthritis. Hyperalgesia and edema were assessed at 0, 3, 7, 14, and 21 days of study after arthritis induction by CFA. Anti-TNFα and Pp38 inhibitor were administered during the 21 days of study. Receptor and intra-cellular enzyme expression were detected by western blotting. Anti-TNFα administration in the AA group decreased paw volume and hyperalgesia until the 14th day of study; on the 21st day, those symptoms increased. Daily administration of anti-TNFα antibody caused significant decrease in spinal mOR protein and Pp38/p38 MAPK enzyme level expression on the 14th and 21st days compared to the AA control group. Our data suggested that phosphorylation of spinal p38 MAPK enzyme played an important role in bidirectional effects of serum TNFα on inflammatory symptoms via spinal mOR expression variation.

  14. Anti-arthritic Effects of Total Flavonoids from Juniperus sabina on Complete Freund's Adjuvant Induced Arthritis in Rats

    PubMed Central

    Zhao, Jun; Liu, Tao; Xu, Fang; You, Shuping; Xu, Fang; Li, Chenyang; Gu, Zhengyi

    2016-01-01

    Context: Twigs and leaves of Juniperus sabina L. have been traditionally used as the medicinal herb in China for the treatment of many ailments including rheumatoid arthritis (RA). Aims: To confirm the therapeutic effect of total flavonoids from J. sabina (JSTF) on RA-induced by Complete Freund's Adjuvant (CFA) in rats. Settings and Design: Wistar rats (200 ± 20 g) were immunized by intradermal injection of 0.1 mL of CFA into the right hind metatarsal footpad. JSTF was administered orally at the dose of 125,250 and 500 mg/kg on 14 days after the induction of adjuvant arthritis. Tripterygium glycoside (20 mg/kg) was used as a positive control. Paw swelling, arthritic score, body weight loss, serum cytokines, inflammatory mediators, and histological change were measured. Results: We found that JSTF could ameliorate paw swelling of CFA rats, and significantly inhibit arthritic score (P < 0.05). The overproduction of tumor necrosis factor alpha and interleukin 1beta were remarkably suppressed in the serum of JSTF (125,500 mg/kg) treated rats (P < 0.05). Histopathological studies also showed a marked decrease of synovial inflammatory infiltration and synovial lining hyperplasia in the joints of JSTF-treated animals. Six flavonoids were isolated and from JSTF by various chromatographic methods and identified as follows: Catechin, quercitrin, isoquercitrin, isoscutellarein 7-O-β-D-xylopyranoside, isoscutellarein 7-O-β-D-xylopyranose-(1 → 3)-α-L-rhamnoside, and rutin. Conclusions: These results suggest the potential therapeutically effect of JSTF as an anti-arthritis agent toward CFA-induced arthritis in rats, and verified therapeutic applications of J. sabina on RA in folk medicine. SUMMARY Twigs and leaves of Juniperus sabina L. have been traditionally used as the medicinal herb in China for the treatment of rheumatoid arthritisJSTF could ameliorate paw swelling of CFA rats, and significantly inhibit arthritic scoreHistopathological studies showed a marked decrease

  15. Antioxidant Effect of Spirulina (Arthrospira) maxima on Chronic Inflammation Induced by Freund's Complete Adjuvant in Rats

    PubMed Central

    Gutiérrez-Rebolledo, Gabriel Alfonso; Galar-Martínez, Marcela; García-Rodríguez, Rosa Virginia; Chamorro-Cevallos, Germán A.; Hernández-Reyes, Ana Gabriela

    2015-01-01

    Abstract One of the major mechanisms in the pathogenesis of chronic inflammation is the excessive production of reactive oxygen and reactive nitrogen species, and therefore, oxidative stress. Spirulina (Arthrospira) maxima has marked antioxidant activity in vivo and in vitro, as well as anti-inflammatory activity in certain experimental models, the latter activity being mediated probably by the antioxidant activity of this cyanobacterium. In the present study, chronic inflammation was induced through injection of Freund's complete adjuvant (CFA) in rats treated daily with Spirulina (Arthrospira) maxima for 2 weeks beginning on day 14. Joint diameter, body temperature, and motor capacity were assessed each week. On days 0 and 28, total and differential leukocyte counts and serum oxidative damage were determined, the latter by assessing lipid peroxidation and protein carbonyl content. At the end of the study, oxidative damage to joints was likewise evaluated. Results show that S. maxima favors increased mobility, as well as body temperature regulation, and a number of circulating leukocytes, lymphocytes, and monocytes in specimens with CFA-induced chronic inflammation and also protects against oxidative damage in joint tissue as well as serum. In conclusion, the protection afforded by S. maxima against development of chronic inflammation is due to its antioxidant activity. PMID:25599112

  16. Antioxidant Effect of Spirulina (Arthrospira) maxima on Chronic Inflammation Induced by Freund's Complete Adjuvant in Rats.

    PubMed

    Gutiérrez-Rebolledo, Gabriel Alfonso; Galar-Martínez, Marcela; García-Rodríguez, Rosa Virginia; Chamorro-Cevallos, Germán A; Hernández-Reyes, Ana Gabriela; Martínez-Galero, Elizdath

    2015-08-01

    One of the major mechanisms in the pathogenesis of chronic inflammation is the excessive production of reactive oxygen and reactive nitrogen species, and therefore, oxidative stress. Spirulina (Arthrospira) maxima has marked antioxidant activity in vivo and in vitro, as well as anti-inflammatory activity in certain experimental models, the latter activity being mediated probably by the antioxidant activity of this cyanobacterium. In the present study, chronic inflammation was induced through injection of Freund's complete adjuvant (CFA) in rats treated daily with Spirulina (Arthrospira) maxima for 2 weeks beginning on day 14. Joint diameter, body temperature, and motor capacity were assessed each week. On days 0 and 28, total and differential leukocyte counts and serum oxidative damage were determined, the latter by assessing lipid peroxidation and protein carbonyl content. At the end of the study, oxidative damage to joints was likewise evaluated. Results show that S. maxima favors increased mobility, as well as body temperature regulation, and a number of circulating leukocytes, lymphocytes, and monocytes in specimens with CFA-induced chronic inflammation and also protects against oxidative damage in joint tissue as well as serum. In conclusion, the protection afforded by S. maxima against development of chronic inflammation is due to its antioxidant activity. PMID:25599112

  17. Electroacupuncture Reduces Carrageenan- and CFA-Induced Inflammatory Pain Accompanied by Changing the Expression of Nav1.7 and Nav1.8, rather than Nav1.9, in Mice Dorsal Root Ganglia

    PubMed Central

    Huang, Chun-Ping; Chen, Hsiang-Ni; Su, Hong-Lin; Hsieh, Ching-Liang; Chen, Wei-Hsin; Lai, Zhen-Rung; Lin, Yi-Wen

    2013-01-01

    Several voltage-gated sodium channels (Navs) from nociceptive nerve fibers have been identified as important effectors in pain signaling. The objective of this study is to investigate the electroacupuncture (EA) analgesia mechanism by changing the expression of Navs in mice dorsal root ganglia (DRG). We injected carrageenan and complete Freund's adjuvant (CFA) into the mice plantar surface of the hind paw to induce inflammation and examined the antinociception effect of EA at the Zusanli (ST36) acupoint at 2 Hz low frequency. Mechanical hyperalgesia was evaluated by using electronic von Frey filaments, and thermal hyperalgesia was assessed using Hargreaves' test. Furthermore, we observed the expression and quality of Navs in DRG neurons. Our results showed that EA reduced mechanical and thermal pain in inflammatory animal model. The expression of Nav1.7 and Nav1.8 was increased after 4 days of carrageenan- and CFA-elicited inflammatory pain and further attenuated by 2 Hz EA stimulation. The attenuation cannot be observed in Nav1.9 sodium channels. We demonstrated that EA at Zusanli (ST36) acupoint at 2 Hz low-frequency stimulation attenuated inflammatory pain accompanied by decreasing the expression of Nav1.7 and 1.8, rather than Nav1.9, sodium channels in peripheral DRG neurons. PMID:23573123

  18. Intervention of electroacupuncture on spinal p38 MAPK/ATF-2/VR-1 pathway in treating inflammatory pain induced by CFA in rats

    PubMed Central

    2013-01-01

    Background Previous studies have demonstrated that p38 MAPK signal transduction pathway plays an important role in the development and maintenance of inflammatory pain. Electroacupuncture (EA) can suppress the inflammatory pain. However, the relationship between EA effect and p38 MAPK signal transduction pathway in inflammatory pain remains poorly understood. It is our hypothesis that p38 MAPK/ATF-2/VR-1 and/or p38 MAPK/ATF-2/COX-2 signal transduction pathway should be activated by inflammatory pain in CFA-injected model. Meanwhile, EA may inhibit the activation of p38 MAPK signal transduction pathway. The present study aims to investigate that anti-inflammatory and analgesic effect of EA and its intervention on the p38 MAPK signal transduction pathway in a rat model of inflammatory pain. Results EA had a pronounced anti-inflammatory and analgesic effect on CFA-induced chronic inflammatory pain in rats. EA could quickly raise CFA-rat’s paw withdrawal thresholds (PWTs) and maintain good and long analgesic effect, while it subdued the ankle swelling of CFA rats only at postinjection day 14. EA could down-regulate the protein expressions of p-p38 MAPK and p-ATF-2, reduced the numbers of p-p38 MAPK-IR cells and p-ATF-2-IR cells in spinal dorsal horn in CFA rats, inhibited the expressions of both protein and mRNA of VR-1, but had no effect on the COX-2 mRNA expression. Conclusions The present study indicates that inhibiting the activation of spinal p38 MAPK/ATF-2/VR-1 pathway may be one of the main mechanisms via central signal transduction pathway in the process of anti-inflammatory pain by EA in CFA rats. PMID:23517865

  19. Protective role of theophylline and their interaction with nitric oxide (NO) in adjuvant-induced rheumatoid arthritis in rats.

    PubMed

    Pal, Rishi; Chaudhary, Manju J; Tiwari, Prafulla C; Babu, Suresh; Pant, K K

    2015-12-01

    Theophylline (non-specific PDE inhibitor) and their interactions with nitric oxide modulators were evaluated in adjuvant-induced arthritic model of rats. Wistar rats (200-300g), 8 animals per group were used in the study. The animals were injected with 0.1mL of squalene and 0.2mL of complete Freund's adjuvant on day (0) in sub-planter region of right hind paw controls received only saline. The treatment with theophylline and nitric oxide modulators were done from day 14 to day 28. Arthritis indexes, ankle diameter, paw volume, and body weight were determined to assess RA progression from day (0) to day 28. On day 28 animals were sacrificed and their blood collected for IL-10 and TNF-α cytokine levels and hind paw for pathological analysis. Synovial fluid from joint spaces of CFA inoculated rats was collected to estimate TNF-α level in synovial fluid. The data obtained was analyzed by two-way ANOVA followed by the Newman-Keuls post-hoc test. Theophylline (10 and 20mg/kg) significantly decreased adjuvant induced increased arthritis-index, paw volume and ankle diameter (p<0.05 in all parameters) compared to only adjuvant control group. It also reversed adjuvant induced slight decrease in body weight to normalcy. l-Arginine 100mg/kg+theophylline 20mg/kg suppressed TNF-α and elevates IL-10 level as well as reversed adjuvant-induced elevated arthritic parameters as compared to only adjuvant and prednisone group (p<0.001). Synovial TNF-α level of adjuvant only group was several fold higher than its serum level. Treatment with theophylline 20mg/kg significantly reduces synovial TNF-α level as compared to adjuvant only group. Theophylline 20mg/kg+L-NAME 10mg/kg significantly reversed these adjuvant-induced changes in immunological, histopathological and arthritis parameters (p<0.05). PMID:26349791

  20. Immune Modulation of B. terrestris Worker (a Type of Bumblebee), Extract on CFA-induced Paw Edema in Rats

    PubMed Central

    Kim, Soon Ja; Han, Jea Woong; Yoon, Hyung Joo; Hwang, Jae Sam; Yun, Eun Young

    2014-01-01

    To develop a composition for enhancing immunity, based on alcohol extracts of the bumblebee as an active ingredient, bumblebee ethanol extracts were evaluated for their protective effect in chronic models of inflammation, adjuvant induced rat arthritis. B. terrestris worker extract (SDIEX) and, B. hypocrita sapporoensis lava an pupa extract (SPDYBEX), significantly decreased paw edema in arthritic rats, at a dose 100 mg/kg, respectively. The cytokine levels related inflammation of COX-2, sPLA2, VEGF, and TNF-α, were decreased, compared to positive control, indomethacin (5 mg/kg). Histopathological data demonstrated decreases inflammatory activity, hind paw edema, and repaired hyaline articular cartilage in DRG over a 2 wk administration. HPLC and GC-MS analysis of SDIEX and SPDYBEX revealed the presence of cantharidin. PMID:25584147

  1. Evaluation of Protective Efficacy of Avicennia marina (Forssk.) Vierh Leaves against Complete Freund᾽s Adjuvant-induced Arthritis in Wistar

    PubMed Central

    Zamani Gandomani, Mahdi; Forouzandeh Malati, Elaheh

    2014-01-01

    Aviecennia marina (Avicenniaceae) is an endemic plant that widely distributed in the Southern parts of Iran. This plant has been used as treatment of rheumatism arthritis among the inhabitants of Southern parts of Iran. The Avicennia marina hydroalcoholic extract was prepared and its protective efficacy was investigated using measurement of ankle diameter, total WBC and RBC count, ESR, and Pro-inflammatory cytokines levels in the complete Freund᾽s adjuvant (CFA)-induced arthritic rat. The increment in ESR and total WBC, reduction in RBC count and hemoglobin levels observed in the arthritic animals were also found to be significantly restored in HEA treated rats. A. marina at 400 mg/Kg significantly decreases the serum pro-inflammatory cytokines as well as normalizes ankle diameter of CFA rats. A. marina (400 mg/Kg) significantly normalizes changes observed in arthritic rats to near normal conditions, indicates that A. marina has promising protective efficacy against arthritic rats. PMID:25276195

  2. Therapeutic effect of umbelliferon-α-D-glucopyranosyl-(2(I)→1(II))-α-D-glucopyranoside on adjuvant-induced arthritic rats.

    PubMed

    Kumar, Vikas; Anwar, Firoz; Verma, Amita; Mujeeb, Mohd

    2015-06-01

    The aim and objective of the present investigation was to evaluate the antiarthritic and antioxidant effect of umbelliferon-α-D-glucopyranosyl-(2I→1II)-α-D-glucopyranoside (UFD) in chemically induced arthritic rats. The different doses of the UFD were tested against the turpentine oil (TO), formaldehyde induced acute arthritis and complete fruend's adjuvant (CFA) induced chronic arthritis in Wistar rats. Arthritic assessment and body weight was measured at regular interval till 28 days. On day 28, all the groups animals were anaesthetized, blood were collected from the puncturing the ratro orbital and estimated the hematological parameters. The animals were sacrificed; synovial tissue was extracted and estimated the malonaldehyde (MDA), glutathione (GSH), glutathione peroxidase (GPx) and superoxide dismutase (SOD). The different doses of the UFD showed the protective effect against turpentine oil, formaldehyde induced acute arthritis and CFA induced chronic arthritis at dose dependent manner. Acute model of arthritis such as TOand formaldehyde induced inflammation due to releasing of the inflammatory mediators; significantly inhibited by the UFD at dose dependent manner. CFA induced arthritic rats treated with the different doses of the UFD showed the inhibitory effect on the delayed increase in joint diameter as seen in arthritic control group rats. UFD significantly improved the arthritic index, body weight and confirmed the antiarthritic effect. UFD showed the effect on the hematological parameter such as improved the level of the RBC, Hb and decline the level of the EBC, ESR and confirmed the immune suppressive effect. UFD significantly improved the level of the endogenous antioxidant and confirmed the antioxidant effect. This present investigation suggests that the UFD has prominent antiarthritic impact which can be endorsed to its antiarthritic and antioxidant effects. PMID:26028721

  3. Nociceptive sensitivity and opioid antinociception and antihyperalgesia in Freund's adjuvant-induced arthritic male and female rats.

    PubMed

    Cook, Charles D; Nickerson, Michael D

    2005-04-01

    The present study was designed to examine sex differences in complete Freund's adjuvant (CFA)-induced mechanical hyperalgesia and sex differences in opioid antinociception and anti-hyperalgesia. Female rats developed inflammation and hyperalgesia faster and exhibited greater peak hyperalgesia than male rats. In arthritic (CFA-treated) rats, lower thresholds were observed during estrus and proestrus, and in nonarthritic (vehicle-treated) rats, lower thresholds were observed during proestrus. Morphine and oxycodone were more potent in male than female arthritic rats, and butorphanol was more potent and effective in male than female arthritic rats. The potency of morphine was increased in arthritic rats, although to a greater magnitude in males. The potency of oxycodone was increased in male but not female arthritic rats. The potency of butorphanol was increased in arthritic male rats and the maximal antinociceptive effect of butorphanol was increased in arthritic female rats, but it did not result in greater than 20% antinociception. Morphine, oxycodone, and butorphanol all produced antihyperalgesic effects (returning thresholds of arthritic rats to the thresholds of nonarthritic rats) with greater potency in males than females. The peripherally acting opioid agonist loperamide produced intermediate levels of antinociception in male and female arthritic rats and no antinociception in nonarthritic rats. Loperamide was more potent in male than female arthritic rats at producing antihyperalgesia. These data demonstrate sex differences in arthritis-induced hyperalgesia and responsiveness to opioid analgesics. In arthritic rats, the antinociceptive effects of opioid agonists are most probably mediated by both central and peripheral opioid receptors, whereas their antihyperalgesic effects are mediated primarily by actions at peripheral opioid receptors. PMID:15608071

  4. Ciclamilast Ameliorates Adjuvant-Induced Arthritis in a Rat Model

    PubMed Central

    Zhang, Zhi-cheng; Zhang, Shui-juan; Jin, Bo; Wu, Yujin; Yang, Xin-fu; Yu, Bing; Xie, Qiang-min

    2015-01-01

    We assessed the effect of a novel and selective phosphodiesterase 4 (PDE4) inhibitor, ciclamilast, on chronic inflammation in adjuvant-induced arthritis (AIA), a rat model of rheumatoid arthritis (RA), and acute inflammation in the rat and mouse model of carrageenan-induced paw edema and peritonitis. Our results showed that daily oral administration of ciclamilast at 1, 3, and 10 mg/kg dose-dependently inhibited the increase in hind paw volume of rats with AIA. The inhibition of paw edema was associated with inhibition of both the production of cytokines such as TNF-α, IL-1β, and IL-6 and cell infiltration assessed in subcutaneous paw tissue. Moreover, there was significantly less tissue destruction in the ciclamilast-treated rats compared to the vehicle-treated rats, as assessed by radiographic analysis and histopathological evaluation. In the two acute inflammation models, ciclamilast inhibited carrageenan-induced paw edema in rats and inflammatory cell migration into the peritoneal cavity in mice in a dose-dependent manner. These results not only suggest that ciclamilast, as a disease-modifying antirheumatic drug (DMARD), can attenuate RA but also provide proof of principle that a PDE4 inhibitor may be useful for the treatment of arthritis. PMID:26000303

  5. Effect of galantamine on adjuvant-induced arthritis in rats.

    PubMed

    Gowayed, Mennatallah A; Refaat, Rowaida; Ahmed, Walid M; El-Abhar, Hanan S

    2015-10-01

    Stimulation of the vagus nerve suppresses cytokine production and macrophage activation, via the interaction of its neurotransmitter acetylcholine (ACh) with the α7 subunit of the nicotinic acetylcholine receptor (α7nAChR), present on neurons and inflammatory cells. The present study aimed to verify the potential anti-inflammatory effect of galantamine against experimental arthritis induced in rats. Fourteen days post adjuvant injection, Sprague-Dawley rats were treated orally with three doses of galantamine (1.25, 2.5 and 5 mg/kg) or leflunomide (10 mg/kg) for 2 weeks and arthritis progression was assessed by hind paw swelling. Additionally, serum biomarkers, viz., anti-cyclic citrullinated peptide antibodies (Anti-CCP), tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10) and monocyte chemoattractant protein-1 (MCP-1) were measured. Radiological examination of the hind paws was also carried out to evaluate the degree of joint damage. Adjuvant arthritis led to a significant weight loss, marked swelling of the hind paw and alteration in the serum levels of anti-CCP, TNF-α, IL-10 and MCP-1. These alterations were associated with significant radiological changes of the joints. Galantamine, in a dose-dependent manner, reduced significantly all biomarkers of inflammation, with the highest dose showing the best beneficial anti-inflammatory effect that was superior in magnitude to the reference drug leflunomide in most of the studied parameters. In conclusion, these results suggest that galantamine may represent a novel, inexpensive and effective therapeutic strategy in the treatment of rheumatoid arthritis. PMID:26189022

  6. Evening primrose oil and celecoxib inhibited pathological angiogenesis, inflammation, and oxidative stress in adjuvant-induced arthritis: novel role of angiopoietin-1.

    PubMed

    El-Sayed, R M; Moustafa, Y M; El-Azab, M F

    2014-10-01

    Rheumatoid arthritis is a chronic inflammatory disease characterized by overproduction of inflammatory mediators along with undermined oxidative defensive mechanisms. Pathological angiogenesis was found to play a critical role in the progression of this disease. The current study was carried out to evaluate the anti-angiogenic, anti-inflammatory, and anti-oxidant effects of evening primrose oil (EPO), rich in gamma linolenic acid (GLA), either alone or in combination with aspirin or celecoxib, on adjuvant-induced arthritis. Arthritis was induced by subcutaneous injection of complete Freund's adjuvant (CFA) in the right hind paw of male albino rats. All treatments were administered orally from day 0 (EPO, 5 g/kg b.w.) or day 4 (celecoxib, 5 mg/kg; aspirin, 150 mg/kg) till day 27 after CFA injection. In the arthritic group, the results revealed significant decrease in the body weight and increase in ankle circumference, plasma angiopoietin-1 (ANG-1) and tumor necrosis factor-alpha (TNF-α) levels. Anti-oxidant status was suppressed as manifested by significant decline in reduced glutathione content along with decreased enzymatic activity of superoxide dismutase and increased lipid peroxidation. Oral administration of EPO exerted normalization of body weight, ANG-1, and TNF-α levels with restoration of activity as shown by reduced malondialdehyde levels. Moreover, histopathological examination demonstrated that EPO significantly reduced the synovial hyperplasia and inflammatory cells invasion in joint tissues, an effect that was enhanced by combination with aspirin or celecoxib. The joint use of GLA-rich natural oils, which possess anti-angiogenic, anti-inflammatory, and anti-oxidant activities, with traditional analgesics represents a promising strategy to restrain the progression of rheumatoid arthritis. PMID:24664592

  7. The adjuvant MF59 induces ATP release from muscle that potentiates response to vaccination.

    PubMed

    Vono, Maria; Taccone, Marianna; Caccin, Paola; Gallotta, Marilena; Donvito, Giovanna; Falzoni, Simonetta; Palmieri, Emiliano; Pallaoro, Michele; Rappuoli, Rino; Di Virgilio, Francesco; De Gregorio, Ennio; Montecucco, Cesare; Seubert, Anja

    2013-12-24

    Vaccines are the most effective agents to control infections. In addition to the pathogen antigens, vaccines contain adjuvants that are used to enhance protective immune responses. However, the molecular mechanism of action of most adjuvants is ill-known, and a better understanding of adjuvanticity is needed to develop improved adjuvants based on molecular targets that further enhance vaccine efficacy. This is particularly important for tuberculosis, malaria, AIDS, and other diseases for which protective vaccines do not exist. Release of endogenous danger signals has been linked to adjuvanticity; however, the role of extracellular ATP during vaccination has never been explored. Here, we tested whether ATP release is involved in the immune boosting effect of four common adjuvants: aluminum hydroxide, calcium phosphate, incomplete Freund's adjuvant, and the oil-in-water emulsion MF59. We found that intramuscular injection is always associated with a weak transient release of ATP, which was greatly enhanced by the presence of MF59 but not by all other adjuvants tested. Local injection of apyrase, an ATP-hydrolyzing enzyme, inhibited cell recruitment in the muscle induced by MF59 but not by alum or incomplete Freund's adjuvant. In addition, apyrase strongly inhibited influenza-specific T-cell responses and hemagglutination inhibition titers in response to an MF59-adjuvanted trivalent influenza vaccine. These data demonstrate that a transient ATP release is required for innate and adaptive immune responses induced by MF59 and link extracellular ATP with an enhanced response to vaccination. PMID:24324152

  8. The Safety of Adjuvanted Vaccines Revisited: Vaccine-Induced Narcolepsy.

    PubMed

    Ahmed, S Sohail; Montomoli, Emanuele; Pasini, Franco Laghi; Steinman, Lawrence

    2016-01-01

    Despite the very high benefit-to-risk ratio of vaccines, the fear of negative side effects has discouraged many people from getting vaccinated, resulting in the reemergence of previously controlled diseases such as measles, pertussis and diphtheria. This fear has been amplified more recently by multiple epidemiologic studies that confirmed the link of an AS03-adjuvanted pandemic influenza vaccine (Pandemrix, GlaxoSmithKline Biologicals, Germany) used in Europe during the 2009 H1N1 influenza pandemic [A(H1N1) pdm09] with the development of narcolepsy, a chronic sleep disorder, in children and adolescents. However, public misperceptions of what adjuvants are and why they are used in vaccines has created in some individuals a closed "black box" attitude towards all vaccines. The focus of this review article is to revisit this "black box" using the example of narcolepsy associated with the European AS03-adjuvanted pandemic influenza vaccine. PMID:27228647

  9. Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) 2013: Unveiling the pathogenic, clinical and diagnostic aspects.

    PubMed

    Perricone, Carlo; Colafrancesco, Serena; Mazor, Roei D; Soriano, Alessandra; Agmon-Levin, Nancy; Shoenfeld, Yehuda

    2013-12-01

    In 2011 a new syndrome termed 'ASIA Autoimmune/Inflammatory Syndrome Induced by Adjuvants' was defined pointing to summarize for the first time the spectrum of immune-mediated diseases triggered by an adjuvant stimulus such as chronic exposure to silicone, tetramethylpentadecane, pristane, aluminum and other adjuvants, as well as infectious components, that also may have an adjuvant effect. All these environmental factors have been found to induce autoimmunity by themselves both in animal models and in humans: for instance, silicone was associated with siliconosis, aluminum hydroxide with post-vaccination phenomena and macrophagic myofasciitis syndrome. Several mechanisms have been hypothesized to be involved in the onset of adjuvant-induced autoimmunity; a genetic favorable background plays a key role in the appearance on such vaccine-related diseases and also justifies the rarity of these phenomena. This paper will focus on protean facets which are part of ASIA, focusing on the roles and mechanisms of action of different adjuvants which lead to the autoimmune/inflammatory response. The data herein illustrate the critical role of environmental factors in the induction of autoimmunity. Indeed, it is the interplay of genetic susceptibility and environment that is the major player for the initiation of breach of tolerance. PMID:24238833

  10. Mucosal Pre-Exposure to Th17-Inducing Adjuvants Exacerbates Pathology after Influenza Infection

    PubMed Central

    Gopal, Radha; Rangel-Moreno, Javier; Fallert Junecko, Beth A.; Mallon, Daniel J.; Chen, Kong; Pociask, Derek A.; Connell, Terry D.; Reinhart, Todd A.; Alcorn, John F.; Ross, Ted M.; Kolls, Jay K.; Khader, Shabaana A.

    2015-01-01

    Mucosal vaccines are thought to confer superior protection against mucosal infectious diseases. In addition, mucosal routes of vaccine delivery preferentially induce the generation of T helper 17 (Th17) cells, which produce the cytokine IL-17. Th17 cells are critical in mediating vaccine-induced immunity against several mucosal infectious diseases. However, IL-17 is also a potent proinflammatory cytokine, and we recently showed that IL-17 mediates immunopathology and lung injury after influenza infection in mice. In the present study, we tested the hypothesis that mucosal pre-exposure to Th17-inducing adjuvants can promote disease exacerbation upon subsequent infection with influenza virus. Mice mucosally pre-exposed to Th17-inducing adjuvants, such as type II heat-labile enterotoxin or cholera toxin, resulted in increased morbidity and exacerbated lung inflammation upon subsequent infection with influenza virus. Furthermore, the increased morbidity was accompanied by increased expression of inflammatory chemokines and increased accumulation of neutrophils. Importantly, blockade of the IL-17 pathway in mice pre-exposed to Th17-inducing adjuvants resulted in attenuation of the inflammatory phenotype seen in influenza-infected mice. Our findings indicate that, before mucosal Th17-inducing adjuvants can be used in vaccine strategies, the short- and long-term detrimental effects of such adjuvants on disease exacerbation and lung injury in response to infections, such as influenza, should be carefully studied. PMID:24183780

  11. Adjuvants Induce Distinct Immunological Phenotypes in a Bovine Tuberculosis Vaccine Model▿

    PubMed Central

    Vordermeier, H. Martin; Dean, Gillian S.; Rosenkrands, Ida; Agger, Else M.; Andersen, Peter; Kaveh, Daryan A.; Hewinson, R. Glyn; Hogarth, Philip J.

    2009-01-01

    Tuberculosis (TB) remains one of the most important infectious diseases of humans and animals. Mycobacterium bovis BCG, the only currently available TB vaccine, demonstrates variable levels of efficacy; therefore, a replacement or supplement to BCG is required. Protein subunit vaccines have shown promise but require the use of adjuvants to enhance their immunogenicity. Using the protective mycobacterial antigen Rv3019c, we have evaluated the induction of relevant immune responses by adjuvant formulations directly in the target species for bovine TB vaccines and compared these to responses induced by BCG. We demonstrate that two classes of adjuvant induce distinct immune phenotypes in cattle, a fact not previously reported for mice. A water/oil emulsion induced both an effector cell and a central memory response. A cationic-liposome adjuvant induced a central memory response alone, similar to that induced by BCG. This suggests that water/oil emulsions may be the most promising formulations. These results demonstrate the importance of testing adjuvant formulations directly in the target species and the necessity of measuring different types of immune response when evaluating immune responses. PMID:19641101

  12. Effects of one minute and ten minutes of walking activity in rats with arthritis induced by complete Freund's adjuvant on pain and edema symptoms.

    PubMed

    Gomes, Raquel Pinheiro; Bressan, Elisângela; Silva, Tatiane Morgana da; Gevaerd, Monique da Silva; Tonussi, Carlos Rogério; Domenech, Susana Cristina

    2014-01-01

    This study evaluated the effects of two protocols of exercise on nociception, edema and cell migration in rats with CFA-induced arthritis. Female Wistar rats (200 - 250 g, n = 50) was monoarthritis-induced by complete Freund's adjuvant (CFA; Mycobacterium butyricum, 0.5 mg/mL; 50 μL) into the right knee joint (TF; n = 24) or right ankle joint (TT; n = 26). Incapacitation was measured by the paw elevation time (TEP; s) in 1-min periods of observation. The edema of the knee or ankle joints was evaluated by the variation of the articular diameter (DA, cm) and by the paw volume variation (EP, mL), respectively. Both were measured during 10 consecutive days. Two protocols of exercise were performed: (a) in the constant exercise group (TF, n = 6; TT, n = 6) performing 1 minute of daily exercise on the cylinder; (b) variable exercise group (TF, n = 6; TT, n = 7), the exercise increased by 1 minute per day. The control groups (TF, n = 12; TT, n = 13) didn't perform the exercise. After 10 days, the animals were euthanized for total (CT; cells/mm3) and differential leukocyte counts (mononuclear - MON, and polymorphonuclear - PMN, cells/mm3) of the articular inflammatory exudate. The variable exercise protocol inhibited incapacitation and edema for both joints. However, cell migration decreased only in the TF.The constant exercise reduced edema in both joints, and cell migration was decreased in the TT. However, the incapacitation was not reduced. Variable exercise seemed to be more effective in reducing the inflammatory parameters than constant exercise. PMID:24878853

  13. Immune mechanisms in the transfer of experimental autoimmune encephalomyelitis without adjuvant

    SciTech Connect

    Silberg, D.G.

    1985-01-01

    Experimental autoimmune encephalomyelitis (EAE) can be induced in Lewis rats without the use of adjuvant. Spleen cells of naive rats were sensitized to myelin basic protein (MBP) in vitro. Transfer of these cells did not result in the development of EAE. However, spleen cells from primary recipients, taken 10 days post transfer, and cultured with MBP (secondary culture, transferred EAE to secondary recipients. EAE can be induced in primary recipients by the transfer of secondary cultured cells or cultured cells or challenge with MBP in complete Freund's adjuvant (CFA) or incomplete Freund's adjuvant (IFA) 10 days after injection of naive cultured cells. The finding that MBP-CFA challenged 1' recipients developed EAE, suggests that the rats have been primed to MBP through the naive cultured cell transfer. The cells from naive culture that sensitize the primary recipient were radioresistant (1500 R), probably macrophages. This is in contrast to the cells transferring EAE to the secondary recipient, which were radiosensitive. Unlike the spleen cells which transfer EAE from MBP-CFA sensitized rats, the cells in the secondary transfer could not be activated to transfer EAE when cultured with concanavalin A. Clinical EAE in the secondary recipient was more severe when these rats were irradiated (200 R) prior to transfer. There is evidence that low dose irradiation eliminates naturally occurring suppressor cells. EAE also developed in lethally irradiated (850 R) recipients of secondary cultured cells, suggesting that the transferred cells can induce EAE alone or by recruiting radioresistant cells in the secondary host.

  14. The influence of simvastatin in rats mandible and femur bone mass under Freund's adjuvant arthritis.

    PubMed

    Seferos, Nikos; Pantopoulou, Alkistis; Kotsiou, Antonia; Rallis, Georgios; Tesseromatis, Christine

    2012-01-01

    OBJECTIVES. Complete Freund's Adjuvant (CFA)-induced arthritis in rats has been used widely as a model of rodent arthropathy and polyarthritis followed by osteoporosis, decreased bone formation and increased bone formation. Osteoporosis is characterized by rapid reduce of bone mass affecting more than 100 million people worldwide. Periodontitis a chronic inflammatory, of multifactorian origin disease has been associated with general osteoporosis. Protective bone-specific anabolic and antiresorptive effects of HMG-CoA reductase inhibitors have also been evaluated in normal and osteoporotic bone. AIM. The aim of the study was to investigate mandible and femur bone density in Freund's adjuvant induced arthritis rats under the influence of simvastatin. METHODS. Three groups (A, B, C) of 7 Wistar male rats each aged 3 months, (292±48.38 g) were used. A control. Group B and C subjected experimental arthritis via complete Freund's adjuvant injected in right paw. Group C was treated with simvastatin 0.5 mg/kg/daily po 14 days. Femur, mandible were isolated and sizes parameters, biochemical serum findings and BMD were estimated. RESULTS. CFA established by paw diameter, adrenals and spleen weight increase and thymus weight decrease, while biochemical serum findings were also affected. Reduced femur, mandible weight and general bone mass parameters BMD evaluated via DEXA occurred and restored under simvastatin treatment. CONCLUSIONS. CFA induced mandible and femur injuries are repaired by ssimvatatin treatment that could be therapeutically useful. PMID:23037783

  15. Antigens linked to synthetic microspheres induce immune responses in primates in the absence of adjuvant.

    PubMed

    Sedlik, C; Perraut, R; Bonnemains, B; Leclerc, C

    1996-01-01

    Although most strategies of vaccination require immunopotentiation to induce efficient immune responses, the development of new adjuvants for human vaccines is highly limited by safety problems. In order to overcome this problem, we developed a new vaccine formulation based on the covalent linkage of protein or peptide to synthetic microspheres. In previous experiments performed in mice, we demonstrated that these particulate antigens induce strong antigen-specific CD4+ T cell proliferative responses in the absence of adjuvant. In the present study, we analyzed the immunogenicity in primate Saimiri sciureus monkeys of two different proteins linked to synthetic microspheres. Immune responses induced by these particulate proteins administered without adjuvant were compared to those stimulated by the soluble antigens injected with alum. We currently demonstrated that, in monkeys, particulate antigens administered without adjuvant, induced good PBMC proliferative response and antibody production. Furthermore, the analysis of antibody responses using mAbs specific for different Saimiri sciureus immunoglobulins showed that the antibody response profiles were different in monkeys immunized with soluble versus particulate form of antigens. Results of this study demonstrate that particulate form of antigen may stimulate qualitatively different immune responses as compared to alum and therefore suggest that this new antigen formulation could be an attractive candidate for the development of vaccines. PMID:8852604

  16. Immunization of Saimiri sciureus Monkeys with a Recombinant Hybrid Protein Derived from the Plasmodium falciparum Antigen Glutamate-Rich Protein and Merozoite Surface Protein 3 Can Induce Partial Protection with Freund and Montanide ISA720 Adjuvants

    PubMed Central

    Carvalho, Leonardo J. M.; Alves, Francisco A.; Bianco, Cesare; Oliveira, Salma G.; Zanini, Graziela M.; Soe, Soe; Druilhe, Pierre; Theisen, Michael; Muniz, José A. P. C.; Daniel-Ribeiro, Cláudio T.

    2005-01-01

    The immunogenicity and efficacy of a hybrid recombinant protein derived from the N-terminal end of the glutamate-rich protein (GLURP) and the C-terminal portion of the merozoite surface protein 3 (MSP3) of Plasmodium falciparum was evaluated in Saimiri sciureus monkeys. The GLURP/MSP3 hybrid protein, expressed in Lactococcus lactis, was administered in association with alum, Montanide ISA720, or complete or incomplete Freund adjuvant (CFA/IFA) in groups of five animals each. The three formulations were shown to be immunogenic, but the one with alum was shown to be weak compared to the other two, particularly CFA/IFA, which provided very high antibody titers (enzyme-linked immunosorbent assay titers of >3,000,000 and immunofluorescence antibody test titers of 6,400). After a challenge infection with P. falciparum FUP strain, all five monkeys from the GLURP/MSP3-alum group showed a rapid increase in parasitemia, reaching 10% and were treated early. The two monkeys with the highest antibody titers in group GLURP/MSP3-Montanide ISA720 had a delay in the course of parasitemia and were treated late due to a low hematocrit. In the GLURP/MSP3-CFA/IFA group, parasitemia remained below this threshold in four of the five animals and, after it reached a peak, parasitemia started to decrease and monkeys were treated late. When all animals were grouped according to the outcome, a statistically significant association between high antibody titers and partial protection was observed. The challenge infection boosted the antibody titers, and the importance of this event for vaccine efficacy in areas where this parasite is endemic is discussed. In conclusion, these data suggest that GLURP and MSP3 can induce protection against malaria infection if antibodies are induced at properly high titers. PMID:15699417

  17. Attenuated Escherichia coli strains expressing the colonization factor antigen I (CFA/I) and a detoxified heat-labile enterotoxin (LThK63) enhance clearance of ETEC from the lungs of mice and protect mice from intestinal ETEC colonization and LT-induced fluid accumulation.

    PubMed

    Byrd, Wyatt; Boedeker, Edgar C

    2013-03-15

    Although enterotoxigenic Escherichia coli (ETEC) infections are important causes of infantile and traveler's diarrhea there is no licensed vaccine available for those at-risk. Our goal is to develop a safe, live attenuated ETEC vaccine. We used an attenuated E. coli strain (O157:H7, Δ-intimin, Stx1-neg, Stx2-neg) as a vector (ZCR533) to prepare two vaccine strains, one strain expressing colonization factor antigen I (ZCR533-CFA/I) and one strain expressing CFA/I and a detoxified heat-labile enterotoxin (ZCR533-CFA/I+LThK63) to deliver ETEC antigens to mucosal sites in BALB/c mice. Following intranasal and intragastric immunization with the vaccine strains, serum IgG and IgA antibodies were measured to the CFA/I antigen, however, only serum IgG antibodies were detected to the heat-labile enterotoxin. Intranasal administration of the vaccine strains induced respiratory and intestinal antibody responses to the CFA/I and LT antigens, while intragastric administration induced only intestinal antibody responses with no respiratory antibodies detected to the CFA/I and LT antigens. Mice immunized intranasally with the vaccine strains showed enhanced clearance of wild-type (wt) ETEC bacteria from the lungs. Mice immunized intranasally and intragastrically with the vaccine strains were protected from intestinal colonization following oral challenge with ETEC wt bacteria. Mice immunized intragastrically with the ZCR533-CFA/I+LThK63 vaccine strain had less fluid accumulate in their intestine following challenge with ETEC wt bacteria or with purified LT as compared to the sham mice indicating that the immunized mice were protected from LT-induced intestinal fluid accumulation. Thus, mice intragastrically immunized with the ZCR533-CFA/I+LThK63 vaccine strain were able to effectively neutralize the activity of the LT enterotoxin. However, no difference in intestinal fluid accumulation was detected in the mice immunized intranasally with the vaccine strain as compared to the sham

  18. Effects of adjuvants for human use in systemic lupus erythematosus (SLE)-prone (New Zealand black/New Zealand white) F1 mice.

    PubMed

    Favoino, E; Favia, E I; Digiglio, L; Racanelli, V; Shoenfeld, Y; Perosa, F

    2014-01-01

    The safety of four different adjuvants was assessed in lupus-prone New Zealand black/New Zealand white (BW)F1 mice. Four groups of mice were injected intraperitoneally with incomplete Freund's adjuvant (IFA), complete Freund's adjuvant (CFA), squalene (SQU) or aluminium hydroxide (ALU). An additional group received plain phosphate-buffered saline (PBS) (UNT group). Mice were primed at week 9 and boosted every other week up to week 15. Proteinuria became detectable at weeks 17 (IFA group), 24 (CFA group), 28 (SQU and ALU groups) and 32 (UNT group). Different mean values were obtained among the groups from weeks 17 to 21 [week 17: one-way analysis of variance (anova) P = 0·016; weeks 18 and 19: P = 0·048; weeks 20 and 21: P = 0·013] being higher in the IFA group than the others [Tukey's honestly significant difference (HSD) post-test P < 0·05]. No differences in anti-DNA antibody levels were observed among groups. Anti-RNP/Sm antibody developed at week 19 in only one CFA-treated mouse. Mean mouse weight at week 18 was lower in the ALU group than the IFA (Tukey's HSD post-test P = 0·04), CFA (P = 0·01) and SQU (P < 0·0001) groups, while the mean weight in the SQU group was higher than in the IFA (P = 0·009), CFA (P = 0·013) and UNT (P = 0·005) groups. The ALU group weight decreased by almost half between weeks 29 and 31, indicating some toxic effect of ALU in the late post-immunization period. Thus, SQU was the least toxic adjuvant as it did not (i) accelerate proteinuria onset compared to IFA; (ii) induce toxicity compared to ALU or (iii) elicit anti-RNP/Sm autoantibody, as occurred in the CFA group. PMID:24112107

  19. Berberis aristata Ameliorates Adjuvant-Induced Arthritis by Inhibition of NF-κB and Activating Nuclear Factor-E2-related Factor 2/hem Oxygenase (HO)-1 Signaling Pathway.

    PubMed

    Kumar, Rohit; Nair, Vinod; Gupta, Yogendra Kumar; Singh, Surender; Arunraja, S

    2016-08-01

    The present study was carried out to investigate the anti-arthritic activity of Berberis aristata hydroalcoholic extract (BAHE) in formaldehyde-induced arthritis and adjuvant-induced arthritis (AIA) model. Arthritis was induced by administration of either formaldehyde (2% v/v) or CFA into the subplantar surface of the hind paw of the animal. In formaldehyde-induced arthritis and AIA, treatment of BAHE at doses 50, 100 and 200 mg/kg orally significantly decreased joint inflammation as evidenced by decrease in joint diameter and reduced inflammatory cell infiltration in histopathological examination. BAHE treatment demonstrated dose-dependent improvement in the redox status of synovium (decrease in GSH, MDA, and NO levels and increase in SOD and CAT activities). The beneficial effect of BAHE was substantiated with decreased expression of inflammatory markers such as IL-1β, IL-6, TNF-R1, and VEGF by immunohistochemistry analysis in AIA model. BAHE increased HO-1/Nrf-2 and suppressed NF-κB mRNA and protein expression in adjuvant immunized joint. Additionally, BAHE abrogated degrading enzymes, as there was decreased protein expression of MMP-3 and -9 in AIA. In conclusion, we demonstrated the anti-arthritic activity of Berberis aristata hydroalcoholic extract via the mechanism of inhibition of NF-κB and activation of Nrf-2/HO-1. PMID:27294302

  20. PMA Induces Vaccine Adjuvant Activity by the Modulation of TLR Signaling Pathway

    PubMed Central

    Oh, Dool-Ri; Kang, Hu Won; Kim, Jong-Ro; Kim, Sunoh; Park, In-Kyu; Rhee, Joon Haeng; Oh, Won Keun; Kim, Young Ran

    2014-01-01

    Toll-like receptor (TLR) ligands are being developed for use as vaccine adjuvants and as immunomodulators because of their ability to stimulate innate and adaptive immune responses. Flagellin, a TLR5 ligand, was reported to show potent mucosal vaccine adjuvant activity. To identify ligands that potentiate the adjuvant activity of flagellin, we screened a plant library using HEK293T cells transiently cotransfected with phTLR5 and pNF-κB-SEAP plasmids. The 90% EtOH extract from Croton tiglium showed significant NF-κB transactivation in a TLR5-independent manner along with the increase of a flagellin activity. We have studied to characterize an active component from Croton tiglium and to elucidate the action mechanisms. Phorbol 12-myristate 13-acetate (PMA) was isolated as an active component of Croton tiglium by activity-guided fractionation, column chromatography, HPLC, NMR, and MS. PMA at a range of nM induced PKC-dependent NF-κB activation and IL-8 production in both TLR5− and TLR5+ assay systems. In in vivo mouse vaccination model, PMA induced antigen-specific IgG and IgA antibody responses and increased IL-12 production corresponding to T cell responses in spleen lymphocytes. These results suggest that PMA would serve as an efficacious mucosal vaccine adjuvant. PMID:24948847

  1. Effect of adjuvants on immunization with dengue virus-induced cytotoxic factor.

    PubMed Central

    Mukerjee, R; Chaturvedi, U C

    1995-01-01

    Specific active immunization with dengue type 2 virus (DV)-induced cytokine, cytotoxic factor (CF), prevents CF-mediated pathology in mice. The present study was undertaken to determine the optimum dose of CF and the effect of different adjuvants on the immune response as assessed by the study of anti-CF antibody titre by ELISA and protection against increase in capillary permeability to challenging dose of 3 micrograms CF. The maximum protection of 94 +/- 4% against increase in capillary permeability was observed at week 4 after immunization with 5 micrograms dose of CF mixed with Freund's incomplete adjuvant (FIA), which gradually decreased to 21 +/- 10% on week 24. With a dose of 10 micrograms the protection obtained was 79 +/- 5%, but persisted for a longer time at a higher level. The response was poor with 1 microgram dose of CF. The mean anti-CF antibody titres gradually decreased after reaching the peak at week 4 after immunization. Mice immunized with different adjuvants emulsified with 5 micrograms CF were challenged at different intervals with 3 micrograms CF. Maximum protection observed with CF + tetanus toxoid (TT) and 84/246 was about 93 +/- 2% and 97 +/- 2%, while that with alhydrogel was 33 +/- 12% and with bacille Calmette-Guérin (BCG) was 67 +/- 4%. At week 24 after immunization, however, the best response was obtained with 10 micrograms of adjuvant 84/246. Intracerebral challenge with 10 or 100 LD50 dose of dengue type 2 virus showed significantly prolonged mean survival time and delayed onset of signs of sickness in immunized mice compared with normal mice. The maximum survival time was with adjuvant 84/246 even at week 24. The findings thus show that the optimum dose of CF is 5 micrograms and the adjuvant of choice is 84/246. PMID:8536363

  2. Distinct Pathways of Humoral and Cellular Immunity Induced with the Mucosal Administration of a Nanoemulsion Adjuvant

    PubMed Central

    Makidon, Paul E.; Janczak, Katarzyna W.; Blanco, Luz P.; Swanson, Benjamin; Smith, Douglas M.; Pham, Tiffany; Szabo, Zsuzsanna; Kukowska-Latallo, Jolanta F.; Baker, James R.

    2014-01-01

    Nasal administration of an oil-in-water nanoemulsion (NE) adjuvant W805EC produces potent systemic and mucosal, Th-1– and Th-17–balanced cellular responses. However, its molecular mechanism of action has not been fully characterized and is of particular interest because NE does not contain specific ligands for innate immune receptors. In these studies, we demonstrate that W805EC NE adjuvant activates innate immunity, induces specific gene transcription, and modulates NF-κB activity via TLR2 and TLR4 by a mechanism that appears to be distinct from typical TLR agonists. Nasal immunization with NE-based vaccine showed that the TLR2, TLR4, and MyD88 pathways and IL-12 and IL-12Rβ1 expression are not required for an Ab response, but they are essential for the induction of balanced Th-1 polarization and Th-17 cellular immunity. NE adjuvant induces MHC class II, CD80, and CD86 costimulatory molecule expression and dendritic cell maturation. Further, upon immunization with NE, adjuvant mice deficient in the CD86 receptor had normal Ab responses but significantly reduced Th-1 cellular responses, whereas animals deficient in both CD80 and CD86 or lacking CD40 failed to produce either humoral or cellular immunity. Overall, our data show that intranasal administration of Ag with NE induces TLR2 and TLR4 activation along with a MyD88-independent Ab response and a MyD88-dependent Th-1 and Th-17 cell–mediated immune response. These findings suggest that the unique properties of NE adjuvant may offer novel opportunities for understanding previously unrecognized mechanisms of immune activation important for generating effective mucosal and systemic immune responses. PMID:24532579

  3. CFA or CFP: A Guide for Professors

    ERIC Educational Resources Information Center

    Moy, Ronald L.

    2011-01-01

    The CFA Institute and the CFP Board of Standards provide professional certifications in the field of finance. In this paper, I provide my experience with the CFA and CFP programs in order to give other professors some insight into the process of attaining the designations. I hope to provide answers to some of the questions that other faculty…

  4. Distinct serum proteome profiles associated with collagen-induced arthritis and complete Freund's adjuvant-induced inflammation in CD38⁻/⁻ mice: The discriminative power of protein species or proteoforms.

    PubMed

    Rosal-Vela, Antonio; García-Rodríguez, Sonia; Postigo, Jorge; Iglesias, Marcos; Longobardo, Victoria; Lario, Antonio; Merino, Jesús; Merino, Ramón; Zubiaur, Mercedes; Sancho, Jaime

    2015-10-01

    Collagen-type-II-induced arthritis (CIA) is an autoimmune disease, which involves a complex host systemic response including inflammatory and autoimmune reactions. CIA is milder in CD38(-/-) than in wild-type (WT) mice. ProteoMiner-equalized serum samples were subjected to 2D-DiGE and MS-MALDI-TOF/TOF analyses to identify proteins that changed in their relative abundances in CD38(-/-) versus WT mice either with arthritis (CIA(+) ), with no arthritis (CIA(-) ), or with inflammation (complete Freund's adjuvant (CFA)-treated mice). Multivariate analyses revealed that a multiprotein signature (n = 28) was able to discriminate CIA(+) from CIA(-) mice, and WT from CD38(-/-) mice within each condition. Likewise, a distinct multiprotein signature (n = 16) was identified which differentiated CIA(+) CD38(-/-) mice from CIA(+) WT mice, and lastly, a third multiprotein signature (n = 18) indicated that CD38(-/-) and WT mice could be segregated in response to CFA treatment. Further analyses showed that the discriminative power to distinguish these groups was reached at protein species level and not at the protein level. Hence, the need to identify and quantify proteins at protein species level to better correlate proteome changes with disease processes. It is crucial for plasma proteomics at the low-abundance protein species level to apply the ProteoMiner enrichment. All MS data have been deposited in the ProteomeXchange with identifiers PXD001788, PXD001799 and PXD002071 (http://proteomecentral.proteomexchange.org/dataset/PXD001788, http://proteomecentral.proteomexchange.org/dataset/PXD001799 and http://proteomecentral.proteomexchange.org/dataset/PXD002071). PMID:26175002

  5. Effects of Adjuvant Analgesics on Cerebral Ischemia-Induced Mechanical Allodynia.

    PubMed

    Matsuura, Wataru; Harada, Shinichi; Tokuyama, Shogo

    2016-01-01

    Central post-stroke pain (CPSP), a potential sequela of stroke, is classified as neuropathic pain. Although we recently established a CPSP-like model in mice, the effects of adjuvant analgesics as therapeutic drugs for neuropathic pain in this model are unknown. Hence, the aim of the present study was to assess the usefulness of our model by evaluating the effects of adjuvant analgesics used for treating neuropathic pain in this mouse model of CPSP. Male ddY mice were subjected to 30 min of bilateral carotid artery occlusion (BCAO). The development of hind paw mechanical allodynia was measured after BCAO using the von Frey test. The mechanical allodynia was significantly increased on day 3 after BCAO compared with that during the pre-BCAO assessment. BCAO-induced mechanical allodynia was significantly decreased by intraperitoneal injections of imipramine (a tricyclic antidepressant), mexiletine (an antiarrhythmic), gabapentin (an antiepileptic), or a subcutaneous injection of morphine (an opioid receptor agonist) compared with that following vehicle treatment in BCAO-mice. By contrast, milnacipran (a serotonin and norepinephrine reuptake inhibitor), paroxetine (selective serotonin reuptake inhibitor), carbamazepine (antiepileptic), and indomethacin (nonsteroidal anti-inflammatory drug) did not affect the BCAO-induced mechanical allodynia. Our results show that BCAO in mice may be useful as an animal model of CPSP. In addition, BCAO-induced mechanical allodynia may be suppressed by some adjuvant analgesics used to treat neuropathic pain. PMID:27150152

  6. Establishment of a rat model of adjuvant-induced osteoarthritis of the lumbar facet joint.

    PubMed

    Shuang, Feng; Zhu, Jialiang; Song, Keran; Hou, Shuxun; Liu, Yan; Zhang, Chunli; Tang, Jiaguang

    2014-12-01

    To study the establishment of adjuvant-induced osteoarthritis of the lumbar facet joint in a rat model. Complete Freund's adjuvant (experimental group) and saline (control group) were randomly injected into the right and left side of rat, respectively. The rats were killed, and degeneration of lumbar facet joint was evaluated at macroscopic level and scored based on OARSI scores system. Moreover, Interleukin-1β and tumor necrosis factor-α levels in the synovium were measured. The macroscopic scores and OARSI scores of experimental group were higher than the control group (P < 0.05). The concentration of tumor necrosis factor-α was significantly increased only on 3- and 7-day post-surgery when compared with controls, and interleukin-1β was increased on days 3,7 and 14 post-surgery (P < 0.05). The rat model of adjuvant can induce degeneration of the lumbar facet joint. It can be useful for studies on mechanisms and treatment of lumbar facet joint osteoarthritis. PMID:24973958

  7. Adjuvants and immunization strategies to induce influenza virus hemagglutinin stalk antibodies.

    PubMed

    Goff, Peter H; Eggink, Dirk; Seibert, Christopher W; Hai, Rong; Martínez-Gil, Luis; Krammer, Florian; Palese, Peter

    2013-01-01

    The global population remains vulnerable in the face of the next pandemic influenza virus outbreak, and reformulated vaccinations are administered annually to manage seasonal epidemics. Therefore, development of a new generation of vaccines is needed to generate broad and persistent immunity to influenza viruses. Here, we describe three adjuvants that enhance the induction of stalk-directed antibodies against heterologous and heterosubtypic influenza viruses when administered with chimeric HA proteins. Addavax, an MF59-like nanoemulsion, poly(I:C), and an RNA hairpin derived from Sendai virus (SeV) Cantell were efficacious intramuscularly. The SeV RNA and poly(I:C) also proved to be effective respiratory mucosal adjuvants. Although the quantity and quality of antibodies induced by the adjuvants varied, immunized mice demonstrated comparable levels of protection against challenge with influenza A viruses on the basis of HA stalk reactivity. Finally, we present that intranasally, but not intramuscularly, administered chimeric HA proteins induce mucosal IgA antibodies directed at the HA stalk. PMID:24223176

  8. The vaccine-site microenvironment induced by injection of incomplete Freund's adjuvant, with or without melanoma peptides

    PubMed Central

    Harris, Rebecca C.; Chianese-Bullock, Kimberly A.; Petroni, Gina R.; Schaefer, Jochen T.; Brill, Louis B.; Molhoek, Kerrington R.; Deacon, Donna H.; Patterson, James W.; Slingluff, Craig L.

    2011-01-01

    Cancer vaccines have not been optimized. They depend on adjuvants to create an immunogenic microenvironment for antigen presentation. However, remarkably little is understood about cellular and molecular changes induced by these adjuvants in the vaccine microenvironment. We hypothesized that vaccination induces dendritic cell activation in the dermal vaccination microenvironment but that regulatory processes may also limit the effectiveness of repeated vaccination. We evaluated biopsies from immunization sites in two clinical trials of melanoma patients. In one study (Mel38), patients received one injection with an adjuvant mixture alone, comprised of incomplete Freund's adjuvant (IFA) plus granulocyte-macrophage colony stimulating factor (GM-CSF). In a second study, patients received multiple vaccinations with melanoma peptide antigens plus IFA. Single injections with adjuvant alone induced dermal inflammatory infiltrates consisting of B cells, T cells, mature dendritic cells (DC) and vessels resembling high endothelial venules (HEV). These cellular aggregates usually lacked organization and were transient. In contrast, multiple repeated vaccinations with peptides in adjuvant induced more organized and persistent lymphoid aggregates containing separate B and T cell areas, mature DC, HEV-like vessels, and lymphoid chemokines. Within these structures, there are proliferating CD4+ and CD8+ T lymphocytes, as well as FoxP3+CD4+ lymphocytes, suggesting a complex interplay of lymphoid expansion and regulation within the dermal immunization microenvironment. Further study of the physiology of the vaccine site microenvironment promises to identify opportunities for enhancing cancer vaccine efficacy by modulating immune activation and regulation at the site of vaccination. PMID:22130163

  9. Aluminum hydroxide adjuvant induces macrophage differentiation towards a specialized antigen-presenting cell type.

    PubMed

    Rimaniol, Anne-Cécile; Gras, Gabriel; Verdier, François; Capel, Francis; Grigoriev, Vladimir B; Porcheray, Fabrice; Sauzeat, Elisabeth; Fournier, Jean-Guy; Clayette, Pascal; Siegrist, Claire-Anne; Dormont, Dominique

    2004-08-13

    Aluminum hydroxide (AlOOH) has been used for many years as a vaccine adjuvant, but little is known about its mechanism of action. We investigated in this study the in vitro effect of aluminum hydroxide adjuvant on isolated macrophages. We showed that AlOOH-stimulated macrophages contain large and persistent intracellular crystalline inclusions, a characteristic property of muscle infiltrated macrophages described in animal models of vaccine injection, as well as in the recently described macrophagic myofasciitis (MMF) histological reaction in humans. AlOOH-loaded macrophages exhibited phenotypical and functional modifications, as they expressed the classical markers of myeloid dendritic cells (HLA-DR(high)/CD86(high)/CD83(+)/CD1a(-)/CD14(-)) and displayed potent ability to induce MHC-II-restricted antigen specific memory responses, but kept a macrophage morphology. This suggests a key role of macrophages, in the reaction to AlOOH-adjuvanted vaccines and these mature antigen-presenting macrophages may therefore be of particular importance in the establishment of memory responses and in vaccination mechanisms leading to long-lasting protection. PMID:15297065

  10. Linking Estrogen-Induced Apoptosis With Decreases in Mortality Following Long-term Adjuvant Tamoxifen Therapy

    PubMed Central

    2014-01-01

    The impressive first results of the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) and the adjuvant Tamoxifen To offer more (aTTom) trials both demonstrate that 10 years of tamoxifen is superior to five years of treatment. Tamoxifen is a nonsteroidal antiestrogen that blocks estrogen-stimulated tumor growth. Paradoxically, mortality decreases dramatically only in the decade after long-term tamoxifen is stopped. It is proposed that the evolution and clonal selection of micrometastases that acquire tamoxifen resistance now become increasingly vulnerable to endogenous estrogen-induced apoptosis. Laboratory and clinical studies confirm the concept, and supporting clinical evidence from the estrogen-alone trial in the Women’s Health Initiative (WHI), demonstrate that long-term estrogen-deprived women given exogenous physiologic estrogen have a decreased incidence of breast cancer and decreased mortality. It is proposed that a natural process of apoptosis is recruited to execute the long-term survival benefit of stopping ten years of adjuvant tamoxifen, but only after clonal selection of vulnerable breast cancer cells in an estrogen-deprived environment. PMID:25269699

  11. Oxidative state and oxidative metabolism of the heart from rats with adjuvant-induced arthritis.

    PubMed

    Schubert, Amanda Caroline; Wendt, Mariana Marques Nogueira; de Sá-Nakanishi, Anacharis Babeto; Amado, Ciomar Aparecida Bersani; Peralta, Rosane Marina; Comar, Jurandir Fernando; Bracht, Adelar

    2016-06-01

    The aim of the present work was to investigate, in a more extensive way, the oxidative state and parameters related to energy metabolism of the heart tissue of rats using the model of adjuvant-induced arthritis. The latter is a model for the human arthritic disease. Measurements were done in the total tissue homogenate, isolated mitochondria and cytosolic fraction. The adjuvant-induced arthritis caused several modifications in the oxidative state of the heart which, in general, indicate an increased oxidative stress (+80% reactive oxygen species), protein damage (+53% protein carbonyls) and lipid damage (+63% peroxidation) in the whole tissue. The distribution of these changes over the various cell compartments was frequently unequal. For example, protein carbonyls were increased in the whole tissue and in the cytosol, but not in the mitochondria. No changes in GSH content of the whole tissue were found, but it was increased in the mitochondria (+33%) and decreased in the cytosol (-19%). The activity of succinate dehydrogenase was 77% stimulated by arthritis; the activities of glutamate dehydrogenase, isocitrate dehydrogenase and cytochrome c oxidase were diminished by 31, 25 and 35.3%, respectively. In spite of these alterations, no changes in the mitochondrial respiratory activity and in the efficiency of energy transduction were found. It can be concluded that the adjuvant-induced arthritis in rats causes oxidative damage to the heart with an unequal intracellular distribution. Compared to the liver and brain the modifications caused by arthritis in the heart are less pronounced on variables such as GSH levels and protein integrity. Possibly this occurs because the antioxidant system of the heart is less impaired by arthritis than that reported for the former tissues. Even so, the modifications caused by arthritis represent an imbalanced situation that probably contributes to the cardiac symptoms of the arthritis disease. PMID:27032477

  12. Antiarthritic activity of a polyherbal formulation against Freund's complete adjuvant induced arthritis in Female Wistar rats

    PubMed Central

    Petchi, R. Ramesh; Parasuraman, S.; Vijaya, C.; Gopala Krishna, S. V.; Kumar, M. Kiran

    2015-01-01

    Objectives: To formulate a polyherbal formulation and evaluate its antiarthritic activity against Freund's complete adjuvant induced arthritis in Female Wistar rats. Materials and Methods: Glycosmis pentaphylla, Tridax procumbens, and Mangifera indica are well-known plants available throughout India and they are commonly used for the treatment of various diseases including arthritis. The polyherbal formulation was formulated using the ethanol extracts of the stem bark of G. pentaphylla, whole plant of T. procumbens, and leaves of M. indica. The polyherbal formulation contains the ethanol extracts of G. pentaphylla, T. procumbens, and M. indica in the ratio of 2:2:1. The quality of the finished product was evaluated as per the World Health Organization's guidelines for the quality control of herbal materials. Arthritis was induced in female Wistar rats using Freund's complete adjuvant (FCA), and the antiarthritic effect of polyherbal formulation was studied at doses of 250 and 500 mg/kg. The effects were compared with those of indomethacin (10 mg/kg). At the end of the study, blood samples were collected for biochemical and hematological analysis. The radiological examination was carried out before terminating the study. Results: Polyherbal formulation showed significant antiarthritic activity at 250 and 500 mg/kg, respectively, and this effect was comparable with that of indomethacin. The antiarthritic activity of polyherbal formulation is supported by biochemical and hematological analysis. Conclusion: The polyherbal formulation showed signinicant antiarthritic activity against FCA-induced arthritis in female Wistar rats. PMID:26229343

  13. MHC class I-restricted cytotoxic lymphocyte responses induced by enterotoxin-based mucosal adjuvants.

    PubMed

    Simmons, C P; Mastroeni, P; Fowler, R; Ghaem-maghami, M; Lycke, N; Pizza, M; Rappuoli, R; Dougan, G

    1999-12-15

    The ability of enterotoxin-based mucosal adjuvants to induce CD8+ MHC class I-restricted CTL responses to a codelivered bystander Ag was examined. Escherichia coli heat-labile toxin (LT), or derivatives of LT carrying mutations in the A subunit (LTR72, LTK63), were tested in parallel with cholera toxin (CT) or a fusion protein consisting of the A1 subunit of CT fused to the Ig binding domain of Staphylococcus aureus protein A (called CTA1-DD). Intranasal (i.n.) immunization of C57BL/6 mice with CT, CTA1-DD, LT, LTR72, LTK63, but not rLT-B, elicited MHC class I-restricted CD8+ T cell responses to coadministered OVA or the OVA CTL peptide SIINFEKL (OVA257-264). CT, LT, and LTR72 also induced CTL responses to OVA after s.c. or oral coimmunization whereas LTK63 only activated responses after s.c. coimmunization. rLT-B was unable to adjuvant CTL responses to OVA or OVA257-264 administered by any route. Mice treated with an anti-CD4 mAb to deplete CD4+ T cells mounted significant OVA-specific CTL responses after i.n. coadministration of LT with OVA or OVA257-264. Both 51Cr release assays and IFN-gamma enzyme-linked immunospot assays indicated that IFN-gamma-/- and IL-12 p40-/- gene knockout mice developed CTL responses equivalent to those detected in normal C57BL/6 mice. The results highlight the versatility of toxin-based adjuvants and suggest that LT potentiates CTL responses independently of IL-12 and IFN-gamma and probably by a mechanism unrelated to cross-priming. PMID:10586042

  14. Therapeutic Effect of Ficus lacor Aerial Roots of Various Fractions on Adjuvant-Induced Arthritic Rats

    PubMed Central

    Sindhu, Rakesh K.; Arora, Sandeep

    2013-01-01

    The present study was carried out to evaluate antiarthritic potential and phytochemical screening of various extracts of Ficus lacor aerial roots. The antiarthritic activity was evaluated by adjuvant-induced arthritis at the dose of 50 and 100 mg/kg body weight and the standard drug used was indomethacin. The extracts administered in higher doses reduced the lesions to a greater extent showing a dose-dependent decrease in lesions comparable with standard drug indomethacin. The extracts of FLPE and FLET showed significant increase in body weight as compared to arthritic control group as well as an increase in liver weight, a decrease in liver weight, and an increase in spleen weight in arthritis control. The extracts of FLPE and FLET showed significant decrease in WBC count, increase in hemoglobin contents, and RBC count as compared to control group. FLEA and FLCF were not able to produce a significant effect. There was significant reduction in production of IL-1 and TNF-α level between model group and control group in serum. In conclusion, we demonstrate that, at 100 mg/kg body weight, doses of FLPE and PLET extracts were highly effective in preventing and suppressing the development of adjuvant-induced arthritis. PMID:24167737

  15. Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome) in commercial sheep.

    PubMed

    Luján, Lluís; Pérez, Marta; Salazar, Eider; Álvarez, Neila; Gimeno, Marina; Pinczowski, Pedro; Irusta, Silvia; Santamaría, Jesús; Insausti, Nerea; Cortés, Yerzol; Figueras, Luis; Cuartielles, Isabel; Vila, Miguel; Fantova, Enrique; Chapullé, José Luis Gracia

    2013-07-01

    We describe a form of the autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome) in commercial sheep, linked to the repetitive inoculation of aluminum-containing adjuvants through vaccination. The syndrome shows an acute phase that affects less than 0.5% of animals in a given herd, it appears 2-6 days after an adjuvant-containing inoculation and it is characterized by an acute neurological episode with low response to external stimuli and acute meningoencephalitis, most animals apparently recovering afterward. The chronic phase is seen in a higher proportion of flocks, it can follow the acute phase, and it is triggered by external stimuli, mostly low temperatures. The chronic phase begins with an excitatory phase, followed by weakness, extreme cachexia, tetraplegia and death. Gross lesions are related to a cachectic process with muscular atrophy, and microscopic lesions are mostly linked to a neurodegenerative process in both dorsal and ventral column of the gray matter of the spinal cord. Experimental reproduction of ovine ASIA in a small group of repeatedly vaccinated animals was successful. Detection of Al(III) in tissues indicated the presence of aluminum in the nervous tissue of experimental animals. The present report is the first description of a new sheep syndrome (ovine ASIA syndrome) linked to multiple, repetitive vaccination and that can have devastating consequences as it happened after the compulsory vaccination against bluetongue in 2008. The ovine ASIA syndrome can be used as a model of other similar diseases affecting both human and animals. A major research effort is needed in order to understand its complex pathogenesis. PMID:23579772

  16. Adjuvant oils induce arthritis in the DA rat. I. Characterization of the disease and evidence for an immunological involvement.

    PubMed

    Kleinau, S; Erlandsson, H; Holmdahl, R; Klareskog, L

    1991-12-01

    An intradermal injection of Freund's incomplete adjuvant oil (FIA) without further additives was shown to induce erosive polyarthritis in dark Agouti (DA) rats, but not in Lewis rats. Histological examination revealed joint inflammation, first with polymorphonuclear cells and synovial hyperplasia, and subsequently, with multinucleated giant cells. Both constituents of FIA, mineral oil and Arlacel A, as well as Pristane oil were arthritogenic, whereas vegetable oil were not. Re-administration of adjuvant oil after recovery failed to induce arthritis, thus making possible a role of specific immunity in this new form of arthritis in rats. PMID:1812893

  17. Free radical scavenging activity of Cleome gynandra L. leaves on adjuvant induced arthritis in rats.

    PubMed

    Narendhirakannan, R T; Subramanian, S; Kandaswamy, M

    2005-08-01

    The generation of free radicals has been implicated in the causation of several diseases of known and unknown etiologies such as, rheumatoid arthritis, diabetes, cancer, etc., and compounds that can scavenge free radicals have great potential in ameliorating these disease processes. The present study was aimed to investigate the possible anti-oxidant potential of Cleome gynandra leaf extract at a dose of 150 mg/kg body weight for 30 days on adjuvant induced arthritis in experimental rats. Oral administration of C. gynandra leaf extract significantly increased the levels of lipid peroxides and activities of catalase, glutathione peroxidase and decreased the levels of reduced glutathione and superoxide dismutase activity in arthritis induced rats. The free radical scavenging activity of the plant was further evidenced by histological observations made on the limb tissue. The presence of biologically active ingredients and vital trace elements in the leaves readily account for free radical scavenging property of C. gynandra. PMID:16132687

  18. Cord factor and peptidoglycan recapitulate the Th17-promoting adjuvant activity of mycobacteria through Mincle/CARD9 signaling and the inflammasome

    PubMed Central

    Shenderov, Kevin; Barber, Daniel L; Mayer-Barber, Katrin D; Gurcha, Sudagar S; Jankovic, Dragana; Feng, Carl G; Oland, Sandy; Hieny, Sara; Caspar, Pat; Yamasaki, Sho; Lin, Xin; Ting, Jenny P-Y; Trinchieri, Giorgio; Besra, Gurdyal S; Cerundolo, Vincenzo; Sher, Alan

    2013-01-01

    Although adjuvants are critical vaccine components, their modes of action are poorly understood. Here, we investigated the mechanisms by which the heat-killed mycobacteria in complete Freund’s adjuvant (CFA) promote T helper 17 (Th17) CD4+ T cell responses. We found that IL-17 secretion by CD4+ T cells following CFA immunization requires MyD88 and IL-1β/IL-1 receptor (IL-1R) signaling. Through measurement of antigen-specific responses after adoptive transfer of OTII cells, we confirmed that MyD88-dependent signaling controls Th17 differentiation rather than simply production of IL-17. Additional experiments showed that CFA-induced Th17 differentiation involves IL-1β processing by the inflammasome, as mice lacking caspase 1, ASC, or NLRP3 exhibit partially defective responses after immunization. Biochemical fractionation studies further revealed that peptidoglycan is the major component of heat-killed mycobacteria responsible for inflammasome activation. By assaying Il1b transcripts in the injection site skin of CFA-immunized mice, we found that signaling through the adaptor molecule CARD9 plays a major role in triggering pro-IL-1β expression. Moreover, we demonstrated that recognition of the mycobacterial glycolipid trehalose dimycolate (cord factor) by the C type lectin receptor mincle partially explains this CARD9 requirement. Importantly, purified peptidoglycan and cord factor administered in mineral oil synergized to recapitulate the Th17-promoting activity of CFA, and, as expected, this response was diminished in caspase 1-and CARD9-deficient mice. Taken together, these findings suggest a general strategy for the rational design of Th17-skewing adjuvants by combining agonists of the CARD9 pathway with inflammasome activators. PMID:23630357

  19. Regression of Adjuvant-Induced Arthritis in Rats Following Bone Marrow Transplantation

    NASA Astrophysics Data System (ADS)

    van Bekkum, Dirk W.; Bohre, Els P. M.; Houben, Paul F. J.; Knaan-Shanzer, Shoshan

    1989-12-01

    Total body irradiation followed by bone marrow transplantation was found to be an effective treatment for adjuvant arthritis induced in rats. This treatment is most effective when applied shortly after the clinical manifestation of arthritis--i.e., 4-7 weeks after administration of Mycobacterium tuberculosis. Transplantation of bone marrow at a later stage results in a limited recovery, in that the inflammatory reaction regresses but the newly formed excessive bone is not eliminated. Local irradiation of the affected joints had no effect on the disease. It could also be excluded that the recovery of arthritis following marrow transplantation is due to lack of available antigen. Transplantation of syngeneic bone marrow is as effective as that of allogeneic bone marrow from a rat strain that is not susceptible to induction of adjuvant arthritis. The beneficial effect of this treatment cannot be ascribed to the immunosuppressive effect of total body irradiation, since treatment with the highly immunosuppressive drug Cyclosporin A resulted in a regression of the joint swelling but relapse occurred shortly after discontinuation of the treatment.

  20. Paradoxical effects of tumour necrosis factor-α in adjuvant-induced arthritis

    PubMed Central

    Williams, Richard O

    2008-01-01

    Anti-tumour necrosis factor (TNF)α therapy is highly effective in rheumatoid arthritis and it is surprising, therefore, that a recent study showed that intraperitoneal administration of recombinant TNFα reduced the severity of adjuvant-induced arthritis and decreased IFNγ expression in cultured draining lymph node cells. Furthermore, in untreated arthritic rats, maximal TNFα expression in draining lymph node cells coincided with spontaneous disease remission, suggesting a role for endogenous TNFα in recovery from arthritis. If confirmed in further studies, these findings suggest that, in addition to its well-established pro-inflammatory properties, TNFα may also play a disease-limiting role in this model of rheumatoid arthritis by suppressing effector T cell responses. PMID:18564403

  1. Mechanism of Xinfeng Capsule on Adjuvant-Induced Arthritis via Analysis of Urinary Metabolomic Profiles

    PubMed Central

    Jiang, Hui; Liu, Jian; Wang, Ting; Gao, Jia-rong; Sun, Yue; Huang, Chuan-bing; Meng, Mei; Qin, Xiu-juan

    2016-01-01

    We aimed to explore the potential effects of Xinfeng capsule (XFC) on urine metabolic profiling in adjuvant-induced arthritis (AA) rats by using gas chromatography time-of-flight mass spectrometry (GC-TOF/MS). GC-TOF/MS technology was combined with multivariate statistical approaches, such as principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal projections to latent structures discriminant analysis (OPLS-DA). These methods were used to distinguish the healthy group, untreated group, and XFC treated group and elucidate potential biomarkers. Nine potential biomarkers such as hippuric acid, adenine, and L-dopa were identified as potential biomarkers, indicating that purine metabolism, fat metabolism, amino acid metabolism, and energy metabolism were disturbed in AA rats. This study demonstrated that XFC is efficacious for RA and explained its potential metabolomics mechanism. PMID:26989506

  2. TLR9-adjuvanted pneumococcal conjugate vaccine induces antibody-independent memory responses in HIV-infected adults.

    PubMed

    Offersen, Rasmus; Melchjorsen, Jesper; Paludan, Søren R; Østergaard, Lars; Tolstrup, Martin; Søgaard, Ole S

    2012-08-01

    HIV-patients have excess of pneumococcal infection. We immunized 40 HIV-patients twice with pneumococcal conjugate vaccine (Prevnar, Pfizer) +/- a TLR9 agonist (CPG 7909). Peripheral blood mononuclear cells were stimulated with pneumococcal polysaccharides and cytokine concentrations measured. The CPG 7909 adjuvant group had significantly higher relative cytokine responses than the placebo group for IL-1β, IL-2R, IL-6, IFN-γ and MIP-β, which, did not correlate with IgG antibody responses. These findings suggests that CPG 7909 as adjuvant to pneumococcal conjugate vaccine induces cellular memory to pneumococcal polysaccharides in HIV-patients, independently of the humoral response. PMID:22854665

  3. Inhibition of HIF-1{alpha} activity by BP-1 ameliorates adjuvant induced arthritis in rats

    SciTech Connect

    Shankar, J.; Thippegowda, P.B.; Kanum, S.A.

    2009-09-18

    Rheumatoid arthritis (RA) is a chronic inflammatory, angiogenic disease. Inflamed synovitis is a hallmark of RA which is hypoxic in nature. Vascular endothelial growth factor (VEGF), one of the key regulators of angiogenesis, is overexpressed in the pathogenesis of RA. VEGF expression is regulated by hypoxia-inducible factor-1{alpha} (HIF-1{alpha}), a master regulator of homeostasis which plays a pivotal role in hypoxia-induced angiogenesis. In this study we show that synthetic benzophenone analogue, 2-benzoyl-phenoxy acetamide (BP-1) can act as a novel anti-arthritic agent in an experimental adjuvant induced arthritis (AIA) rat model by targeting VEGF and HIF-1{alpha}. BP-1 administered hypoxic endothelial cells and arthritic animals clearly showed down regulation of VEGF expression. Further, BP-1 inhibits nuclear translocation of HIF-1{alpha}, which in turn suppresses transcription of the VEGF gene. These results suggest a further possible clinical application of the BP-1 derivative as an anti-arthritic agent in association with conventional chemotherapeutic agents.

  4. The combination of ISCOMATRIX adjuvant and TLR agonists induces regression of established solid tumors in vivo.

    PubMed

    Silva, Anabel; Mount, Adele; Krstevska, Karoline; Pejoski, David; Hardy, Matthew P; Owczarek, Catherine; Scotney, Pierre; Maraskovsky, Eugene; Baz Morelli, Adriana

    2015-03-01

    The development of therapeutic vaccines for treatment of established cancer has proven challenging. Cancer vaccines not only need to induce a robust tumor Ag-specific immune response but also need to overcome the tolerogenic and immunosuppressive microenvironments that exist within many solid cancers. ISCOMATRIX adjuvant (ISCOMATRIX) is able to induce both tumor Ag-specific cellular and Ab responses to protect mice against tumor challenge, but this is insufficient to result in regression of established solid tumors. In the current study, we have used B16-OVA melanoma, Panc-OVA pancreatic, and TRAMP-C1 prostate cancer mouse tumor models to test therapeutic efficacy of ISCOMATRIX vaccines combined with other immune modulators. The coadministration of an ISCOMATRIX vaccine with the TLR3 agonist, polyinosinic-polycytidylic acid, and TLR9 agonist, CpG, reduced tumor growth in all tumor models and the presence of ISCOMATRIX in the formulation was critical for the therapeutic efficacy of the vaccine. This vaccine combination induced a robust and multifunctional CD8(+) T cell response. Therapeutic protection required IFN-γ and CD8(+) T cells, whereas NK and CD4(+) T cells were found to be redundant. ISCOMATRIX vaccines combined with TLR3 and TLR9 agonists represent a promising cancer immunotherapy strategy. PMID:25646304

  5. The codon-optimization of cfaE gene and evaluating its high expression capacity and conserved immunogenicity in Escherichia coli.

    PubMed

    Mansouri, Maysam; Mousavy, Seyed Jafar; Ehsaei, Zahra; Nazarian, Shahram; Zali, Mohammad Reza; Moazzeni, Seyed Mohammad

    2013-05-01

    Enterotoxigenic Escherichia coli (ETEC) is the most common cause of children diarrhea in the world. Adhesion of ETEC to small intestine is an important virulence trait. One of the most prevalent colonization factors (CFs) in human is CFA/I fimbriae and CfaE which is the required binding factor for adhesion of ETEC to intestinal mucosa. We optimized cfaE gene codons according to codon bias of E. coli to achieve a high level of recombinant protein expression. The optimized gene was expressed in E. coli and rCFaE protein was used for mice immunization. Blocking activity of the obtained antibody was examined by microplate agglutination inhibition test. SDS-PAGE analysis indicated that the optimized sequence of cfaE produces a suitable amount of rCFaE in comparison with native gene sequence. This optimized rCFaE protein could induces strong humoral response in mice and the antibody obtained against rCFaE inhibited the adhesion of ETEC to human group A erythrocytes. It is concluded that codon optimization is a useful approach for obtaining large quantities of recombinant rCFaE protein. With regard to the results of hemagglutination inhibition test, codon optimization and increased production of recombinant protein expressed in E. coli did not affect the immunogenicity potential of CFaE. PMID:23453276

  6. CD226 as a genetic adjuvant to enhance immune efficacy induced by Ag85A DNA vaccination.

    PubMed

    Li, Yan; Yang, Fangli; Zhu, Junfeng; Sang, Lixuan; Han, Xue; Wang, Danan; Shan, Fengping; Li, Shengjun; Sun, Xun; Lu, Changlong

    2015-03-01

    Antigen-85A (Ag85A) is one of the major proteins secreted by Mycobacterium tuberculosis. Many studies on animal models have shown that vaccination with the recombinant Ag85A-DNA or Ag85A protein induces powerful immune response. However, these vaccines cannot generate sufficient protective immunity in the systemic compartment. CD226, a member of the immunoglobulin superfamily, is expressed in the majority of NK cells, T cells, monocytes, and platelets, and can be served as a co-stimulator that contributes to multiple innate and adaptive responses. However, there has been no study where either CD226 protein or DNA has been used as an adjuvant for vaccine development. The aim of this study was to develop a novel Ag85A DNA vaccine with CD226 as the genetic adjuvant to increase the immune efficacy induced by Ag85A. Oral vaccination with pcDNA3.1-Ag85A-CD226 DNA induced potent immune responses in mice. CD226 was an effective genetic adjuvant that improved the immune efficacy induced by Ag85A and enhanced the activity of cytotoxic T lymphocytes (CTL) and NK cells in mice. Th1 dominant cytokines (i.e. IL-2, IFN-γ and TNF-α), cellular immunity (i.e. CD4(+)IFN-γ(+)T cells and CD8(+)IFN-γ(+)T cells in splenocytes) and MLNs were also significantly elevated by pcDNA3.1-Ag85A-CD226 DNA vaccination. Our results suggest that CD226 is an effective adjuvant to enhance the immune efficacy induced by Ag85A. Our findings provide a new strategy for the development of a DNA vaccine co-expressing Ag85A and CD226. PMID:25582686

  7. A Nomogram for Predicting the Benefit of Adjuvant Cytokine-Induced Killer Cell Immunotherapy in Patients with Hepatocellular Carcinoma

    PubMed Central

    Pan, Qiu-Zhong; Wang, Qi-Jing; Dan, Jia-Qiang; Pan, Ke; Li, Yong-Qiang; Zhang, Yao-Jun; Zhao, Jing-Jing; Weng, De-Sheng; Tang, Yan; Huang, Li-Xi; He, Jia; Chen, Shi-Ping; Ke, Miao-La; Chen, Min-Shan; Wicha, Max S.; Chang, Alfred E.; Zeng, Yi-Xin; Li, Qiao; Xia, Jian-Chuan

    2015-01-01

    The benefits of adjuvant cytokine-induced killer (CIK) cell immunotherapy for hepatocellular carcinoma (HCC) remain mixed among patients. Here, we constructed a prognostic nomogram to enable individualized predictions of survival benefit of adjuvant CIK cell treatment for HCC patients. Survival analysis showed that the median overall survival (OS) and progression-free survival (PFS) for patients in the hepatectomy/CIK combination group were 41 and 16 months, respectively, compared to 28 and 12 months for patients in the hepatectomy alone group (control). Based on multivariate analysis of the entire cohort, independent factors for OS were tumor size, tumor capsule, pathological grades, total bilirubin, albumin, prothrombin time, alpha-fetoprotein, and tumor number, which were incorporated into the nomogram. The survival prediction model performed well, as assessed by the c-index and calibration curve. Internal validation revealed a c-index of 0.698, which was significantly greater than the c-index value of the TNM (tumor–node–metastasis) staging systems of 0.634. The calibration curves fitted well. In conclusions, our developed nomogram resulted in more accurate individualized predictions of the survival benefit from adjuvant CIK cell treatment after hepatectomy. The model may provide valuable information to aid in the decision making regarding the application of adjuvant CIK cell immunotherapy. PMID:25776856

  8. Cord factor and peptidoglycan recapitulate the Th17-promoting adjuvant activity of mycobacteria through mincle/CARD9 signaling and the inflammasome.

    PubMed

    Shenderov, Kevin; Barber, Daniel L; Mayer-Barber, Katrin D; Gurcha, Sudagar S; Jankovic, Dragana; Feng, Carl G; Oland, Sandy; Hieny, Sara; Caspar, Pat; Yamasaki, Sho; Lin, Xin; Ting, Jenny P-Y; Trinchieri, Giorgio; Besra, Gurdyal S; Cerundolo, Vincenzo; Sher, Alan

    2013-06-01

    Although adjuvants are critical vaccine components, their modes of action are poorly understood. In this study, we investigated the mechanisms by which the heat-killed mycobacteria in CFA promote Th17 CD4(+) T cell responses. We found that IL-17 secretion by CD4(+) T cells following CFA immunization requires MyD88 and IL-1β/IL-1R signaling. Through measurement of Ag-specific responses after adoptive transfer of OTII cells, we confirmed that MyD88-dependent signaling controls Th17 differentiation rather than simply production of IL-17. Additional experiments showed that CFA-induced Th17 differentiation involves IL-1β processing by the inflammasome, as mice lacking caspase-1, ASC, or NLRP3 exhibit partially defective responses after immunization. Biochemical fractionation studies further revealed that peptidoglycan is the major component of heat-killed mycobacteria responsible for inflammasome activation. By assaying Il1b transcripts in the injection site skin of CFA-immunized mice, we found that signaling through the adaptor molecule caspase activation and recruitment domain 9 (CARD9) plays a major role in triggering pro-IL-1β expression. Moreover, we demonstrated that recognition of the mycobacterial glycolipid trehalose dimycolate (cord factor) by the C-type lectin receptor mincle partially explains this CARD9 requirement. Importantly, purified peptidoglycan and cord factor administered in mineral oil synergized to recapitulate the Th17-promoting activity of CFA, and, as expected, this response was diminished in caspase-1- and CARD9-deficient mice. Taken together, these findings suggest a general strategy for the rational design of Th17-skewing adjuvants by combining agonists of the CARD9 pathway with inflammasome activators. PMID:23630357

  9. Glutaminase Increases in Rat Dorsal Root Ganglion Neurons after Unilateral Adjuvant-Induced Hind Paw Inflammation

    PubMed Central

    Hoffman, E. Matthew; Zhang, Zijia; Schechter, Ruben; Miller, Kenneth E.

    2016-01-01

    Glutamate is a neurotransmitter used at both the peripheral and central terminals of nociceptive primary sensory neurons, yet little is known concerning regulation of glutamate metabolism during peripheral inflammation. Glutaminase (GLS) is an enzyme of the glutamate-glutamine cycle that converts glutamine into glutamate for neurotransmission and is implicated in producing elevated levels of glutamate in central and peripheral terminals. A potential mechanism for increased levels of glutamate is an elevation in GLS expression. We assessed GLS expression after unilateral hind paw inflammation by measuring GLS immunoreactivity (ir) with quantitative image analysis of L4 dorsal root ganglion (DRG) neurons after one, two, four, and eight days of adjuvant-induced arthritis (AIA) compared to saline injected controls. No significant elevation in GLS-ir occurred in the DRG ipsilateral to the inflamed hind paw after one or two days of AIA. After four days AIA, GLS-ir was elevated significantly in all sizes of DRG neurons. After eight days AIA, GLS-ir remained elevated in small (<400 µm2), presumably nociceptive neurons. Western blot analysis of the L4 DRG at day four AIA confirmed the elevated GLS-ir. The present study indicates that GLS expression is increased in the chronic stage of inflammation and may be a target for chronic pain therapy. PMID:26771651

  10. Lipid-Core Nanocapsules Improved Antiedematogenic Activity of Tacrolimus in Adjuvant-Induced Arthritis Model.

    PubMed

    Friedrich, Rossana B; Coradini, Karine; Fonseca, Francisco N; Guterres, Silvia S; Beck, Ruy C R; Pohlmann, Adriana R

    2016-02-01

    Despite significant technological advances, rheumatoid arthritis remains an incurable disease with great impact on the life quality of patients. We studied the encapsulation of tacrolimus in lipidcore nanocapsules (TAC-LNC) as a strategy to enhance its systemic anti-arthritic properties. TAC-LNC presented unimodal distribution of particles with z-average diameter of 212 +/- 11, drug content close to the theoretical value (0.80 mg mL(-1)), and 99.43% of encapsulation efficiency. An in vitro sustained release was determined for TAC-LNC with anomalous transport mechanism (n = 0.61). In vivo studies using an arthritis model induced by Complete Freund's Adjuvant demonstrated that the animals treated with TAC-LNC presented a significantly greater inhibition of paw oedema after intraperitoneal administration. Furthermore, the encapsulation of TAC in lipid-core nanocapsules was potentially able to prevent hyperglycemia in the animals. In conclusion, TAC-LNC was prepared with 100% yield of nanoscopic particles having satisfactory characteristics for systemic use. This formulation represents a promising strategy to the treatment of rheumatoid arthritis in the near future. PMID:27433576

  11. Intraarticular gene transfer of SPRY2 suppresses adjuvant-induced arthritis in rats.

    PubMed

    Zhang, Wei; Zhu, Jingying; Du, Zhiyan; Yu, Jiyun; Xu, Yuanji; Wang, Fang

    2015-08-01

    AKT and ERK pathways have been implicated as therapeutic targets for human rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) inhibition, and thus RA treatment. Sprouty2 (SPRY2) has been known as a tumor suppressor by blocking both ERK and AKT signaling cascades. Whether SPRY2 can function as a suppressor of tumor-like inflammatory FLS and RA through negatively regulating AKT and ERK activation has not been reported. The purpose of this study was to determine whether SPRY2 might have antiarthritic effects in experimental animal model of RA. We first determined that expression of SPRY2 mRNA was decreased in FLS from patients with RA compared with patients with osteoarthritis (OA). Further studies demonstrated that intraarticular gene transfer with AdSPRY2, the recombinant adenovirus containing SPRY2 complementary DNA, resulted in a significant suppression of rat adjuvant-induced arthritis (AIA) compared with the control AdGFP, the adenoviral vector encoding green fluorescent protein, as reflected in both clinical and histological observations. AdSPRY2 suppressed the production of proinflammatory cytokines and matrix metalloproteinases (MMPs), and the activation of ERK and AKT signals in AIA ankle joints. These results suggest that using SPRY2 to block the AKT and ERK pathways effectively reduces the inflammatory responses and arthritic progression in AIA. Thus, the development of an immunoregulatory strategy based on SPRY2 may therefore have therapeutic potential in the treatment of RA. PMID:25935347

  12. Xanthones from Securidaca inappendiculata exert significant therapeutic efficacy on adjuvant-induced arthritis in mice.

    PubMed

    Zuo, Jian; Xia, Yan; Li, Xiang; Chen, Jian-Wei

    2014-06-01

    The study was designed to investigate effects of the xanthones from Securidaca inappendiculata on adjuvant-induced arthritis (AA) mice in vivo. Arthritis severity was evaluated by arthritic score, body weight loss, paw circumference, histological changes and hyperplasia of lymphatic tissues. Plasma samples were collected for estimation of interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-α), monocyte chemotactic protein 1 (MCP-1) and vascular endothelial growth factor (VEGF) using enzyme-linked immunosorbent assay method. The levels of glutathione (GSH), malondialdehyde (MDA), N-acetyl glucosaminidase (NAG) and sialic acid (SA) in liver were assessed by colorimetric method. Xanthones significantly ameliorated the severity of AA indicated by the physical parameters changes, and reverted the abnormal changes of MDA, GSH, NAG and SA in liver. Levels of IL-1, TNF-α, MCP-1 and VEGF reduced dramatically meanwhile. The effects of xanthones on AA were the outcome of the multitargets activities, and probably associated with NF-κB signaling pathway. PMID:24419745

  13. A Bacterial Flagellin, Vibrio vulnificus FlaB, Has a Strong Mucosal Adjuvant Activity To Induce Protective Immunity

    PubMed Central

    Lee, Shee Eun; Kim, Soo Young; Jeong, Byung Chul; Kim, Young Ran; Bae, Soo Jang; Ahn, Ouk Seon; Lee, Je-Jung; Song, Ho-Chun; Kim, Jung Mogg; Choy, Hyon E.; Chung, Sun Sik; Kweon, Mi-Na; Rhee, Joon Haeng

    2006-01-01

    Flagellin, the structural component of flagellar filament in various locomotive bacteria, is the ligand for Toll-like receptor 5 (TLR5) of host cells. TLR stimulation by various pathogen-associated molecular patterns leads to activation of innate and subsequent adaptive immune responses. Therefore, TLR ligands are considered attractive adjuvant candidates in vaccine development. In this study, we show the highly potent mucosal adjuvant activity of a Vibrio vulnificus major flagellin (FlaB). Using an intranasal immunization mouse model, we observed that coadministration of the flagellin with tetanus toxoid (TT) induced significantly enhanced TT-specific immunoglobulin A (IgA) responses in both mucosal and systemic compartments and IgG responses in the systemic compartment. The mice immunized with TT plus FlaB were completely protected from systemic challenge with a 200× minimum lethal dose of tetanus toxin. Radiolabeled FlaB administered into the nasal cavity readily reached the cervical lymph nodes and systemic circulation. FlaB bound directly to human TLR5 expressed on cultured epithelial cells and consequently induced NF-κB and interleukin-8 activation. Intranasally administered FlaB colocalized with CD11c as patches in putative dendritic cells and caused an increase in the number of TLR5-expressing cells in cervical lymph nodes. These results indicate that flagellin would serve as an efficacious mucosal adjuvant inducing protective immune responses through TLR5 activation. PMID:16369026

  14. Alum, an Aluminum Based Adjuvant, Induces Sjögren’s Syndrome-like Disorder in Mice

    PubMed Central

    Bagavant, Harini; Nandula, Seshagiri Rao; Kaplonek, Paulina; Rybakowska, Paulina D.; Deshmukh, Umesh S.

    2014-01-01

    Objective Adjuvant induced innate immune responses have been suspected to play a role in the initiation of certain autoimmune disorders. This study investigates the role of alum, an aluminum based adjuvant in the induction of Sjögren’s syndrome-like disorder in mice. Methods Inbred, female New Zealand Mixed (NZM) 2758 strain of mice were injected with alum. Control mice were treated similarly with PBS. Mice were monitored for salivary gland dysfunction by measuring pilocarpine induced salivation. Presence of lymphocytic infiltrates within the submandibular glands was studied by histopathology. Autoantibodies to Ro and La proteins were analyzed by ELISA and the presence of anti-nuclear antibodies (ANA) was analyzed by indirect immunofluorescence. Results By eight weeks after treatment, the saliva production in alum treated mice was significantly decreased in comparison to the PBS treated mice. This functional loss persisted till the termination of experiments at 20wks. The incidence and severity of sialoadenitis was significantly higher in the alum treated mice. Although there were no differences in the levels of anti-Ro/La autoantibodies in sera of alum and PBS treated groups, the alum group showed higher ANA reactivity. Conclusion In the NZM2758 mice, alum induces a Sjögren’s syndrome-like disorder that is characterized by chronic salivary gland dysfunction and the presence of lymphocytic infiltrates within the salivary glands. Thus, the potential of aluminum based adjuvants for induction of autoimmunity should be closely monitored in individuals genetically susceptible to developing autoimmune disorders. PMID:24739520

  15. Lymphoid abnormalities in rats with adjuvant-induced arthritis. I. Mitogen responsiveness and lymphokine synthesis.

    PubMed Central

    Gilman, S C; Daniels, J F; Wilson, R E; Carlson, R P; Lewis, A J

    1984-01-01

    Lewis rats injected in the hind paw with Mycobacterium butyricum develop a severe polyarthritis which shares certain features in common with rheumatoid arthritis in man. Spleen and peripheral blood mononuclear cells from rats with this form of arthritic disease proliferate poorly in vitro in response to concanavalin A (con A), phytohaemagglutinin (PHA), and pokeweed mitogen (PWM). The splenic hyporesponsiveness appears within four days of M. butyricum injection (three to five days prior to the development of detectable arthritis), reaches a peak 16-22 days following injection, and persists for at least 40 days. Buffalo strain rats injected with M. butyricum do not develop arthritis, and their spleen cells respond normally to con A, PHA, and PWM. In response to lipopolysaccharide (LPS) the synthesis of interleukin 1 (IL-1) by spleen or peritoneal macrophages from arthritic Lewis rats equalled or exceeded that of macrophages from normal rats. In contrast splenic T cells from arthritic rats produced reduced amounts of interleukin 2 (IL-2; T cell growth factor) in response to stimulation with PHA or con A. Moreover, con-A-activated spleen cells from arthritic rats failed to bind IL-2 and to respond to this growth factor with increased 3H-TdR uptake as did normal spleen cells. In-vitro treatment of 'arthritic' cells with 10(-5) M indomethacin did not restore to normal their reduced mitogen responsiveness, and spleen cells from normal and arthritic rats were equally sensitive to the inhibitory effects of prostaglandin E2 on con-A-induced proliferative responses. These results indicate that peripheral lymphoid function is compromised in rats with adjuvant-induced arthritis and that this functional deficit is mediated by aberrant synthesis of and response to IL-2 by T cells of arthritic animals. PMID:6335388

  16. Breaking Tolerance in Transgenic Mice Expressing the Human TSH Receptor A-Subunit: Thyroiditis, Epitope Spreading and Adjuvant as a ‘Double Edged Sword’

    PubMed Central

    McLachlan, Sandra M.; Aliesky, Holly A.; Chen, Chun-Rong; Chong, Gao; Rapoport, Basil

    2012-01-01

    Transgenic mice with the human thyrotropin-receptor (TSHR) A-subunit targeted to the thyroid are tolerant of the transgene. In transgenics that express low A-subunit levels (Lo-expressors), regulatory T cell (Treg) depletion using anti-CD25 before immunization with adenovirus encoding the A-subunit (A-sub-Ad) breaks tolerance, inducing extensive thyroid lymphocytic infiltration, thyroid damage and antibody spreading to other thyroid proteins. In contrast, no thyroiditis develops in Hi-expressor transgenics or wild-type mice. Our present goal was to determine if thyroiditis could be induced in Hi-expressor transgenics using a more potent immunization protocol: Treg depletion, priming with Complete Freund's Adjuvant (CFA) + A-subunit protein and further Treg depletions before two boosts with A-sub-Ad. As controls, anti-CD25 treated Hi- and Lo-expressors and wild-type mice were primed with CFA+ mouse thyroglobulin (Tg) or CFA alone before A-sub-Ad boosting. Thyroiditis developed after CFA+A-subunit protein or Tg and A-sub-Ad boosting in Lo-expressor transgenics but Hi- expressors (and wild-type mice) were resistant to thyroiditis induction. Importantly, in Lo-expressors, thyroiditis was associated with the development of antibodies to the mouse TSHR downstream of the A-subunit. Unexpectedly, we observed that the effect of bacterial products on the immune system is a “double-edged sword”. On the one hand, priming with CFA (mycobacteria emulsified in oil) plus A-subunit protein broke tolerance to the A-subunit in Hi-expressor transgenics leading to high TSHR antibody levels. On the other hand, prior treatment with CFA in the absence of A-subunit protein inhibited responses to subsequent immunization with A-sub-Ad. Consequently, adjuvant activity arising in vivo after bacterial infections combined with a protein autoantigen can break self-tolerance but in the absence of the autoantigen, adjuvant activity can inhibit the induction of immunity to autoantigens (like the

  17. Sjögren's syndrome: another facet of the autoimmune/inflammatory syndrome induced by adjuvants (ASIA).

    PubMed

    Colafrancesco, S; Perricone, C; Priori, R; Valesini, G; Shoenfeld, Y

    2014-06-01

    Recently, a new syndrome, namely the "Autoimmune/inflammatory syndrome induced by adjuvants" (ASIA) has been defined. In this syndrome different conditions characterized by common signs and symptoms and induced by the presence of an adjuvant are included. The adjuvant is a substance capable of boosting the immune response and of acting as a trigger in the development of autoimmune diseases. Post-vaccination autoimmune phenomena represent a major issue of ASIA. Indeed, despite vaccines represent a mainstay in the improvement of human health, several of these have been implicated as a potential trigger for autoimmune diseases. Sjogren's Syndrome (SjS) is a systemic chronic autoimmune inflammatory disease characterized by the presence of an inflammatory involvement of exocrine glands accompanied by systemic manifestations. Own to the straight association between infectious agents exposure (mainly viruses) and sicca syndrome development, the possible link between vaccine and SjS is not surprising. Indeed, a few cases of SjS following vaccine delivery have been reported. At the same extent, the induction of SjS following silicone exposure has been described too. Thus, the aim of this review was to focus on SjS and its possible development following vaccine or silicone exposure in order to define another possible facet of the ASIA syndrome. PMID:24774584

  18. Effects of Apium graveolens Extract on the Oxidative Stress in the Liver of Adjuvant-Induced Arthritic Rats.

    PubMed

    Sukketsiri, Wanida; Chonpathompikunlert, Pennapa; Tanasawet, Supita; Choosri, Nutjanat; Wongtawatchai, Tulaporn

    2016-06-01

    Apium graveolens Linn. (Apiaceae) is an indigenous plant of the North and South Americas, Southern Europe, and Asia and has been widely used as a food or a traditional medicine for treatment of inflammation and arthritis. The purpose of this study was to investigate the antioxidant effects of a methanolic extract of A. graveolens (AGE) against liver oxidative stress in an adjuvant-induced arthritic rat model. The AGE (250, 500, and 1,000 mg/kg) was given orally for 24 consecutive days after induction by injecting complete Freund's adjuvant. Liver and spleen weights were recorded. The superoxide anion level, total peroxide (TP), glutathione peroxidase (GPx) activity, superoxide dismutase (SOD) activity, total antioxidant status, and oxidative stress index (OSI) were also measured. AGE treatment significantly decreased the levels of the superoxide anion, TP, and OSI whereas the GPx and SOD activities significantly increased in the liver of the arthritic rats. These results indicated that AGE showed an ameliorative effect against liver oxidative stress in adjuvant-induced arthritic rats by reducing the generation of liver free radicals and increasing the liver antioxidant enzyme activity. PMID:27390722

  19. Protective Immunity and Reduced Renal Colonization Induced by Vaccines Containing Recombinant Leptospira interrogans Outer Membrane Proteins and Flagellin Adjuvant

    PubMed Central

    Monaris, D.; Sbrogio-Almeida, M. E.; Dib, C. C.; Canhamero, T. A.; Souza, G. O.; Vasconcellos, S. A.; Ferreira, L. C. S.

    2015-01-01

    Leptospirosis is a global zoonotic disease caused by different Leptospira species, such as Leptospira interrogans, that colonize the renal tubules of wild and domestic animals. Thus far, attempts to develop effective leptospirosis vaccines, both for humans and animals, have failed to induce immune responses capable of conferring protection and simultaneously preventing renal colonization. In this study, we evaluated the protective immunity induced by subunit vaccines containing seven different recombinant Leptospira interrogans outer membrane proteins, including the carboxy-terminal portion of the immunoglobulinlike protein A (LigAC) and six novel antigens, combined with aluminum hydroxide (alum) or Salmonella flagellin (FliC) as adjuvants. Hamsters vaccinated with the different formulations elicited high antigen-specific antibody titers. Immunization with LigAC, either with alum or flagellin, conferred protective immunity but did not prevent renal colonization. Similarly, animals immunized with LigAC or LigAC coadministered with six leptospiral proteins with alum adjuvant conferred protection but did not reduce renal colonization. In contrast, immunizing animals with the pool of seven antigens in combination with flagellin conferred protection and significantly reduced renal colonization by the pathogen. The present study emphasizes the relevance of antigen composition and added adjuvant in the efficacy of antileptospirosis subunit vaccines and shows the complex relationship between immune responses and renal colonization by the pathogen. PMID:26108285

  20. Effects of Apium graveolens Extract on the Oxidative Stress in the Liver of Adjuvant-Induced Arthritic Rats

    PubMed Central

    Sukketsiri, Wanida; Chonpathompikunlert, Pennapa; Tanasawet, Supita; Choosri, Nutjanat; Wongtawatchai, Tulaporn

    2016-01-01

    Apium graveolens Linn. (Apiaceae) is an indigenous plant of the North and South Americas, Southern Europe, and Asia and has been widely used as a food or a traditional medicine for treatment of inflammation and arthritis. The purpose of this study was to investigate the antioxidant effects of a methanolic extract of A. graveolens (AGE) against liver oxidative stress in an adjuvant-induced arthritic rat model. The AGE (250, 500, and 1,000 mg/kg) was given orally for 24 consecutive days after induction by injecting complete Freund’s adjuvant. Liver and spleen weights were recorded. The superoxide anion level, total peroxide (TP), glutathione peroxidase (GPx) activity, superoxide dismutase (SOD) activity, total antioxidant status, and oxidative stress index (OSI) were also measured. AGE treatment significantly decreased the levels of the superoxide anion, TP, and OSI whereas the GPx and SOD activities significantly increased in the liver of the arthritic rats. These results indicated that AGE showed an ameliorative effect against liver oxidative stress in adjuvant-induced arthritic rats by reducing the generation of liver free radicals and increasing the liver antioxidant enzyme activity. PMID:27390722

  1. Protective Immunity and Reduced Renal Colonization Induced by Vaccines Containing Recombinant Leptospira interrogans Outer Membrane Proteins and Flagellin Adjuvant.

    PubMed

    Monaris, D; Sbrogio-Almeida, M E; Dib, C C; Canhamero, T A; Souza, G O; Vasconcellos, S A; Ferreira, L C S; Abreu, P A E

    2015-08-01

    Leptospirosis is a global zoonotic disease caused by different Leptospira species, such as Leptospira interrogans, that colonize the renal tubules of wild and domestic animals. Thus far, attempts to develop effective leptospirosis vaccines, both for humans and animals, have failed to induce immune responses capable of conferring protection and simultaneously preventing renal colonization. In this study, we evaluated the protective immunity induced by subunit vaccines containing seven different recombinant Leptospira interrogans outer membrane proteins, including the carboxy-terminal portion of the immunoglobulinlike protein A (LigA(C)) and six novel antigens, combined with aluminum hydroxide (alum) or Salmonella flagellin (FliC) as adjuvants. Hamsters vaccinated with the different formulations elicited high antigen-specific antibody titers. Immunization with LigA(C), either with alum or flagellin, conferred protective immunity but did not prevent renal colonization. Similarly, animals immunized with LigA(C) or LigA(C) coadministered with six leptospiral proteins with alum adjuvant conferred protection but did not reduce renal colonization. In contrast, immunizing animals with the pool of seven antigens in combination with flagellin conferred protection and significantly reduced renal colonization by the pathogen. The present study emphasizes the relevance of antigen composition and added adjuvant in the efficacy of antileptospirosis subunit vaccines and shows the complex relationship between immune responses and renal colonization by the pathogen. PMID:26108285

  2. Trends in vaccine adjuvants.

    PubMed

    Schijns, Virgil E J C; Lavelle, Ed C

    2011-04-01

    Adjuvants are essential components of most clinically used vaccines. This is because the majority of nonliving vaccines are relatively poor inducers of adaptive immunity unless effective adjuvants are co-administered. Aluminum salts (alum) have been used as adjuvants with great success for almost a century and have been particularly effective at promoting protective humoral immunity. However, alum is not optimally effective for diseases where cell-mediated immunity is required for protection. Furthermore, adjuvants including oil-in-water emulsions have shown improved efficacy for avian influenza protection suggesting that even for diseases where humoral immunity can confer protection, there is scope for developing improved adjuvants. There have been major developments in antigen discovery over the past decade, which has accelerated the vaccine development process for new indications and this demands a new generation of adjuvants that can drive and specifically direct the desired immune responses. A number of systems are under investigation that combine different types of adjuvants into specific formulations with greater activity. Additionally, targeting of vaccines to specific immune cells shows great promise. In the case of cancer and chronic infectious diseases, it may be difficult to develop effective vaccines without blocking immune regulatory pathways, which impede cell-mediated responses. However, increased understanding of immunology and particularly the innate immune system is informing vaccine adjuvant research and consequently driving the development of novel and specifically directed vaccine adjuvant strategies. In this article we address the importance of adjuvants in vaccine development, the known mode of action of specific adjuvants and recent developments in this important field. PMID:21506650

  3. 2. Historic American Buildings Survey J. Alexander, (for CFA) Photographer, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    2. Historic American Buildings Survey J. Alexander, (for CFA) Photographer, 1971 DETAIL, MAIN ENTRANCE - Arthur C. Stanley House, 2370 Massachusetts Avenue Northwest, Washington, District of Columbia, DC

  4. Clonidine as an adjuvant to ropivacaine-induced supraclavicular brachial plexus block for upper limb surgeries

    PubMed Central

    Patil, Kalyani Nilesh; Singh, Noopur Dasmit

    2015-01-01

    Background and Aims: Ropivacaine is a new amide, long acting, pure S-enantiomer, local anesthetic, with differential blocking effect. The addition of clonidine to local anesthetic improves the quality of peripheral nerve blocks. This study was conducted to evaluate the effect of clonidine on characteristics of ropivacaine-induced supraclavicular brachial plexus block. Material and Methods: A total of 60 adult patients were randomly recruited to two groups of 30 each: Group I: 30 ml 0.75% ropivacaine + 1 ml normal saline. Group II: 30 ml 0.75% ropivacaine + 1 mcg/kg clonidine diluted to 1 ml with normal saline. Results: The onset of sensorimotor block was earlier in Group II (4.36 ± 0.81 min for sensory block and 9.83 ± 1.12 min for motor block) than in Group I (4.84 ± 0.65 min for sensory block and 10.85 ± 0.79 min for motor block). The duration of both sensory and motor block were significantly prolonged by clonidine (P < 0.001). The duration of analgesia was also prolonged in patients receiving clonidine (613.10 ± 51.797 min vs. 878.33 ± 89.955 min). Although incidence of hypotension and bradycardia was higher in Group II when compared to Group I, it was not clinically significant. Conclusions: Ropivacaine 0.75% is well-tolerated and provides effective surgical anesthesia as well as relief of postoperative pain. Clonidine as an adjuvant to ropivacaine significantly enhances the quality of supraclavicular brachial plexus block by faster onset, prolonged duration of sensory and motor block and improved postoperative analgesia, without associated adverse effects at the dose used. PMID:26330717

  5. Imaging of Carrageenan-Induced Local Inflammation and Adjuvant-Induced Systemic Arthritis with [11C]PBR28 PET

    PubMed Central

    Shao, Xia; Wang, Xueding; English, Sean J; Desmond, Timothy; Sherman, Phillip S; Quesada, Carole A; Piert, Morand R

    2013-01-01

    Introduction [11C]PBR28 binding to translocator protein (TSPO) was evaluated for imaging of acute and chronic inflammation using two established rat models. Methods Acute inflammation was induced by local Carrageenan-injection into the paw of Fisher 344 rats (model A). T-cell mediated adjuvant arthritis was induced by heat-inactivated Mycobacterium butyricum injection in Lewis rats (model B). Micro-PET scan was performed after injection of approximately 35 MBq [11C]PBR28. In model A, volumes of interest (VOIs) were defined in the paw of Fisher 344 rats (n=6) with contralateral sham treatment as control. For model B, VOIs were defined in the tail, sacroiliac joints, hips, knees and thigh muscles of M. butyricum treated animals (n=8) and compared with sham-treated controls (n=4). The peak 11C-PBR28 SUV (SUVpeak) and area under the curve (AUCSUV) of 60-minute time-activity data were calculated. Immunohistochemistry for CD68, a macrophage stain, was performed from paw tissues. In addition, the [11C]PBR28 cell uptake was measured in lipopolysaccharide (LPS)-stimulated and non-stimulated macrophage cultures. Results LPS-stimulated macrophages displayed dose-dependent increased [11C]PBR28 uptake, which was blocked by non-labeled PBR28. In both models, radiotracer uptake of treated lesions increased rapidly within minutes and displayed overall accumulative kinetics. The SUVpeak and AUCSUV of Carrageenan-treated paws was significantly increased compared to controls. Also, the [11C]PBR28 uptake ratio of Carrageenan-treated vs. sham-treated paw correlated significantly with CD68 staining ratios of the same animals. In adjuvant arthritis, significantly increased [11C]PBR28 SUVpeak and AUCSUV values were identified at the tail, knees, and sacroiliac joints, while no significant differences were identified in the lumbar spine and hips. Conclusions Based on our initial data, [11C]PBR28 PET appears to have potential for imaging of various inflammatory processes involving

  6. [Influenza vaccine and adjuvant].

    PubMed

    Nakayama, Tetsuo

    2011-01-01

    Adjuvant is originated from the Latin word "adjuvare" which means "help" in English to enhance the immunological responses when given together with antigens. The beginning of adjuvant was mineral oil which enhanced the immune response when it was given with inactivated Salmonella typhimurium. Aluminium salt was used to precipitate diphtheria toxoid and increased level of antibody response was demonstrated when administered with alum-precipitated antigens. Since 1930, aluminium salt has been used as DTaP (diphtheria-tetanus-acellular pertussis vaccine) adjuvant. Many candidates were tested for adjuvant activity but only aluminum salt is allowed to use for human vaccines. New adjuvant MF59, oil-in-water emulsion type, was developed for influenza vaccine for elderly (Fluad) and series of AS adjuvant are used for hepatitis B, pandemic flue, and human papiloma virus vaccines. Oil-adjuvanted influenza pandemic vaccines induced higher antibody response than alum-adjuvanted vaccine with higher incidence of adverse events, especially for local reactions. Alum-adjuvanted whole virion inactivated H5N1 vaccine was developed in Japan, and it induced relatively well immune responses in adults. When it applied for children, febrile reaction was noted in approximately 60% of the subjects, with higher antibodies. Recent investigation on innate immunity demonstrates that adjuvant activity is initiated from the stimulation on innate immunity and/or inflammasome, resulting in cytokine induction and antigen uptake by monocytes and macrophages. The probable reason for high incidence of febrile reaction should be investigated to develop a safe and effective influenza vaccine. PMID:22129866

  7. alpha-Galactosylceramide can act as a nasal vaccine adjuvant inducing protective immune responses against viral infection and tumor.

    PubMed

    Ko, Sung-Youl; Ko, Hyun-Jeong; Chang, Woo-Sung; Park, Se-Ho; Kweon, Mi-Na; Kang, Chang-Yuil

    2005-09-01

    alpha-Galactosylceramide (alpha-GalCer) is a ligand of invariant Valpha14+ NKT cells and is presented by CD1d molecule on APC. NKT cells produce a large amount of Th1 and Th2 cytokines in response to alpha-GalCer-presented APC. In this study, we assessed whether alpha-GalCer could act as an effective nasal vaccine adjuvant for mucosal vaccine that would be capable of inducing systemic as well as mucosal immune responses. When alpha-GalCer was administered with OVA via the intranasal route to C57BL/6 and BALB/c mice, significant OVA-specific mucosal secretory IgA, systemic IgG, and CTL responses were induced with mixed Th1 and Th2 cytokine profiles seen in both strains of mice. Interestingly, as BALB/c mice were intranasally immunized with PR8 hemagglutinin Ag isolated from influenza virus A/PR/8/34 together with alpha-GalCer, significant protection was afforded against influenza viral infection. When alpha-GalCer was coimmunized with a replication-deficient live adenovirus to BALB/c mice, it significantly induced both humoral and cellular immune responses. In addition, intranasal administration of OVA with alpha-GalCer showed complete protection against EG7 tumor challenge in C57BL/6. The adjuvant effects induced by intranasal coadministration with alpha-GalCer were blocked in CD1d-/- mice, indicating that the immune responses were exclusively mediated by CD1d molecule on APC. Most interestingly, intranasally coadministered alpha-GalCer activated naive T cells and triggered them to differentiate into functional effector T cells when CFSE-labeled OT-1 cells were adoptively transferred into syngeneic mice. Overall, our results are the first to show that alpha-GalCer can act as a nasal vaccine adjuvant inducing protective immune responses against viral infections and tumors. PMID:16116223

  8. The effect of curcumin and its nanoformulation on adjuvant-induced arthritis in rats

    PubMed Central

    Zheng, Zhaoling; Sun, YanHua; Liu, Ziliang; Zhang, Mingqin; Li, Chunqing; Cai, Hui

    2015-01-01

    Background Rheumatoid arthritis (RA), induced by the prolonged inappropriate inflammatory responses, is one of the most prevalent of all chronic inflammatory joint diseases. Curcumin (CM), a yellow hydrophobic polyphenol derived from the herb turmeric, has various pharmacological activities against many chronic diseases and acts by inhibiting cell proliferation and metastasis and downregulating various factors, including nuclear factor kappa B, interleukin-1β and TNF-α. Given the pathogenesis of RA, we hypothesized that the drug also has antiarthritic effects. The aims of the present study included the following: 1) examining the therapeutic effect of CM administered via intravenous (iv) injection on RA and 2) formulating the drug into oil–water nanoemulsions (Ns) to overcome the low oral bioavailability of CM and achieve oral delivery of the drug. Methods The effect of CM administered through iv injection on adjuvant-induced arthritis in rats was studied in terms of paw swelling, weight indices of the thymus and spleen, and pathological changes in nuclear factor kappa B expression and inflammatory cytokines. Methotrexate was used as a positive control. The CM-Ns were prepared using a high-pressure homogenizing method and characterized with respect to the particle size and morphology. The stability of the CM-Ns in simulated gastrointestinal (GI) fluids and in vitro release were also investigated. A pharmacokinetic study of the CM-Ns and suspensions in which the plasma levels were determined using an high performance liquid chromatography method and the pharmacokinetic parameters were calculated based on a statistical moment theory was also performed in rats. Results CM administered via iv injection had a therapeutic effect on RA similar to methotrexate. CM-Ns with a diameter of approximately 150 nm were successfully prepared, and the drug was well encapsulated into the Ns without degradation in simulated GI conditions. The area under the curve (AUC) and Cmax

  9. Protective efficacy evaluation induced by recombinant protein LHD-Sj23-GST of Schistosoma japonicum emulsified with three different adjuvants.

    PubMed

    Zhu, Z; Fu, Z; Zhang, M; Han, Y; Hong, Y; Li, D; Zhao, Z; Shi, Y; Li, X; Lin, J

    2012-06-01

    As a complement to chemotherapy and other control approaches, the development of an effective vaccine is necessary to combat Schistosomiasis japonica that remains a serious public health problem in China. In the present study, mice were vaccinated with purified recombinant protein LHD-Sj23-GST (large hydrophilic domain of 23 kDa antigen of S. japonicum fused with Sj26GST) emulsified with Freund's adjuvant (FA), Montanide ISA 206 and Montanide ISA 70 M and challenged with cercariae, the protective efficacy induced by the recombinant protein was evaluated, and the LHD-Sj23-GST-specific IgG and its subtypes were determined. The result revealed that a significant worm burden reduction (58.8%, 26.3% and 54.3%; P<0.05) was obtained in mice vaccinated with LHD-Sj23-GST emulsified with three different adjuvants compared to those mice treated with respective adjuvant only. ELISA test suggested that the high-level production of LHD-Sj23-GST-specific IgG1, IgG2a and IgG3 antibodies may participate in protecting against schistosome infection. PMID:22329493

  10. Pathogen-Mimicking Polymeric Nanoparticles based on Dopamine Polymerization as Vaccines Adjuvants Induce Robust Humoral and Cellular Immune Responses.

    PubMed

    Liu, Qi; Jia, Jilei; Yang, Tingyuan; Fan, Qingze; Wang, Lianyan; Ma, Guanghui

    2016-04-01

    Aiming to enhance the immunogenicity of subunit vaccines, a novel antigen delivery and adjuvant system based on dopamine polymerization on the surface of poly(D,L-lactic-glycolic-acid) nanoparticles (NPs) with multiple mechanisms of immunity enhancement is developed. The mussel-inspired biomimetic polydopamine (pD) not only serves as a coating to NPs but also functionalizes NP surfaces. The method is facile and mild including simple incubation of the preformed NPs in the weak alkaline dopamine solution, and incorporation of hepatitis B surface antigen and TLR9 agonist unmethylated cytosine-guanine (CpG) motif with the pD surface. The as-constructed NPs possess pathogen-mimicking manners owing to their size, shape, and surface molecular immune-activating properties given by CpG. The biocompatibility and biosafety of these pathogen-mimicking NPs are confirmed using bone marrow-derived dendritic cells. Pathogen-mimicking NPs hold great potential as vaccine delivery and adjuvant system due to their ability to: 1) enhance cytokine secretion and immune cell recruitment at the injection site; 2) significantly activate and maturate dendritic cells; 3) induce stronger humoral and cellular immune responses in vivo. Furthermore, this simple and versatile dopamine polymerization method can be applicable to endow NPs with characteristics to mimic pathogen structure and function, and manipulate NPs for the generation of efficacious vaccine adjuvants. PMID:26849717

  11. Trypanosoma cruzi Adjuvants Potentiate T Cell-Mediated Immunity Induced by a NY-ESO-1 Based Antitumor Vaccine

    PubMed Central

    Junqueira, Caroline; Guerrero, Ana Tereza; Galvão-Filho, Bruno; Andrade, Warrison A.; Salgado, Ana Paula C.; Cunha, Thiago M.; Ropert, Catherine; Campos, Marco Antônio; Penido, Marcus L. O.; Mendonça-Previato, Lúcia; Previato, José Oswaldo; Ritter, Gerd; Cunha, Fernando Q.; Gazzinelli, Ricardo T.

    2012-01-01

    Immunological adjuvants that induce T cell-mediate immunity (TCMI) with the least side effects are needed for the development of human vaccines. Glycoinositolphospholipids (GIPL) and CpGs oligodeoxynucleotides (CpG ODNs) derived from the protozoa parasite Trypanosoma cruzi induce potent pro-inflammatory reaction through activation of Toll-Like Receptor (TLR)4 and TLR9, respectively. Here, using mouse models, we tested the T. cruzi derived TLR agonists as immunological adjuvants in an antitumor vaccine. For comparison, we used well-established TLR agonists, such as the bacterial derived monophosphoryl lipid A (MPL), lipopeptide (Pam3Cys), and CpG ODN. All tested TLR agonists were comparable to induce antibody responses, whereas significant differences were noticed in their ability to elicit CD4+ T and CD8+ T cell responses. In particular, both GIPLs (GTH, and GY) and CpG ODNs (B344, B297 and B128) derived from T. cruzi elicited interferon-gamma (IFN-γ) production by CD4+ T cells. On the other hand, the parasite derived CpG ODNs, but not GIPLs, elicited a potent IFN-γ response by CD8+ T lymphocytes. The side effects were also evaluated by local pain (hypernociception). The intensity of hypernociception induced by vaccination was alleviated by administration of an analgesic drug without affecting protective immunity. Finally, the level of protective immunity against the NY-ESO-1 expressing melanoma was associated with the magnitude of both CD4+ T and CD8+ T cell responses elicited by a specific immunological adjuvant. PMID:22567144

  12. Combination therapies in adjuvant with topical ALA-mediated photodynamic therapy for DMBA-induced hamster buccal pouch premalignant lesions

    NASA Astrophysics Data System (ADS)

    Yang, Deng-Fu; Hsu, Yih-Chih

    2012-03-01

    In Taiwan, oral cancer has becomes the fastest growth male cancer disease due to the betel nut chewing habit combing with smoking and alcohol-drinking lifestyle of people. In order to eliminate the systemic phototoxic effect of 5-aminolevulinic acid (ALA), this study was designed to use a topical ALA-mediated PDT for treatment of DMBA-induced hamster buccal pouch precancerous lesions. DMBA was applied to one of the buccal pouches of hamsters thrice a week for 10 to 12 weeks. Cancerous lesions were induced and proven by histological examination. These DMBA-induced cancerous lesions were used for testing the efficacy of topical ALA-mediated PDT. Before PDT, fluorescence spectroscopy was used to determine when ALA reached its peak level in the lesional epithelial cells after topical application of ALA gel. We found that ALA reached its peak level in precancerous lesions about 2.5 hrs after topical application of ALA gel. The cancerous lesions in hamsters were then treated with topical ALA -mediated PDT with light exposure dose of 150 J/cm2 using LED 635 nm fiber-guided light device. Visual examination demonstrated that adjuvant topical ALA -mediated PDT group has shown better therapeutic results in compared to those of non-adjuvant topical ALA-mediated PDT group for DMBA-induced hamster buccal pouch precancerous lesions.

  13. Chemokine-adjuvanted electroporated DNA vaccine induces substantial protection from simian immunodeficiency virus vaginal challenge.

    PubMed

    Kutzler, M A; Wise, M C; Hutnick, N A; Moldoveanu, Z; Hunter, M; Reuter, M A; Yuan, S; Yan, J; Ginsberg, A A; Sylvester, A; Pahar, B; Carnathan, D G; Kathuria, N; Khan, A S; Montefiori, D; Sardesai, N Y; Betts, M R; Mestecky, J; Marx, P A; Weiner, D B

    2016-01-01

    There have been encouraging results for the development of an effective HIV vaccine. However, many questions remain regarding the quality of immune responses and the role of mucosal antibodies. We addressed some of these issues by using a simian immunodeficiency virus (SIV) DNA vaccine adjuvanted with plasmid-expressed mucosal chemokines combined with an intravaginal SIV challenge in rhesus macaque (RhM) model. We previously reported on the ability of CCR9 and CCR10 ligand (L) adjuvants to enhance mucosal and systemic IgA and IgG responses in small animals. In this study, RhMs were intramuscularly immunized five times with either DNA or DNA plus chemokine adjuvant delivered by electroporation followed by challenge with SIVsmE660. Sixty-eight percent of all vaccinated animals (P<0.01) remained either uninfected or had aborted infection compared with only 14% in the vaccine naïve group. The highest protection was observed in the CCR10L chemokines group, where six of nine animals had aborted infection and two remained uninfected, leading to 89% protection (P<0.001). The induction of mucosal SIV-specific antibodies and neutralization titers correlated with trends in protection. These results indicate the need to further investigate the contribution of chemokine adjuvants to modulate immune responses and the role of mucosal antibodies in SIV/HIV protection. PMID:25943275

  14. Chemokine Adjuvanted Electroporated-DNA Vaccine Induces Substantial Protection from Simian Immunodeficiency Virus Vaginal Challenge

    PubMed Central

    Hutnick, N A; Moldoveanu, Z; Hunter, M; Reuter, M; Yuan, S; Yan, J; Ginsberg, A; Sylvester, A; Pahar, B; Carnathan, D; Kathuria, N; Khan, A S; Montefiori, D; Sardesai, N Y; Betts, M R; Mestecky, J; Marx, P; Weiner, D B

    2015-01-01

    There have been encouraging results for the development of an effective HIV vaccine. However, many questions remain regarding the quality of immune responses and the role of mucosal antibodies. We addressed some of these issues by using a simian immunodeficiency virus (SIV) DNA vaccine adjuvanted with plasmid-expressed mucosal chemokines combined with an intravaginal SIV challenge in rhesus macaque (RhM) model. We previously reported on the ability of CCR9 and CCR10 ligand (L) adjuvants to enhance mucosal and systemic IgA and IgG in small animals. In this study, RhMs were intramuscularly immunized five times with either DNA or DNA plus chemokine adjuvant delivered by electroporation followed by challenge with SIVsmE660. Sixty-eight percent of all vaccinated animals (P=0.0016) remained either uninfected or had aborted infection compared to only 14% in the vaccine naïve group. The highest protection was observed in the CCR10L chemokines group, where 6 of 9 animals had aborted infection and two remained uninfected, leading to 89% protection (P=0.0003). The induction of mucosal SIV-specific antibodies and neutralization titers correlated with trends in protection. These results indicate the need to further investigate the contribution of chemokine adjuvants to modulate immune responses and the role of mucosal antibodies in SIV/HIV protection. PMID:25943275

  15. Intravenous Calcium and Magnesium for Oxaliplatin-Induced Sensory Neurotoxicity in Adjuvant Colon Cancer: NCCTG N04C7

    PubMed Central

    Grothey, Axel; Nikcevich, Daniel A.; Sloan, Jeff A.; Kugler, John W.; Silberstein, Peter T.; Dentchev, Todor; Wender, Donald B.; Novotny, Paul J.; Chitaley, Umesh; Alberts, Steven R.; Loprinzi, Charles L.

    2011-01-01

    Purpose Cumulative sensory neurotoxicity (sNT) is the dose-limiting toxicity of oxaliplatin, which commonly leads to early discontinuation of oxaliplatin-based therapy in the palliative and adjuvant settings. In a nonrandomized, retrospective study, intravenous (IV) calcium/magnesium (Ca/Mg) was associated with reduced oxaliplatin-induced sNT. Methods Patients with colon cancer undergoing adjuvant therapy with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) were randomly assigned to Ca/Mg (1g calcium gluconate plus 1g magnesium sulfate pre- and post-oxaliplatin) or placebo, in a double-blinded manner. The primary end point was the percentage of patients with grade 2 or greater sNT at any time during or after oxaliplatin-based therapy by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 3) criteria. An oxaliplatin-specific sNT scale and patient questionnaires were also used to assess sNT. After 104 of 300 planned patients were enrolled, the study was closed. This was due to preliminary reports from another trial that suggested that Ca/Mg decreased treatment efficacy; these data were subsequently found to be incorrect. Results Overall, 102 patients were available for analysis. Ca/Mg decreased the incidence of chronic, cumulative, grade 2 or greater sNT, as measured by NCI CTCAE (P = .038) and also by the oxaliplatin-specific sNT scale (P = .018). In addition, acute muscle spasms associated with oxaliplatin were significantly reduced (P = .01) No effect on acute, cold-induced sNT was found. No substantial differences in adverse effects were noted between Ca/Mg and placebo. Conclusion Despite early termination and decreased statistical power, this study supports IV Ca/Mg as an effective neuroprotectant against oxaliplatin-induced cumulative sNT in adjuvant colon cancer. PMID:21189381

  16. Synergistic activity of curcumin with methotrexate in ameliorating Freund's Complete Adjuvant induced arthritis with reduced hepatotoxicity in experimental animals.

    PubMed

    Banji, David; Pinnapureddy, Jyothi; Banji, Otilia J F; Saidulu, A; Hayath, Md Sikinder

    2011-10-01

    Methotrexate is employed in low doses for the treatment of rheumatoid arthritis. One of the major drawbacks with methotrexate is hepatotoxicity resulting in poor compliance of therapy. Curcumin is an extensively used spice possessing both anti-arthritic and hepatoprotective potential. The present study was aimed at investigating the effect of curcumin (30 and 100 mg/kg) in combination with subtherapeutic dose of methotrexate (1 mg/kg) is salvaging hepatotoxicity, oxidative stress and producing synergistic anti-arthritic action with methotrexate. Wistar albino rats were induced with arthritis by subplantar injection of Freund's Complete Adjuvant and pronounced arthritis was seen after 9 days of injection. Groups of animals were treated with subtherapeutic dose of methotrexate followed half an hour later with 30 and 100mg/kg of curcumin from day 9 up to days 45 by intraperitoneal route. Methotrexate treatment in Freund's Complete Adjuvant induced arthritic animals produced elevation in the levels of aminotransferases, alkaline phosphatase, total and direct bilirubin. Enhanced oxidative stress in terms of measured lipid peroxides was observed in the methotrexate treated group. Curcumin significantly circumvented hepatotoxicity induced by methotrexate as evidenced by a change in biochemical markers possibly due to its strong anti-oxidant action. Hepatoprotective potential of curcumin was also confirmed from histological evaluation. Sub-therapeutic dose of methotrexate elicited substantial anti-arthritic action when used in combination with curcumin implying that the latter potentiated its action. Concomitant administration of curcumin with methotrexate was also found to minimize liver damage. PMID:21693118

  17. Protective antitumor immunity induced by tumor cell lysates conjugated with diphtheria toxin and adjuvant epitope in mouse breast tumor models

    PubMed Central

    Wang, Ze-Yu; Xing, Yun; Liu, Bin; Lu, Lei; Huang, Xiao; Ge, Chi-Yu; Yao, Wen-Jun; Xu, Mao-Lei; Gao, Zhen-Qiu; Cao, Rong-Yue; Wu, Jie; Li, Tai-Ming

    2012-01-01

    Cancer cell vaccine-based immunotherapy has received increasing interest in many clinical trials involving patients with breast cancer. Combining with appropriate adjuvants can enhance the weak immunogenic properties of tumor cell lysates (TCL). In this study, diphtheria toxin (DT) and two tandem repeats of mycobacterial heat shock protein 70 (mHSP70) fragment 407-426 (M2) were conjugated to TCL with glutaraldehyde, and the constructed cancer cell vaccine was named DT-TCL-M2. Subcutaneous injection of DT-TCL-M2 in mice effectively elicited tumor-specific polyclonal immune responses, including humoral and cellular immune responses. High levels of antibodies against TCL were detected in the serum of immunized mice with ELISA and verified with Western blot analyses. The splenocytes from immunized mice showed potent cytotoxicity on Ehrlich ascites carcinoma cells. Moreover, the protective antitumor immunity induced by DT-TCL-M2 inhibited tumor growth in a mouse breast tumor model. DT-TCL-M2 also attenuated tumor-induced angiogenesis and slowed tumor growth in a mouse intradermal tumor model. These findings demonstrate that TCL conjugated with appropriate adjuvants induced effective antitumor immunity in vivo. Improvements in potency could further make cancer cell vaccines a useful and safe method for preventing cancer recurrence after resection. PMID:22464650

  18. Using Poly I:C as an adjuvant does not induce or exacerbate models of systemic lupus erythematosus.

    PubMed

    Annable, Tami; Tomassian, Tamar; Jain, Siddhartha; Leibbrandt, Martha; Cooke, Michael P; Deane, Jonathan A

    2015-02-01

    Subunit vaccines are typically poorly immunogenic when administered alone, and require adjuvants for robust responses. Triggering TLRs to boost antigen-specific adaptive immunity is an attractive approach to increase the potency and quality of vaccines. However, recent reports suggest that alterations in TLR expression are associated with the pathogenesis of inflammatory and autoimmune diseases. To compare genetic studies with adjuvant studies, we examined whether stimulation through a TLR agonist induces or increases the autoimmune phenotype of healthy or autoimmune mice. C57BL/6, MRL/lpr, and Fcγr2b-deficient mice were dosed i.p. with Poly I:C every other day for 3 weeks, and monitored for signs of autoimmunity over 3 months. A separate group of mice was vaccinated three times i.m. with rPA anthrax antigen with or without Poly I:C with 2 weeks between doses. Immunized groups exhibited robust responses to vaccine and C57BL/6 and MRL/lpr mice showed a statistically significant increase in anti-rPA IgG responses in the presence of Poly I:C. Interestingly, Fcγr2b-/- mice showed increases with the base rPA vaccine, which was not significantly increased when Poly I:C was used as an adjuvant. In the chronically dosed groups, we also observed subtle alterations in levels of total antibody and some autoantibodies. However, there were no statistically significant differences in autoimmune syndrome, as measured by proteinurea, kidney pathology, weight loss, and mortality, with Poly I:C administration in chronic or vaccination mode. Taken together, these results suggest that administration of TLR3 agonists in chronic or vaccination mode does not induce or exacerbate models of systemic lupus erythematosus. PMID:25483245

  19. Role of Sinomenine on Complete Freund's Adjuvant-Induced Arthritis in Rats.

    PubMed

    Lan, Zhou; Wei, Meng; Chen, Lvyi; Xie, Guangjing; Liu, Xiao; Zhang, Xiuqiao

    2016-06-01

    The investigation was undertaken to evaluate the effect of sinomenine (Sin) on experimental adjuvant arthritis rats stimulated by Freund's complete adjuvant and explore the corresponding potential molecular mechanism. The content of proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6 were detected. Besides, canonical nuclear factor kappa B (NF-κB) pathway was also assessed to evaluate the antiarthritic potential of sinomenine. Pathological sections of rat paws showed sinomenine and diclofenac sodium significantly alleviated articular cartilage lesion, cellular infiltration, epithelial cell degeneration, synovial tissue vasodilation and congestion. The phosphorylations of inhibitor of kappaB alpha and NF-κB subunit p65 were downregulated with the treatment of sinomenine in dose dependent manners, as well as proinflammatory cytokines. Therefore, it was assumed that sinomenine might be a new therapeutic candidate to treat arthritis. © 2016 IUBMB Life, 68(6):429-435, 2016. PMID:27079983

  20. Aluminum adjuvant linked to Gulf War illness induces motor neuron death in mice.

    PubMed

    Petrik, Michael S; Wong, Margaret C; Tabata, Rena C; Garry, Robert F; Shaw, Christopher A

    2007-01-01

    Gulf War illness (GWI) affects a significant percentage of veterans of the 1991 conflict, but its origin remains unknown. Associated with some cases of GWI are increased incidences of amyotrophic lateral sclerosis and other neurological disorders. Whereas many environmental factors have been linked to GWI, the role of the anthrax vaccine has come under increasing scrutiny. Among the vaccine's potentially toxic components are the adjuvants aluminum hydroxide and squalene. To examine whether these compounds might contribute to neuronal deficits associated with GWI, an animal model for examining the potential neurological impact of aluminum hydroxide, squalene, or aluminum hydroxide combined with squalene was developed. Young, male colony CD-1 mice were injected with the adjuvants at doses equivalent to those given to US military service personnel. All mice were subjected to a battery of motor and cognitive-behavioral tests over a 6-mo period postinjections. Following sacrifice, central nervous system tissues were examined using immunohistochemistry for evidence of inflammation and cell death. Behavioral testing showed motor deficits in the aluminum treatment group that expressed as a progressive decrease in strength measured by the wire-mesh hang test (final deficit at 24 wk; about 50%). Significant cognitive deficits in water-maze learning were observed in the combined aluminum and squalene group (4.3 errors per trial) compared with the controls (0.2 errors per trial) after 20 wk. Apoptotic neurons were identified in aluminum-injected animals that showed significantly increased activated caspase-3 labeling in lumbar spinal cord (255%) and primary motor cortex (192%) compared with the controls. Aluminum-treated groups also showed significant motor neuron loss (35%) and increased numbers of astrocytes (350%) in the lumbar spinal cord. The findings suggest a possible role for the aluminum adjuvant in some neurological features associated with GWI and possibly an

  1. Vaccine adjuvant systems containing monophosphoryl lipid A and QS21 induce strong and persistent humoral and T cell responses against hepatitis B surface antigen in healthy adult volunteers.

    PubMed

    Vandepapelière, Pierre; Horsmans, Yves; Moris, Philippe; Van Mechelen, Marcelle; Janssens, Michel; Koutsoukos, Marguerite; Van Belle, Pascale; Clement, Frédéric; Hanon, Emmanuel; Wettendorff, Martine; Garçon, Nathalie; Leroux-Roels, Geert

    2008-03-01

    A randomised, double-blind study assessing the potential of four adjuvants in combination with recombinant hepatitis B surface antigen has been conducted to evaluate humoral and cell-mediated immune responses in healthy adults after three vaccine doses at months 0, 1 and 10. Three Adjuvant Systems (AS) contained 3-O-desacyl-4'-monophosphoryl lipid A (MPL) and QS21, formulated either with an oil-in-water emulsion (AS02B and AS02V) or with liposomes (AS01B). The fourth adjuvant was CpG oligonucleotide. High levels of antibodies were induced by all adjuvants, whereas cell-mediated immune responses, including cytolytic T cells and strong and persistent CD4(+) T cell response were mainly observed with the three MPL/QS21-containing Adjuvant Systems. The CD4(+) T cell response was characterised in vitro by vigorous lymphoproliferation, high IFN-gamma and moderate IL-5 production. Antigen-specific T cell immune response was further confirmed ex vivo by detection of IL-2- and IFN-gamma-producing CD4(+) T cells, and in vivo by measuring increased levels of IFN-gamma in the serum and delayed-type hypersensitivity (DTH) responses. The CpG adjuvanted vaccine induced consistently lower immune responses for all parameters. All vaccine adjuvants were shown to be safe with acceptable reactogenicity profiles. The majority of subjects reported local reactions at the injection site after vaccination while general reactions were recorded less frequently. No vaccine-related serious adverse event was reported. Importantly, no increase in markers of auto-immunity and allergy was detected over the whole study course. In conclusion, the Adjuvant Systems containing MPL/QS21, in combination with hepatitis B surface antigen, induced very strong humoral and cellular immune responses in healthy adults. The AS01B-adjuvanted vaccine induced the strongest and most durable specific cellular immune responses after two doses. These Adjuvant Systems, when added to recombinant protein antigens, can be

  2. Role of overexpressed CFA/I fimbriae in bacterial swimming

    NASA Astrophysics Data System (ADS)

    Cao, Ling; Suo, Zhiyong; Lim, Timothy; Jun, SangMu; Deliorman, Muhammedin; Riccardi, Carol; Kellerman, Laura; Avci, Recep; Yang, Xinghong

    2012-06-01

    Enterotoxigenic Escherichia coli CFA/I is a protective antigen and has been overexpressed in bacterial vectors, such as Salmonella Typhimurium H683, to generate vaccines. Effects that overexpressed CFA/I may engender on the bacterial host remain largely unexplored. To investigate, we constructed a high CFA/I expression strain, H683-pC2, and compared it to a low CFA/I expression strain, H683-pC, and to a non-CFA/I expression strain, H683-pY. The results showed that H683-pC2 was less able to migrate into semisolid agar (0.35%) than either H683-pC or H683-pY. Bacteria that migrated showed motility halo sizes of H683-pC2 < H683-pC < H683-pY. In the liquid culture media, H683-pC2 cells precipitated to the bottom of the tube, while those of H683-pY did not. In situ imaging revealed that H683-pC2 bacilli tended to auto-agglutinate within the semisolid agar, while H683-pY bacilli did not. When the cfaBE fimbrial fiber encoding genes were deleted from pC2, the new plasmid, pC2(-), significantly recovered bacterial swimming capability. Our study highlights the negative impact of overexpressed CFA/I fimbriae on bacterial swimming motility.

  3. Role of overexpressed CFA/I fimbriae in bacterial swimming.

    PubMed

    Cao, Ling; Suo, Zhiyong; Lim, Timothy; Jun, Sangmu; Deliorman, Muhammedin; Riccardi, Carol; Kellerman, Laura; Avci, Recep; Yang, Xinghong

    2012-06-01

    Enterotoxigenic Escherichia coli CFA/I is a protective antigen and has been overexpressed in bacterial vectors, such as Salmonella Typhimurium H683, to generate vaccines. Effects that overexpressed CFA/I may engender on the bacterial host remain largely unexplored. To investigate, we constructed a high CFA/I expression strain, H683-pC2, and compared it to a low CFA/I expression strain, H683-pC, and to a non-CFA/I expression strain, H683-pY. The results showed that H683-pC2 was less able to migrate into semisolid agar (0.35%) than either H683-pC or H683-pY. Bacteria that migrated showed motility halo sizes of H683-pC2 < H683-pC < H683-pY. In the liquid culture media, H683-pC2 cells precipitated to the bottom of the tube, while those of H683-pY did not. In situ imaging revealed that H683-pC2 bacilli tended to auto-agglutinate within the semisolid agar, while H683-pY bacilli did not. When the cfaBE fimbrial fiber encoding genes were deleted from pC2, the new plasmid, pC2(-), significantly recovered bacterial swimming capability. Our study highlights the negative impact of overexpressed CFA/I fimbriae on bacterial swimming motility. PMID:22562964

  4. Therapeutic Effects of Acetone Extract of Saraca asoca Seeds on Rats with Adjuvant-Induced Arthritis via Attenuating Inflammatory Responses

    PubMed Central

    Gupta, Mradu; Sasmal, Saumyakanti; Mukherjee, Arup

    2014-01-01

    Saraca asoca has been traditionally used in Indian system for treatment of uterine, genital, and other reproductive disorders in women, fever, pain, and inflammation. The hypothesis of this study is that acetone extract of Saraca asoca seeds is an effective anti-inflammatory treatment for arthritis in animal experiments. The antiarthritic effect of its oral administration on Freund's adjuvant-induced arthritis has been studied in Wistar albino rats after acute and subacute toxicities. Phytochemical analysis revealed presence of high concentrations of phenolic compounds such as flavonoids and tannins, while no mortality or morbidity was observed up to 1000 mg/kg dose during acute and subacute toxicity assessments. Regular treatment up to 21 days of adjuvant-induced arthritic rats with Saraca asoca acetone extract (at 300 and 500 mg/kg doses) increases RBC and Hb, decreases WBC, ESR, and prostaglandin levels in blood, and restores body weight when compared with control (normal saline) and standard (Indomethacin) groups. Significant (P < 0.05) inhibitory effect was observed especially at higher dose on paw edema, ankle joint inflammation, and hydroxyproline and glucosamine concentrations in urine. Normal radiological images of joint and histopathological analysis of joint, liver, stomach, and kidney also confirmed its significant nontoxic, antiarthritic, and anti-inflammatory effect. PMID:24729890

  5. Antioxidant and Angiostatic Effect of Spirulina platensis Suspension in Complete Freund’s Adjuvant-Induced Arthritis in Rats

    PubMed Central

    Ali, Eman A. I.; Barakat, Bassant M.; Hassan, Ranya

    2015-01-01

    Background Currently, natural products have built a well-recognized role in the management of many degenerative diseases, mainly rheumatoid arthritis. Recent studies suggest that Spirulina, a unicellular blue-green alga, may have a variety of health benefits and curative properties and is also competent of acting as an anti-inflammatory, antioxidant and recently anti-angiogenic agent. In the present study, the antioxidant and the immunomodulatory effect of Spirulina platensis as well as its anti-angiogenic effect against complete Freund's adjuvant-induced arthritis (AIA) in rat model were tested. Results We found that the development of arthritis was concealed; moreover it successfully inhibited the development of macroscopic as well as microscopic and histopathological lesions in AIA rats when compared to control. Spirulina treated group showed a higher survival rate and moreover, it reduced the clinical score of RA in a dose dependent manner. Furthermore, Spirulina decreased serum levels of COX-2, TNF-α, IL-6, TBARS, VEGF and increased serum levels of GSH compared to the RA non-treated group. Conclusions The present study concluded that Spirulina is able to restrain the changes produced through adjuvant-induced arthritis. The suppressing effect of Spirulina could be attributed, at least in part, to anti-inflammatory, antioxidant and anti-angiogenic properties. PMID:25853428

  6. Therapeutic Effects of Acetone Extract of Saraca asoca Seeds on Rats with Adjuvant-Induced Arthritis via Attenuating Inflammatory Responses.

    PubMed

    Gupta, Mradu; Sasmal, Saumyakanti; Mukherjee, Arup

    2014-01-01

    Saraca asoca has been traditionally used in Indian system for treatment of uterine, genital, and other reproductive disorders in women, fever, pain, and inflammation. The hypothesis of this study is that acetone extract of Saraca asoca seeds is an effective anti-inflammatory treatment for arthritis in animal experiments. The antiarthritic effect of its oral administration on Freund's adjuvant-induced arthritis has been studied in Wistar albino rats after acute and subacute toxicities. Phytochemical analysis revealed presence of high concentrations of phenolic compounds such as flavonoids and tannins, while no mortality or morbidity was observed up to 1000 mg/kg dose during acute and subacute toxicity assessments. Regular treatment up to 21 days of adjuvant-induced arthritic rats with Saraca asoca acetone extract (at 300 and 500 mg/kg doses) increases RBC and Hb, decreases WBC, ESR, and prostaglandin levels in blood, and restores body weight when compared with control (normal saline) and standard (Indomethacin) groups. Significant (P < 0.05) inhibitory effect was observed especially at higher dose on paw edema, ankle joint inflammation, and hydroxyproline and glucosamine concentrations in urine. Normal radiological images of joint and histopathological analysis of joint, liver, stomach, and kidney also confirmed its significant nontoxic, antiarthritic, and anti-inflammatory effect. PMID:24729890

  7. Therapeutic Effect of Saponin Rich Fraction of Achyranthes aspera Linn. on Adjuvant-Induced Arthritis in Sprague-Dawley Rats.

    PubMed

    Kothavade, Pankaj S; Bulani, Vipin D; Nagmoti, Dnyaneshwar M; Deshpande, Padmini S; Gawali, Nitin B; Juvekar, Archana R

    2015-01-01

    Objective. Achyranthes aspera Linn. (AA) is used in folklore for the treatment of various inflammatory ailments and arthritis like conditions. Anti-inflammatory activity of saponin rich (SR) fraction of AA has been previously reported. The objective of this study was to assess the antiarthritic effect of SR fraction of Achyranthes aspera in adjuvant-induced arthritic rats. Methods. Arthritis was assessed by arthritis score, paw volume, changes in tibiotarsal joint thickness, hyperalgesic parameters, and spleen and thymus index. Haematological, serum, biochemical, and inflammatory cytokine and in vivo antioxidant parameters were measured on the last day of the study. Results. SR fraction significantly suppressed paw swelling and arthritic score and improved the pain threshold in motility and stair climbing tests. There was a reversal in the levels of altered parameters, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and antioxidant parameters like superoxide dismutase, catalase, glutathione, malondialdehyde, and nitric oxide. SR fraction significantly decreased plasma levels of tumor necrosis factor-alpha and interleukin-6. Moreover, histopathology revealed a significant reduction in synovial hyperplasia, inflammatory cell infiltration, and bone destruction in the joints. Conclusion. These observations explain the therapeutic benefit of SR fraction of AA in suppressing the progression of adjuvant-induced arthritis in rats. PMID:26273477

  8. Therapeutic Effect of Saponin Rich Fraction of Achyranthes aspera Linn. on Adjuvant-Induced Arthritis in Sprague-Dawley Rats

    PubMed Central

    Kothavade, Pankaj S.; Bulani, Vipin D.; Nagmoti, Dnyaneshwar M.; Deshpande, Padmini S.; Gawali, Nitin B.; Juvekar, Archana R.

    2015-01-01

    Objective. Achyranthes aspera Linn. (AA) is used in folklore for the treatment of various inflammatory ailments and arthritis like conditions. Anti-inflammatory activity of saponin rich (SR) fraction of AA has been previously reported. The objective of this study was to assess the antiarthritic effect of SR fraction of Achyranthes aspera in adjuvant-induced arthritic rats. Methods. Arthritis was assessed by arthritis score, paw volume, changes in tibiotarsal joint thickness, hyperalgesic parameters, and spleen and thymus index. Haematological, serum, biochemical, and inflammatory cytokine and in vivo antioxidant parameters were measured on the last day of the study. Results. SR fraction significantly suppressed paw swelling and arthritic score and improved the pain threshold in motility and stair climbing tests. There was a reversal in the levels of altered parameters, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and antioxidant parameters like superoxide dismutase, catalase, glutathione, malondialdehyde, and nitric oxide. SR fraction significantly decreased plasma levels of tumor necrosis factor-alpha and interleukin-6. Moreover, histopathology revealed a significant reduction in synovial hyperplasia, inflammatory cell infiltration, and bone destruction in the joints. Conclusion. These observations explain the therapeutic benefit of SR fraction of AA in suppressing the progression of adjuvant-induced arthritis in rats. PMID:26273477

  9. Urinary metabolite profiling provides potential differentiation to explore the mechanisms of adjuvant-induced arthritis in rats.

    PubMed

    Jiang, Hui; Liu, Jian; Wang, Ting; Gao, Jia-Rong; Sun, Yue; Huang, Chuan-Bing; Meng, Mei; Qin, Xiu-Juan

    2016-09-01

    To explore the pathogenesis of rheumatoid arthritis (RA) from the perspective of metabolomics, gas chromatography time-of-flight mass spectrometry (GC-TOF/MS) technology was used to observe changes in the metabolic profiles of urine output from rats with adjuvant-induced arthritis (AA). Sprague-Dawley rats were randomly divided into a control group and an experimental group, with eight in each. Rats in the experimental group were induced by intracutaneous innoculation of 0.1 mL Freund's complete adjuvant to right paws. On day 20 after immunization, the metabolic profiles between rat control and experimental groups were compared by combining GC-TOF/MS technology with multivariate statistical approaches, including principal component analysis, partial least squares discriminant analysis and orthogonal projections to latent structures-discriminant analysis. Nine potential biomarkers were identified, including 2,2-dimethylsuccinic acid, tartronic acid, dehydroshikimic acid, hippuric acid, adenine, phenaceturic acid, l-dopa, 1,4-dihydroxy-2-naphthoic acid and melibiose. The findings indicate that the rats with AA are disturbed in metabolism of purine, amino acid, fat and energy. This study also demonstrates that the dysfunction in a range of biosynthetic and catabolic pathways, which leads to increased oxygen free radicals and inflammation, could cause underlying pathogenesis of RA. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26856389

  10. HBV DNA vaccine with adjuvant cytokines induced specific immune responses against HBV infection

    PubMed Central

    Du, De-Wei; Jia, Zhan-Sheng; Li, Guang-Yu; Zhou, Yong-Ying

    2003-01-01

    AIM: To seek for an effective method to improve the immune responses induced by DNA vaccine expressing HBV surface antigen (pCR3.1-S) in Balb/c mice (H-2d). METHODS: The pCR3.1-S plasmid and the eukaryotic expression vectors expressing murine IL-2 (pDOR-IL-2) or IL-12 (pWRG3169) were injected into mice subcutaneously. The immune responses to pCR3.1-S and the adjuvant effect of the cytokines plasmid were studied. Meanwhile the effect of pCR3.1-S on anti-translated subcutaneous tumor of P815 mastocytoma cells stably expressing HBsAg (P815-HBV-S) was also studied. Anti-HBs in serum was detected by enzyme-linked immunoadsordent assay (ELISA) and HBsAg specific cytotoxic T lymphocytes (CTLs) activity was measured by 51Cr release assay. After three weeks of DNA immunization, the cells of P815-HBV-S were inoculated into mice subcutaneously and the tumor growth was measured every five days. The survival rate and living periods of mice were also calculated. RESULTS: After 8 wk DNA immunization, the A 450 nm values of sera in mice immunized with pCR3.1, pCR3.1-S and pCR3.1-S codeliveried with IL-2 or IL-12 plasmids were 0.03 ± 0.01, 1.24 ± 0.10, 1.98 ± 0.17 and 1.67 ± 0.12 respectively. Data in mice codeliveried pCR3.1-S with IL-2 or IL-12 plasmids were significantly higher than that of mice injected pCR3.1 or pCR3.1-S only. The HBsAg specific CTL activities in mice coinjected with pCR3.1-S and IL-2 or IL-12 eukaryotic expression vectors were (61.9 ± 7.1)% and (73.3 ± 8.8)%, which were significantly higher than that of mice injected with pCR3.1 (10.1 ± 2.1)% or pCR3.1-S (50.5 ± 6.4)%. The HBsAg specific CTL activities in mice injected with pCR3.1, pCR3.1-S, pCR3.1-S combined with IL-2 or IL-12 eukaryotic expression vectors decreased significantly to (3.2 ± 0.8)%, (10.6 ± 1.4)%, (13.6 ± 1.3)% and (16.9 ± 2.3)% respectively after the spleen cells were treated by anti-CD8+ monoclonal antibody, but presented no significant change to anti-CD4+ monoclonal antibody or

  11. Anti-inflammatory effect of glycosaminoglycan derived from Gryllus bimaculatus (a type of cricket, insect) on adjuvant-treated chronic arthritis rat model.

    PubMed

    Ahn, Mi Young; Han, Jea Woong; Hwang, Jae Sam; Yun, Eun Young; Lee, Byung Mu

    2014-01-01

    Anti-inflammatory effects of glycosaminoglycan (GAG) derived from cricket (Gryllus bimaculatus, Gb) were investigated in a complete Freund's adjuvant (CFA)-treated chronic arthritic rat model. This GAG produced a significant anti-edema effect as evidenced by inhibition of C-reactive protein (CRP) and rheumatoid factor, and interfered with atherogenesis by reducing proinflammatory cytokine levels of (1) vascular endothelial growth factor (VEGF) production in human umbilical vein endothelial cells (HUVEC), (2) interleukin-6, (3) prostaglandin E2-stimulated lipopolysaccharide in RAW 264.7 cells, and (4) tumor necrosis factor (TNF)-α production in normal splenocytes, in a dose-dependent manner. This GAG was also found to induce nitric oxide (NO) production in HUVEC cells and elevated endothelial nitric oxide synthase (eNOS) activity levels. Histological findings demonstrated the fifth lumbar vertebrae (LV) dorsal root ganglion, which was linked to the paw treated with Gb GAG, was repaired against CFA-induced cartilage destruction. Further, combined indomethacin (5 mg/kg)-Gb GAG (10 mg/kg) inhibited more effectively CFA-induced paw edema at 3 h and 2 or 3 d after treatment to levels comparable to only the anti-inflammatory drug indomethacin. Ultraviolet (UV)-irritated skin inflammation also downregulated nuclear factor κB (NFκB) activity in transfected HaCaT cells. Data suggest that the anti-inflammatory effects of GAG obtained from cricket (Gb) may be useful for treatment of inflammatory diseases including chronic arthritis. PMID:25343284

  12. 1. Historic American Buildings Survey Jack E. Boucher, for CFA, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. Historic American Buildings Survey Jack E. Boucher, for CFA, 1970 SOUTHEAST CORNER AND MASSACHUSETTS AVE., FACADE - Clarence Moore House, 1746 Massachusetts Avenue Northwest, Washington, District of Columbia, DC

  13. Groups of galaxies. III. the CfA survey

    SciTech Connect

    Geller, M.J.; Huchra, J.P.

    1983-06-01

    We present a statistically homogeneous group catalog (CfA) based on the CfA redshift survey (Huchra et al.). Groups in the catalog are all density enhancements in redshift space of a factor greater than 20. Group members are identified according to the procedure described in our previous study (Huchra and Geller) of a shallower whole-sky sample. All groups contain at least three members. Of the 176 groups in the CfA catalog, 102 have been identified in one or more previous studies. Because our algorithm searches for volume rather than surface density enhancements, the groups in a given region generally change only through the addition of fainter members when the magnitude limit of the galaxy catalog increases. In the region of overlap, agreement between our shallow catalog and the CfA catalog is excellent.

  14. 2. Historic American Buildings Survey Jack E. Boucher for CFA, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    2. Historic American Buildings Survey Jack E. Boucher for CFA, 1970 STAIR DETAIL AT FIRST- SECOND- FLOOR LEVEL - Wilkins House, 1700 Massachusetts Avenue Northwest, Washington, District of Columbia, DC

  15. Historic American Buildings Survey Photocopy by CFA, 1972 from The ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Historic American Buildings Survey Photocopy by CFA, 1972 from The Architectural Record, April 1922 pp. 344-5 TYPICAL FLOOR PLAN - McCormick Apartments, 1785 Massachusetts Avenue Northwest, Washington, District of Columbia, DC

  16. 10. Historic American Buildings Survey CFA Staff, Photographer, 1972 FIRST ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    10. Historic American Buildings Survey CFA Staff, Photographer, 1972 FIRST- SECOND- FLOOR PLAN J. L. S. Jennings, Jr., Delineator - Edward H. Everett House, 1606 Twenty-third Street Northwest, Washington, District of Columbia, DC

  17. Influence of adjuvant and antigen dose on protection induced by an inactivated whole vaccine against Neospora caninum infection in mice.

    PubMed

    Rojo-Montejo, Silvia; Collantes-Fernández, Esther; Regidor-Cerrillo, Javier; Rodríguez-Bertos, Antonio; Prenafeta, Antoni; Gomez-Bautista, Mercedes; Ortega-Mora, Luis M

    2011-02-10

    In this study, the protection afforded by a Neospora caninum inactivated vaccine formulated with three different adjuvants (water-in-oil emulsion, aluminum hydroxide with CpG oligodeoxynucleotides and aluminum hydroxide with ginseng extract) and three different parasite doses (10(5), 5 × 10(5) or 10(6) inactivated whole tachyzoites) was evaluated using a mouse model. Mice were immunized subcutaneously twice at three-week intervals with inactivated Nc-Spain 1H tachyzoites and challenged by intraperitoneal inoculation with 10(6) live Nc-1 tachyzoites. The efficacy of the immunization was evaluated in non-pregnant BALB/c mice on days 1 and 5 (acute infection phase) and days 14 and 30 (chronic infection phase) post-challenge. The results showed the ability of water-in-oil emulsion combined with inactivated 5 × 10(5) tachyzoites to induce protection against neosporosis during the chronic stage, limiting parasite multiplication in the brain. Aluminum hydroxide-ginseng extract and inactivated tachyzoites reduced the number of parasites circulating in the blood during acute phase but failed to limit the establishment of chronic infection. On the other hand, a dose-effect was observed in groups vaccinated with aluminum hydroxide-ginseng extract in which the lesion severity increased as the inactivated tachyzoite dose. This study demonstrates that efficacy can significantly vary depending on the adjuvant, the dose of antigen and the phase of N. caninum infection in which the vaccine is tested. PMID:21067865

  18. A self-adjuvanting vaccine induces cytotoxic T lymphocytes that suppress allergy.

    PubMed

    Anderson, Regan J; Tang, Ching-wen; Daniels, Naomi J; Compton, Benjamin J; Hayman, Colin M; Johnston, Karen A; Knight, Deborah A; Gasser, Olivier; Poyntz, Hazel C; Ferguson, Peter M; Larsen, David S; Ronchese, Franca; Painter, Gavin F; Hermans, Ian F

    2014-11-01

    Epitope-based peptide vaccines encompass minimal immunogenic regions of protein antigens to allow stimulation of precisely targeted adaptive immune responses. However, because efficacy is largely determined by the functional status of antigen-presenting cells (APCs) that acquire and present peptides to cells of the adaptive immune system, adjuvant compounds are needed to enhance immunogenicity. We present here a vaccine consisting of an allergen-derived peptide conjugated to a prodrug of the natural killer-like T (NKT) cell agonist α-galactosylceramide, which is highly effective in reducing inflammation in a mouse model of allergic airway inflammation. Unlike other peptide-adjuvant conjugates that directly activate APCs through pattern recognition pathways, this vaccine encourages third-party interactions with NKT cells to enhance APC function. Therapeutic efficacy was correlated with marked increases in the number and functional activity of allergen-specific cytotoxic T lymphocytes (CTLs), leading to suppression of immune infiltration into the lungs after allergen challenge in sensitized hosts. PMID:25282504

  19. A role for mast cells in the development of adjuvant-induced vasculitis and arthritis.

    PubMed Central

    Johnston, B.; Burns, A. R.; Kubes, P.

    1998-01-01

    The objective of this study was to characterize the role of mast cells in the development of vasculitis and joint swelling in adjuvant-immunized rats. Leukocyte trafficking within mesenteric venules (rolling and adhesion) and mast cell activation (ruthenium red uptake) were examined in vivo. Elevated leukocyte trafficking was observed by 4 days after immunization, whereas joint swelling developed between days 10 and 12. Perivascular mast cells took up ruthenium red and appeared activated by electron microscopy at 4 but not 12 days after immunization. Treatment with the mast cell stabilizer cromolyn on days 1 to 4 after immunization blocked ruthenium red uptake at day 4 and reduced leukocyte rolling and adhesion by approximately 50%. This treatment also reduced rolling, adhesion, and joint swelling at day 12 by approximately 50%. Cromolyn treatment over days 9 to 12 reduced joint swelling but increased leukocyte emigration into the mesentery. Peritoneal mast cells isolated 4 days after immunization elicited significant neutrophil chemotaxis in vitro, whereas day 12 mast cells did not. Mast cell activation and vasculitis were absent in adjuvant-resistant Fisher/344 rats. These data suggest that mast cells play an early role in the initiation of vasculitis and may function by day 12 to limit infiltration of leukocytes from the vasculature. In the joint, however, mast cells appear to contribute to inflammation at early as well as later time points. Images Figure 2 PMID:9466582

  20. Small Cationic DDA:TDB Liposomes as Protein Vaccine Adjuvants Obviate the Need for TLR Agonists in Inducing Cellular and Humoral Responses

    PubMed Central

    Milicic, Anita; Kaur, Randip; Reyes-Sandoval, Arturo; Tang, Choon-Kit; Honeycutt, Jared

    2012-01-01

    Most subunit vaccines require adjuvants in order to induce protective immune responses to the targeted pathogen. However, many of the potent immunogenic adjuvants display unacceptable local or systemic reactogenicity. Liposomes are spherical vesicles consisting of single (unilamellar) or multiple (multilamellar) phospholipid bi-layers. The lipid membranes are interleaved with an aqueous buffer, which can be utilised to deliver hydrophilic vaccine components, such as protein antigens or ligands for immune receptors. Liposomes, in particular cationic DDA:TDB vesicles, have been shown in animal models to induce strong humoral responses to the associated antigen without increased reactogenicity, and are currently being tested in Phase I human clinical trials. We explored several modifications of DDA:TDB liposomes - including size, antigen association and addition of TLR agonists – to assess their immunogenic capacity as vaccine adjuvants, using Ovalbumin (OVA) protein as a model protein vaccine. Following triple homologous immunisation, small unilamellar vesicles (SUVs) with no TLR agonists showed a significantly higher capacity for inducing spleen CD8 IFNγ responses against OVA in comparison with the larger multilamellar vesicles (MLVs). Antigen-specific antibody reponses were also higher with SUVs. Addition of the TLR3 and TLR9 agonists significantly increased the adjuvanting capacity of MLVs and OVA-encapsulating dehydration-rehydration vesicles (DRVs), but not of SUVs. Our findings lend further support to the use of liposomes as protein vaccine adjuvants. Importantly, the ability of DDA:TDB SUVs to induce potent CD8 T cell responses without the need for adding immunostimulators would avoid the potential safety risks associated with the clinical use of TLR agonists in vaccines adjuvanted with liposomes. PMID:22470545

  1. Modulation of Th1 cytokines and inflammatory mediators by Euphorbia hirta in animal model of adjuvant-induced arthritis.

    PubMed

    Fayaz Ahmad, Sheikh; Sultan, Phalisteen; Ashour, Abdelkader E; Khan, Tajdar Husain; Attia, Sabry M; Bakheet, Saleh A; Abd-Allah, Adel R A

    2013-10-01

    Euphorbia hirta L. (Euphorbiaceae) (E. hirta) is a tree locally used as a traditional medicine in Africa and Australia to treat numerous diseases such as hypertension, respiratory ailments, tumors, antipyretic, anti-inflammatory activities. In the present study, we investigated the anti-arthritic activity of fresh leaves of E. hirta ethanol extract that was found to inhibit the production of inflammatory mediators and cytokines of adjuvant arthritis in rats. Adjuvant arthritis was induced in rats (Wistar) by the subplantar injection of 0.05 ml freshly prepared suspension (5.0 mg/ml) of steam killed Mycobacterium tuberculli in liquid paraffin. Animals were treated with graded doses of 25, 50, 100 and 200 mg/kg of E. hirta ethanol extract, p.o. E. hirta significantly inhibited the swelling of the adjuvant-induced arthritis. Moreover, E. hirta at higher dose (200 mg/kg) showed 40.54 ± 1.09 % of CD3+, 15.1 ± 0.76 % of CD4+, 12.2 ± 1.18 % of CD8+ T cell receptor and 17.6 ± 1.11 % gated of CD19+ B cell receptor revealing a down regulation of adjuvant-induced arthritis as compared to the corresponding valves of the arthritic control rats. According to the results shown in Tables 1, 2, the production of IL-1β, TNF-α, IL-2 and IFN-γ were increased in splenocytes of arthritic rats and this increased level was reduced by E. hirta. Also, E. hirta significantly down regulated lipopolysaccharide (LPS)-induced production of nitric oxide production in peritoneal macrophages. These results suggest that E. hirta exhibits an improvement in adjuvant-induced arthritis through down regulation of activated macrophages and T lymphocytes functions. Such unique effects of E. hirta shown on adjuvant arthritis rat model may be advantageous to the long-term treatment of clinical rheumatoid arthritis. Table 1 Effect of E. hirta and prednisolone (Pred) on LPS-induced IL-1β and TNF-α productions from splenocytes in Mycobacterium tuberculli-induced inflammatory arthritic rats Treatment

  2. Genetic fusions of a CFA/I/II/IV MEFA (multiepitope fusion antigen) and a toxoid fusion of heat-stable toxin (STa) and heat-labile toxin (LT) of enterotoxigenic Escherichia coli (ETEC) retain broad anti-CFA and antitoxin antigenicity.

    PubMed

    Ruan, Xiaosai; Sack, David A; Zhang, Weiping

    2015-01-01

    Immunological heterogeneity has long been the major challenge in developing broadly effective vaccines to protect humans and animals against bacterial and viral infections. Enterotoxigenic Escherichia coli (ETEC) strains, the leading bacterial cause of diarrhea in humans, express at least 23 immunologically different colonization factor antigens (CFAs) and two distinct enterotoxins [heat-labile toxin (LT) and heat-stable toxin type Ib (STa or hSTa)]. ETEC strains expressing any one or two CFAs and either toxin cause diarrhea, therefore vaccines inducing broad immunity against a majority of CFAs, if not all, and both toxins are expected to be effective against ETEC. In this study, we applied the multiepitope fusion antigen (MEFA) strategy to construct ETEC antigens and examined antigens for broad anti-CFA and antitoxin immunogenicity. CFA MEFA CFA/I/II/IV [CVI 2014, 21(2):243-9], which carried epitopes of seven CFAs [CFA/I, CFA/II (CS1, CS2, CS3), CFA/IV (CS4, CS5, CS6)] expressed by the most prevalent and virulent ETEC strains, was genetically fused to LT-STa toxoid fusion monomer 3xSTaA14Q-dmLT or 3xSTaN12S-dmLT [IAI 2014, 82(5):1823-32] for CFA/I/II/IV-STaA14Q-dmLT and CFA/I/II/IV-STaN12S-dmLT MEFAs. Mice intraperitoneally immunized with either CFA/I/II/IV-STa-toxoid-dmLT MEFA developed antibodies specific to seven CFAs and both toxins, at levels equivalent or comparable to those induced from co-administration of the CFA/I/II/IV MEFA and toxoid fusion 3xSTaN12S-dmLT. Moreover, induced antibodies showed in vitro adherence inhibition activities against ETEC or E. coli strains expressing these seven CFAs and neutralization activities against both toxins. These results indicated CFA/I/II/IV-STa-toxoid-dmLT MEFA or CFA/I/II/IV MEFA combined with 3xSTaN12S-dmLT induced broadly protective anti-CFA and antitoxin immunity, and suggested their potential application in broadly effective ETEC vaccine development. This MEFA strategy may be generally used in multivalent

  3. Models of Inflammation: Carrageenan- or Complete Freund’s Adjuvant-Induced Edema and Hypersensitivity in the Rat

    PubMed Central

    Fehrenbacher, Jill C.; Vasko, Michael R.; Duarte, Djane B.

    2012-01-01

    Animal models of inflammation are used to assess the production of inflammatory mediators at sites of inflammation, the anti-inflammatory properties of agents such as nonsteroidal anti-inflammatory drugs (NSAIDs), and the efficacy of putative analgesic compounds to reverse cutaneous hypersensitivity. This protocol details methods to elicit and measure carrageenan- and complete Freund’s adjuvant-induced cutaneous inflammation. Due to possible differences between the dorsal root sensory system and the trigeminal sensory system, injections of either the footpad or vibrissal pad are described. In this manner, cutaneous inflammation can be assessed in tissue innervated by the lumbar dorsal root ganglion neurons (footpad) and by the trigeminal ganglion neurons (vibrissal pad). PMID:22382999

  4. Binding of CFA/I Pili of Enterotoxigenic Escherichia coli to Asialo-GM1 Is Mediated by the Minor Pilin CfaE.

    PubMed

    Madhavan, T P Vipin; Riches, James D; Scanlon, Martin J; Ulett, Glen C; Sakellaris, Harry

    2016-05-01

    CFA/I pili are representatives of a large family of related pili that mediate the adherence of enterotoxigenic Escherichia coli to intestinal epithelial cells. They are assembled via the alternate chaperone-usher pathway and consist of two subunits, CfaB, which makes up the pilus shaft and a single pilus tip-associated subunit, CfaE. The current model of pilus-mediated adherence proposes that CFA/I has two distinct binding activities; the CfaE subunit is responsible for binding to receptors of unknown structure on erythrocyte and intestinal epithelial cell surfaces, while CfaB binds to various glycosphingolipids, including asialo-GM1. In this report, we present two independent lines of evidence that, contrary to the existing model, CfaB does not bind to asialo-GM1 independently of CfaE. Neither purified CfaB subunits nor CfaB assembled into pili bind to asialo-GM1. Instead, we demonstrate that binding activity toward asialo-GM1 resides in CfaE and this is essential for pilus binding to Caco-2 intestinal epithelial cells. We conclude that the binding activities of CFA/I pili for asialo-GM1, erythrocytes, and intestinal cells are inseparable, require the same amino acid residues in CfaE, and therefore depend on the same or very similar binding mechanisms. PMID:26975993

  5. Ultrastructure of pulmonary granulomatosis induced in rats by intravenous complete Freund's adjuvant.

    PubMed

    Soler, P; Bernaudin, J F; Basset, F

    1975-10-01

    Following the intravenous injection of complete Freund's adjuvant, changes in the rat lung were studied with the electron microscope. Interstitial granulomas were produced and whereas on light microscopy these appeared to consist mainly of epitheloid cells, electron microscopy showed that the granulomas were largely made up of macrophages. Epithelioid cells were in fact few in number, atypical in appearance and limited to the periphery of some granulomas. Fenestrated capillaries were also found at the edge of the granulomas. The alveolar macrophages were increased in number and size but marked cytoplasmic vacuolation and a paucity of lysosomes are consistent with our previous suggestion that the phagocytic and migratory properties of these cells are weakened or inhibited. Alterations were found in both types of alveolar epithelial cell with the appearance of intermediate cell forms. PMID:171827

  6. An Important Role for N-Acylethanolamine Acid Amidase in the Complete Freund's Adjuvant Rat Model of Arthritis.

    PubMed

    Bonezzi, F T; Sasso, O; Pontis, S; Realini, N; Romeo, E; Ponzano, S; Nuzzi, A; Fiasella, A; Bertozzi, F; Piomelli, D

    2016-03-01

    The endogenous lipid amides, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), exert marked antinociceptive and anti-inflammatory effects in animal models by engaging nuclear peroxisome proliferator-activated receptor-α. PEA and OEA are produced by macrophages and other host-defense cells and are deactivated by the cysteine amidase, N-acylethanolamine acid amidase (NAAA), which is highly expressed in macrophages and B-lymphocytes. In the present study, we examined whether a) NAAA might be involved in the inflammatory reaction triggered by injection of complete Freund's adjuvant (CFA) into the rat paw and b) administration of 4-cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]-carbamate (ARN726), a novel systemically active NAAA inhibitor, attenuates such reaction. Injection of CFA into the paw produced local edema and heat hyperalgesia, which were accompanied by decreased PEA and OEA content (assessed by liquid chromatography/mass spectrometry) and increased NAAA levels (assessed by Western blot and ex vivo enzyme activity measurements) in paw tissue. Administration of undec-10-ynyl-N-[(3S)-2-oxoazetidin-3-yl] carbamate (ARN14686), a NAAA-preferring activity-based probe, revealed that NAAA was catalytically active in CFA-treated paws. Administration of ARN726 reduced NAAA activity and restored PEA and OEA levels in inflamed tissues, and significantly decreased CFA-induced inflammatory symptoms, including pus production and myeloperoxidase activity. The results confirm the usefulness of ARN726 as a probe to investigate the functions of NAAA in health and disease and suggest that this enzyme may provide a new molecular target for the treatment of arthritis. PMID:26769918

  7. CfA3: 185 TYPE Ia SUPERNOVA LIGHT CURVES FROM THE CfA

    SciTech Connect

    Hicken, Malcolm; Challis, Peter; Kirshner, Robert P.; Bakos, Gaspar; Berlind, Perry; Brown, Warren R.; Caldwell, Nelson; Calkins, Mike; Cho, Richard; Contreras, Maria; Jha, Saurabh; Matheson, Tom; Modjaz, Maryam; Rest, Armin; Michael Wood-Vasey, W.; Barton, Elizabeth J.; Bragg, Ann; Briceno, Cesar; Ciupik, Larry; Dendy, Kristi-Concannon E-mail: kirshner@cfa.harvard.edu

    2009-07-20

    We present multiband photometry of 185 type-Ia supernovae (SNe Ia), with over 11,500 observations. These were acquired between 2001 and 2008 at the F. L. Whipple Observatory of the Harvard-Smithsonian Center for Astrophysics (CfA). This sample contains the largest number of homogeneously observed and reduced nearby SNe Ia (z {approx}< 0.08) published to date. It more than doubles the nearby sample, bringing SN Ia cosmology to the point where systematic uncertainties dominate. Our natural system photometry has a precision of {approx}<0.02 mag in BVRIr'i' and {approx}<0.04 mag in U for points brighter than 17.5 mag. We also estimate a systematic uncertainty of 0.03 mag in our SN Ia standard system BVRIr'i' photometry and 0.07 mag for U. Comparisons of our standard system photometry with published SN Ia light curves and comparison stars, where available for the same SN, reveal agreement at the level of a few hundredths mag in most cases. We find that 1991bg-like SNe Ia are sufficiently distinct from other SNe Ia in their color and light-curve-shape/luminosity relation that they should be treated separately in light-curve/distance fitter training samples. The CfA3 sample will contribute to the development of better light-curve/distance fitters, particularly in the few dozen cases where near-infrared photometry has been obtained and, together, can help disentangle host-galaxy reddening from intrinsic supernova color, reducing the systematic uncertainty in SN Ia distances due to dust.

  8. Cationic Liposomes Formulated with Synthetic Mycobacterial Cordfactor (CAF01): A Versatile Adjuvant for Vaccines with Different Immunological Requirements

    PubMed Central

    Agger, Else Marie; Rosenkrands, Ida; Hansen, Jon; Brahimi, Karima; Vandahl, Brian S.; Aagaard, Claus; Werninghaus, Kerstin; Kirschning, Carsten; Lang, Roland; Christensen, Dennis; Theisen, Michael; Follmann, Frank; Andersen, Peter

    2008-01-01

    Background It is now emerging that for vaccines against a range of diseases including influenza, malaria and HIV, the induction of a humoral response is insufficient and a substantial complementary cell-mediated immune response is necessary for adequate protection. Furthermore, for some diseases such as tuberculosis, a cellular response seems to be the sole effector mechanism required for protection. The development of new adjuvants capable of inducing highly complex immune responses with strong antigen-specific T-cell responses in addition to antibodies is therefore urgently needed. Methods and Findings Herein, we describe a cationic adjuvant formulation (CAF01) consisting of DDA as a delivery vehicle and synthetic mycobacterial cordfactor as immunomodulator. CAF01 primes strong and complex immune responses and using ovalbumin as a model vaccine antigen in mice, antigen specific cell-mediated- and humoral responses were obtained at a level clearly above a range of currently used adjuvants (Aluminium, monophosphoryl lipid A, CFA/IFA, Montanide). This response occurs through Toll-like receptor 2, 3, 4 and 7-independent pathways whereas the response is partly reduced in MyD88-deficient mice. In three animal models of diseases with markedly different immunological requirement; Mycobacterium tuberculosis (cell-mediated), Chlamydia trachomatis (cell-mediated/humoral) and malaria (humoral) immunization with CAF01-based vaccines elicited significant protective immunity against challenge. Conclusion CAF01 is potentially a suitable adjuvant for a wide range of diseases including targets requiring both CMI and humoral immune responses for protection. PMID:18776936

  9. Anti-inflammatory Effect of Isaria sinclairii Glycosaminoglycan in an Adjuvant-treated Arthritis Rat Model

    PubMed Central

    Jee, Sang Duck; Hwang, Jae Sam; Yun, Eun Young; Ahn, Kwang Seok; Kim, Yeong Shik

    2013-01-01

    The anti-inflammatory effects of glycosaminoglycan (GAG) derived from Isaria sinclairii (IS) and of IS extracts were investigated in a complete Freund’s adjuvant (CFA)-treated chronic arthritis rat model. Groups of rats were treated orally with 30 mg/kg one of the following: [1] saline control, extracts of [2] water-IS, [3] methanol-IS, [4] butanol-IS, [5] ethyl acetate-IS, or [6] Indomethacin® as the positive control for a period of two weeks. The anti-paw edema effects of the individual extracts were in the following order: water-IS ex. > methanol ex. > butanol ex. > ethyl acetate ex. The water/methanol extract from I. sinclairii remarkably inhibited UV-mediated upregulation of NF-κB activity in transfected HaCaT cells. GAG as a water-soluble alcohol precipitated fraction also produced a noticeable anti-edema effect. This GAG also inhibited the pro-inflammatory cytokine levels of prostaglandin E2-stimulated lipopolysaccharide in LAW 264.7 cells, cytokine TNF-α production in splenocytes, and atherogenesis cytokine levels of vascular endothelial growth factor (VEGF) production in HUVEC cells in a dose-dependent manner. In the histological analysis, the LV dorsal root ganglion, including the articular cartilage, and linked to the paw-treated IS GAG, was repaired against CFA-induced cartilage destruction. Combined treatment with Indomethacin® (5 mg/kg) and IS GAG (10 mg/kg) also more effectively inhibited CFA-induced paw edema at 3 hr, 24 hr, and 48 hr to levels comparable to the anti-inflammatory drug, indomethacin. Thus, the IS GAG described here holds great promise as an anti-inflammatory drug in the future. PMID:24386520

  10. Chimeric SV40 virus-like particles induce specific cytotoxicity and protective immunity against influenza A virus without the need of adjuvants

    SciTech Connect

    Kawano, Masaaki; Morikawa, Katsuma; Suda, Tatsuya; Ohno, Naohito; Matsushita, Sho; Akatsuka, Toshitaka; Handa, Hiroshi; Matsui, Masanori

    2014-01-05

    Virus-like particles (VLPs) are a promising vaccine platform due to the safety and efficiency. However, it is still unclear whether polyomavirus-based VLPs are useful for this purpose. Here, we attempted to evaluate the potential of polyomavirus VLPs for the antiviral vaccine using simian virus 40 (SV40). We constructed chimeric SV40-VLPs carrying an HLA-A{sup ⁎}02:01-restricted, cytotoxic T lymphocyte (CTL) epitope derived from influenza A virus. HLA-A{sup ⁎}02:01-transgenic mice were then immunized with the chimeric SV40-VLPs. The chimeric SV40-VLPs effectively induced influenza-specific CTLs and heterosubtypic protection against influenza A viruses without the need of adjuvants. Because DNase I treatment of the chimeric SV40-VLPs did not disrupt CTL induction, the intrinsic adjuvant property may not result from DNA contaminants in the VLP preparation. In addition, immunization with the chimeric SV40-VLPs generated long-lasting memory CTLs. We here propose that the chimeric SV40-VLPs harboring an epitope may be a promising CTL-based vaccine platform with self-adjuvant properties. - Highlights: • We constructed chimeric SV40-VLPs carrying an influenza virus-derived CTL epitope. • Chimeric SV40-VLPs induce influenza-specific CTLs in mice without adjuvants. • Chimeric SV40-VLPs induce heterosubtypic protection against influenza A viruses. • Chimeric SV40-VLPs induce long-lasting memory CTLs. • Chimeric SV40-VLPs is a promising vaccine platform with self-adjuvant properties.

  11. Preliminary X-ray diffraction analysis of CfaA, a molecular chaperone essential for the assembly of CFA/I fimbriae of human enterotoxigenic Escherichia coli

    SciTech Connect

    Bao, Rui; Esser, Lothar; Poole, Steven; McVeigh, Annette; Chen, Yu-xing; Savarino, Stephen J.; Xia, Di

    2014-01-21

    The molecular chaperone CfaA plays a critical role in the bioassembly of the surface-adhesive CFA/I fimbriae of enterotoxigenic E. coli. Purified CfaA was crystallized and the phase solution was determined by the multiple isomorphous replacement coupled with anomalous scattering method.

  12. A novel liposome adjuvant DPC mediates Mycobacterium tuberculosis subunit vaccine well to induce cell-mediated immunity and high protective efficacy in mice.

    PubMed

    Liu, Xun; Da, Zejiao; Wang, Yue; Niu, Hongxia; Li, Ruiying; Yu, Hongjuan; He, Shanshan; Guo, Ming; Wang, Yong; Luo, Yanping; Ma, Xingming; Zhu, Bingdong

    2016-03-01

    Tuberculosis (TB) is a serious disease around the world, and protein based subunit vaccine is supposed to be a kind of promising novel vaccine against it. However, there is no effective adjuvant available in clinic to activate cell-mediated immune responses which is required for TB subunit vaccine. Therefore, it is imperative to develop new adjuvant. Here we reported an adjuvant composed of dimethyl dioctadecylammonium (DDA), Poly I:C and cholesterol (DPC for short). DDA can form a kind of cationic liposome with the ability to deliver and present antigen and can induce Th1 type cell-mediated immune response. Poly I:C, a ligand of TLR3 receptor, could attenuate the pathologic reaction induced by following Mycobacterium tuberculosis challenge. Cholesterol, which could enhance rigidity of lipid bilayer, is added to DDA and Poly I:C to improve the stability of the adjuvant. The particle size and Zeta-potential of DPC were analyzed in vitro. Furthermore, DPC was mixed with a TB fusion protein ESAT6-Ag85B-MPT64(190-198)-Mtb8.4-Rv2626c (LT70) to construct a subunit vaccine. The subunit vaccine-induced immune responses and protective efficacy against M. tuberculosis H37Rv infection in C57BL/6 mice were investigated. The results showed that the DPC adjuvant with particle size of 400nm and zeta potential of 40mV was in good stability. LT70 in the adjuvant of DPC generated strong antigen-specific humoral and cell-mediated immunity, and induced long-term higher protective efficacy against M. tuberculosis infection (5.41±0.38log10CFU) than traditional vaccine Bacillus Calmette-Guerin (BCG) (6.01±0.33log10CFU) and PBS control (6.53±0.26log10CFU) at 30 weeks post-vaccination. In conclusion, DPC would be a promising vaccine adjuvant with the ability to stimulate Th1 type cell-mediated immunity, and could be used in TB subunit vaccine. PMID:26845736

  13. Nonlinear clustering in the CfA redshift survey

    SciTech Connect

    Alimi, J.; Blanchard, A.; Schaeffer, R. Ecole Polytechnique, Palaiseau Paris VII Universite CEA, Service de Physique Theorique de Saclay, Gif-sur-Yvette )

    1990-01-01

    The probability of finding a hole in a randomly placed sphere of volume V has been considered in the Cfa survey by numerous authors. The main emphasis of these studies has been on a scaling law derived from the assumption of hierarchical clustering. Here, the counts in cell statistics P(N) in the CfA redshift survey are analyzed. The results show that the general behavior of the P(N) can be predicted on the sole assumption of the hierarchical hypothesis. Scaling forms can then be predicted which appear to be verified to a fairly good extent in the Cfa redshift survey. This implies that the hypothesis of scale-invariant many-body correlations function provides for a satisfactory description of the count-in-cell statistics. 23 refs.

  14. Construction of Bifidobacterium infantis as a live oral vaccine that expresses antigens of the major fimbrial subunit (CfaB) and the B subunit of heat-labile enterotoxin (LTB) from enterotoxigenic Escherichia coli.

    PubMed

    Ma, Yongping; Luo, Yaolin; Huang, Xueping; Song, Fangzhou; Liu, Geli

    2012-02-01

    We sought to develop Bifidobacterium infantis (BI) as a vehicle for the expression of heterologous antigens. Two proteins of enterotoxigenic Escherichia coli (ETEC) were expressed in BI: CfaB, a major fimbrial subunit protein, and LTB, the B subunit of heat-labile enterotoxin. The expression of CfaB and LTB in BI was verified by electrophoretic analysis. Sprague-Dawley rats were then subjected to intragastric immunization with BI-CfaB and BI-LTB systems both separately and together. ELISA was used to characterize the serum and mucosal immune responses against ETEC antigens. The immunized rats were intraperitoneally challenged with wild-type ETEC H10407 to study the immune response in vivo. The serum titres of IgG and faecal IgA antibodies in the BI-CfaB plus BI-LTB mixed vaccination group were significantly greater than those in the other two groups, which were immunized with a single vaccine (P<0.05). However, no significant difference was seen between the two groups that received a single immunization. These results suggest that expressing CfaB and LTB in BI provides a probiotic system with immunogenic properties. Furthermore, the expression of LTB in BI preserved its mucosal adjuvant effect. So this study confirms that BI can be used as a novel oral vaccine expression system for a heterologous antigen and BI-LTB can provide mucosal adjuvant properties. PMID:22053005

  15. Pentadecapeptide BPC 157 positively affects both non-steroidal anti-inflammatory agent-induced gastrointestinal lesions and adjuvant arthritis in rats.

    PubMed

    Sikiric, P; Seiwerth, S; Grabarevic, Z; Rucman, R; Petek, M; Jagic, V; Turkovic, B; Rotkvic, I; Mise, S; Zoricic, I; Konjevoda, P; Perovic, D; Simicevic, V; Separovic, J; Hanzevacki, M; Ljubanovic, D; Artukovic, B; Bratulic, M; Tisljar, M; Rekic, B; Gjurasin, M; Miklic, P; Buljat, G

    1997-01-01

    Besides a superior protection of the pentadecapeptide BPC 157 (an essential fragment of an organoprotective gastric juice peptide BPC) against different gastrointestinal and liver lesions, an acute anti-inflammatory and analgetic activity was also noted. Consequently, its effect on chronic inflammation lesions, such as adjuvant arthritis, and non-steroidal anti-inflammatory agents (NSAIAs)-induced gastrointestinal lesions was simultaneously studied in rats. In gastrointestinal lesions (indomethacin (30 mg/kg s.c.), aspirin (400 mg/kg i.g.) and diclofenac (125 mg/kg i.p.) studies, BPC 157 (10 micrograms or 10 ng/kg i.p.) was regularly given simultaneously and/or 1 h prior to drug application (indomethacin). In the adjuvant arthritis (tail-application of 0.2 mL of Freund's adjuvant) studies (14 days, 30 days, 1 year) BPC 157 (10 micrograms or 10 ng/kg i.p.), it was given as a single application (at 1 h either before or following the application of Freund's adjuvant) or in a once daily regimen (0-14th day, 14-30th day, 14th day-1 year). Given with the investigated NSAIAs, BPC 157 consistently reduced the otherwise prominent lesions in the stomach of the control rats, as well as the lesions in the small intestine in the indomethacin groups. In the adjuvant arthritis studies, the lesion's development seems to be considerably reduced after single pentadecapeptide medication, and even more attenuated in rats daily treated with BPC 157. As a therapy of already established adjuvant arthritis, its salutary effect consistently appeared already after 2 weeks of medication and it could be clearly seen also after 1 year of application. Taking together all these results, the data likely point to a special anti-inflammatory and mucosal integrity protective effect. PMID:9403784

  16. Delta Inulin Adjuvant Enhances Plasmablast Generation, Expression of Activation-Induced Cytidine Deaminase and B-Cell Affinity Maturation in Human Subjects Receiving Seasonal Influenza Vaccine

    PubMed Central

    Li, Lei; Honda-Okubo, Yoshikazu; Li, Connie; Sajkov, Dimitar; Petrovsky, Nikolai

    2015-01-01

    There is a major need for new adjuvants to improve the efficacy of seasonal and pandemic influenza vaccines. Advax is a novel polysaccharide adjuvant based on delta inulin that has been shown to enhance the immunogenicity of influenza vaccine in animal models and human clinical trials. To better understand the mechanism for this enhancement, we sought to assess its effect on the plasmablast response in human subjects. This pilot study utilised cryopreserved 7 day post-vaccination (7dpv) peripheral blood mononuclear cell samples obtained from a subset of 25 adult subjects from the FLU006-12 trial who had been immunized intramuscularly with a standard dose of 2012 trivalent inactivated influenza vaccine (TIV) alone (n=9 subjects) or combined with 5mg (n=8) or 10mg (n=8) of Advax adjuvant. Subjects receiving Advax adjuvant had increased 7dpv plasmablasts, which in turn exhibited a 2-3 fold higher rate of non-silent mutations in the B-cell receptor CDR3 region associated with higher expression of activation-induced cytidine deaminase (AID), the major enzyme controlling BCR affinity maturation. Together, these data suggest that Advax adjuvant enhances influenza immunity in immunized subjects via multiple mechanisms including increased plasmablast generation, AID expression and CDR3 mutagenesis resulting in enhanced BCR affinity maturation and increased production of high avidity antibody. How Advax adjuvant achieves these beneficial effects on plasmablasts remains the subject of ongoing investigation. Trial Registration Australia New Zealand Clinical Trials Register ACTRN12612000709842 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=362709 PMID:26177480

  17. Effect of pumpkin-seed oil on the level of free radical scavengers induced during adjuvant-arthritis in rats.

    PubMed

    Fahim, A T; Abd-el Fattah, A A; Agha, A M; Gad, M Z

    1995-01-01

    Pumpkin-seed oil (PSO), a natural supplement rich with antioxidant ingredients, was given to rats in which arthritis was induced using Freund's complete adjuvant. Its effect was compared with that of indomethacin, as a classical anti-inflammatory agent. Two experimental patterns were studied, an acute phase that was applied only with PSO and a chronic phase applied for both PSO and indomethacin. Compared to normal untreated rats, it was shown that the induction of arthritis caused a decrease in serum sulphhydryl groups, with an increase in serum ceruloplasmin in both phases. Blood glutathione was first elevated in the acute phase, then its level was reduced in the chronic phase. Serum N-acetyl-beta-D-glucosaminidase activity was elevated only at the acute phase, while plasma total proteins and albumin were reduced at the chronic phase. Liver glucose-6-phosphate dehydrogenase activity was markedly increased, while no changes were observed in the levels of liver lipid peroxides and glutathione. These changes in the studied parameters were attributed to the superoxides and free radicals during arthritic inflammation. Administration of PSO succeeded in modulating most of the altered parameters affected during arthritis, especially at the chronic phase. Also, a remarkable inhibition of paw oedema was observed. A similar pattern was obtained upon treatment with indomethacin except that indomethacin markedly elevated liver lipid peroxides levels. Concurrent administration of PSO with indomethacin caused no changes in the parameters studied compared to that induced by treatment with indomethacin alone. PMID:7784309

  18. Radiofrequency Ablation–Induced Upregulation of Hypoxia-Inducible Factor-1α Can Be Suppressed with Adjuvant Bortezomib or Liposomal Chemotherapy

    PubMed Central

    Moussa, Marwan; Goldberg, S. Nahum; Kumar, Gaurav; Sawant, Rupa R.; Levchenko, Tatyana; Torchilin, Vladimir; Ahmed, Muneeb

    2014-01-01

    Purpose To characterize upregulation of hypoxia-inducible factor (HIF)-1α after radiofrequency (RF) ablation and the influence of an adjuvant HIF-1α inhibitor (bortezomib) and nanodrugs on modulating RF ablation–upregulated hypoxic pathways. Materials and Methods Fisher 344 rats (n = 68) were used. First, RF ablation–induced periablational HIF-1α expression was evaluated in normal liver or subcutaneous R3230 tumors (14–16 mm). Next, the effect of varying RF ablation thermal dose (varying tip temperature 50°C–90°C for 2–20 minutes) on HIF-1α expression was studied in R3230 tumors. Third, RF ablation was performed in R3230 tumors without or with an adjuvant HIF-1α inhibitor, bortezomib (single intraperitoneal dose 0.1 mg/kg). Finally, the combination RF ablation and intravenous liposomal chemotherapeutics with known increases in periablational cellular cytotoxicity (doxorubicin, paclitaxel, and quercetin) was assessed for effect on periablational HIF-1α. Outcome measures included immunohistochemistry of HIF-1α and heat shock protein 70 (marker of nonlethal thermal injury). Results RF ablation increased periablational HIF-1α in both normal liver and R3230 tumor, peaking at 24–72 hours. Tumor RF ablation had similar HIF-1α rim thickness but significantly greater percent cell positivity compared with hepatic RF ablation (P < .001). HIF-1α after ablation was the same regardless of thermal dose. Bortezomib suppressed HIF-1α (rim thickness, 68.7 μm ± 21.5 vs 210.3 μm ± 85.1 for RF ablation alone; P < .02) and increased ablation size (11.0 mm ± 1.5 vs 7.7 mm ± 0.6 for RF ablation alone; P < .002). Finally, all three nanodrugs suppressed RF ablation–induced HIF-1α (ie, rim thickness and cell positivity; P < .02 for all comparisons), with liposomal doxorubicin suppressing HIF-1α the most (P < .03). Conclusions RF ablation upregulates HIF-1α in normal liver and tumor in a temperature-independent manner. This progrowth, hypoxia pathway can be

  19. Structure of CFA/I fimbriae from enterotoxigenic Escherichia coli

    PubMed Central

    Li, Yong-Fu; Poole, Steven; Nishio, Kazuya; Jang, Ken; Rasulova, Fatima; McVeigh, Annette; Savarino, Stephen J.; Xia, Di; Bullitt, Esther

    2009-01-01

    Adhesion pili (fimbriae) play a critical role in initiating the events that lead to intestinal colonization and diarrheal disease by enterotoxigenic Escherichia coli (ETEC), an E. coli pathotype that inflicts an enormous global disease burden. We elucidate atomic structures of an ETEC major pilin subunit, CfaB, from colonization factor antigen I (CFA/I) fimbriae. These data are used to construct models for 2 morphological forms of CFA/I fimbriae that are both observed in vivo: the helical filament into which it is typically assembled, and an extended, unwound conformation. Modeling and corroborative mutational data indicate that proline isomerization is involved in the conversion between these helical and extended forms. Our findings affirm the strong structural similarities seen between class 5 fimbriae (from bacteria primarily causing gastrointestinal disease) and class 1 pili (from bacteria that cause urinary, respiratory, and other infections) in the absence of significant primary sequence similarity. They also suggest that morphological and biochemical differences between fimbrial types, regardless of class, provide structural specialization that facilitates survival of each bacterial pathotype in its preferred host microenvironment. Last, we present structural evidence for bacterial use of antigenic variation to evade host immune responses, in that residues occupying the predicted surface-exposed face of CfaB and related class 5 pilins show much higher genetic sequence variability than the remainder of the pilin protein. PMID:19515814

  20. Structure of CFA/I fimbriae from enterotoxigenic Escherichia coli

    SciTech Connect

    Li, Yong-Fu; Poole, Steven; Nishio, Kazuya; Jang, Ken; Rasulova, Fatima; McVeigh, Annette; Savarino, Stephen J.; Xia, Di; Bullitt, Esther

    2009-10-21

    Adhesion pili (fimbriae) play a critical role in initiating the events that lead to intestinal colonization and diarrheal disease by enterotoxigenic Escherichia coli (ETEC), an E. coli pathotype that inflicts an enormous global disease burden. We elucidate atomic structures of an ETEC major pilin subunit, CfaB, from colonization factor antigen I (CFA/I) fimbriae. These data are used to construct models for 2 morphological forms of CFA/I fimbriae that are both observed in vivo: the helical filament into which it is typically assembled, and an extended, unwound conformation. Modeling and corroborative mutational data indicate that proline isomerization is involved in the conversion between these helical and extended forms. Our findings affirm the strong structural similarities seen between class 5 fimbriae (from bacteria primarily causing gastrointestinal disease) and class 1 pili (from bacteria that cause urinary, respiratory, and other infections) in the absence of significant primary sequence similarity. They also suggest that morphological and biochemical differences between fimbrial types, regardless of class, provide structural specialization that facilitates survival of each bacterial pathotype in its preferred host microenvironment. Last, we present structural evidence for bacterial use of antigenic variation to evade host immune responses, in that residues occupying the predicted surface-exposed face of CfaB and related class 5 pilins show much higher genetic sequence variability than the remainder of the pilin protein.

  1. A Live Vector Expressing HPV16 L1 Generates an Adjuvant-Induced Antibody Response In-vivo

    PubMed Central

    Shirbaghaee, Zeinab; Bolhassani, Azam; Mirshafiey, Abbas; Motevalli, Fatemeh; Zohrei, Negar

    2015-01-01

    Background: The association between human papillomavirus (HPV) infections and cervical cancer has suggested the design of prophylactic and therapeutic vaccines against genital warts. The HPV capsid has made of two L1 and L2 coat proteins that have produced late in viral infections. Regarding to the recent studies, two commercial prophylactic vaccines have based on L1 viral like particles (VLPs) could strongly induce antibody responses, and protect human body from HPV infections. However, the use of these HPV vaccines has hindered due to their high cost and some limitations. Currently, among various vaccination strategies, live vector-based vaccines have attracted a great attention. Objectives: Herein, a non-pathogenic strain of the protozoan organism known as Leishmania tarentolae has utilized to induce potent humoral immunity in mice model. Materials and Methods: At first, cloning of HPV16 L1 gene into Leishmania expression vector has performed and confirmed by PCR and digestion with restriction enzymes. The promastigotes of Leishmania tarentolae (L.tar) have transfected with linearized DNA construct by electroporation. Protein expression has analyzed by SDS-PAGE and western blotting. Then, the immunogenicity of leishmania expressing L1 protein (L.tar-L1) has assessed in mice model. Results: Our data has indicated that subcutaneous immunization of mice with the recombinant L.tar-L1 has led to enhance the levels of IgG1 and lgG2a in comparison with control groups. Furthermore, there was no significant increase in antibody levels between two and three times of immunizations. Conclusions: The recombinant live vector was able to induce humoral immunity in mice without need of any adjuvant. However, further studies have required to increase its efficiency. PMID:26855722

  2. Effect of solid nanoparticle of indomethacin on therapy for rheumatoid arthritis in adjuvant-induced arthritis rat.

    PubMed

    Nagai, Noriaki; Ito, Yoshimasa

    2014-01-01

    We designed new oral formulations containing indomethacin (IMC) solid nanoparticles, and investigate their usefulness by evaluating bioavailability and gastrointestinal lesions. The IMC solid nanoparticles were prepared using methylcellulose (MC), 2-hydroxypropyl-β-cyclodextrin (HPβCD), and the bead mill method, and high quality dispersions containing 1.0% IMC nanoparticles were prepared (IMC(nano), particle size: 76 ± 58 nm, means ± S.D.). The fate of serum IMC and the induction of paw edema in adjuvant-induced arthritis (AA) rats receiving low-doses IMC(nano) (0.4 mg/kg) were similar to those following the administration of a therapeutic dose of conventional IMC prepared with MC and HPβCD (conventional IMC, 2 mg/kg), and the bioavailability in 0.4 mg/kg IMC(nano) was 5.3-fold higher in comparison with that in 2 mg/kg conventional IMC. IMC-induced gastrointestinal lesions in AA rats administered IMC(nano) (8 mg/kg), in consideration of bioavailability, were significantly less than for conventional IMC (40 mg/kg). On the other hand, the toxicity caused by conventional IMC and IMC(nano) was similar in Caco-2 cells. It is possible that the oral administration of IMC solid nanoparticles will show increased effectiveness in treating RA without causing IMC-induced gastrointestinal lesions, since the bioavailability is higher than that of conventional IMC. An oral drug delivery system using drug nanoparticles may expand the usage of NSAIDs for therapy in the inflammatory field. PMID:24989003

  3. Immunopotentiation of Different Adjuvants on Humoral and Cellular Immune Responses Induced by HA1-2 Subunit Vaccines of H7N9 Influenza in Mice.

    PubMed

    Song, Li; Xiong, Dan; Hu, Maozhi; Kang, Xilong; Pan, Zhiming; Jiao, Xinan

    2016-01-01

    In spring 2013, human infections with a novel avian influenza A (H7N9) virus were reported in China. The number of cases has increased with over 200 mortalities reported to date. However, there is currently no vaccine available for the H7 subtype of influenza A virus. Virus-specific cellular immune responses play a critical role in virus clearance during influenza infection. In this study, we undertook a side-by-side evaluation of two different adjuvants, Salmonella typhimurium flagellin (fliC) and polyethyleneimine (PEI), through intraperitoneal administration to assess their effects on the immunogenicity of the recombinant HA1-2 subunit vaccine of H7N9 influenza. The fusion protein HA1-2-fliC and HA1-2 combined with PEI could induce significantly higher HA1-2-specific IgG and hemagglutination inhibition titers than HA1-2 alone at 12 days post-boost, with superior HA1-2 specific IgG titers in the HA1-2-fliC group compared with the PEI adjuvanted group. The PEI adjuvanted vaccine induced higher IgG1/IgG2a ratio and significantly increased numbers of IFN-γ- and IL-4-producing cells than HA1-2 alone, suggesting a mixed Th1/Th2-type cellular immune response with a Th2 bias. Meanwhile, the HA1-2-fliC induced higher IgG2a and IgG1 levels, which is indicative of a mixed Th1/Th2-type profile. Consistent with this, significant levels, and equal numbers, of IFN-γ- and IL-4-producing cells were detected after HA1-2-fliC vaccination. Moreover, the marked increase in CD69 expression and the proliferative index with the HA1-2-fliC and PEI adjuvanted vaccines indicated that both adjuvanted vaccine candidates effectively induced antigen-specific cellular immune responses. Taken together, our findings indicate that the two adjuvanted vaccine candidates elicit effective and HA1-2-specific humoral and cellular immune responses, offering significant promise for the development of a successful recombinant HA1-2 subunit vaccine for H7N9 influenza. PMID:26930068

  4. Immunopotentiation of Different Adjuvants on Humoral and Cellular Immune Responses Induced by HA1-2 Subunit Vaccines of H7N9 Influenza in Mice

    PubMed Central

    Song, Li; Xiong, Dan; Hu, Maozhi; Kang, Xilong; Pan, Zhiming; Jiao, Xinan

    2016-01-01

    In spring 2013, human infections with a novel avian influenza A (H7N9) virus were reported in China. The number of cases has increased with over 200 mortalities reported to date. However, there is currently no vaccine available for the H7 subtype of influenza A virus. Virus-specific cellular immune responses play a critical role in virus clearance during influenza infection. In this study, we undertook a side-by-side evaluation of two different adjuvants, Salmonella typhimurium flagellin (fliC) and polyethyleneimine (PEI), through intraperitoneal administration to assess their effects on the immunogenicity of the recombinant HA1-2 subunit vaccine of H7N9 influenza. The fusion protein HA1-2-fliC and HA1-2 combined with PEI could induce significantly higher HA1-2-specific IgG and hemagglutination inhibition titers than HA1-2 alone at 12 days post-boost, with superior HA1-2 specific IgG titers in the HA1-2-fliC group compared with the PEI adjuvanted group. The PEI adjuvanted vaccine induced higher IgG1/IgG2a ratio and significantly increased numbers of IFN-γ- and IL-4-producing cells than HA1-2 alone, suggesting a mixed Th1/Th2-type cellular immune response with a Th2 bias. Meanwhile, the HA1-2-fliC induced higher IgG2a and IgG1 levels, which is indicative of a mixed Th1/Th2-type profile. Consistent with this, significant levels, and equal numbers, of IFN-γ- and IL-4-producing cells were detected after HA1-2-fliC vaccination. Moreover, the marked increase in CD69 expression and the proliferative index with the HA1-2-fliC and PEI adjuvanted vaccines indicated that both adjuvanted vaccine candidates effectively induced antigen-specific cellular immune responses. Taken together, our findings indicate that the two adjuvanted vaccine candidates elicit effective and HA1-2-specific humoral and cellular immune responses, offering significant promise for the development of a successful recombinant HA1-2 subunit vaccine for H7N9 influenza. PMID:26930068

  5. Autoimmunity in connection with a metal implant: a case of autoimmune/autoinflammatory syndrome induced by adjuvants.

    PubMed

    Loyo, Esthela; Jara, Luis J; López, Persio David; Puig, Ana Carolina

    2013-04-01

    Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) has been recently proposed by Shoenfeld and Agmon-Levin as a new entity that comprises several conditions: the macrophagic-myofasciitis syndrome, the Gulf War syndrome, silicosis and post-vaccination phenomena, autoimmunity related to infectious fragments, hormones, aluminum, silicone, squalene oil, and pristane. We report the case of a 23-year-old woman who developed serial episodes of high fever, extreme fatigue, transient thrombocytopenia, multiple cervical adenopathies, hepatosplenomegaly, anemia, neutropenia, severe proteinuria and urine sediment abnormalities, elevated serum ferritin levels, and transient low positive antinuclear antibodies 1 year after she had a nickel-titanium chin implant for cosmetic reasons. The clinical picture simulated a variety of probable diseases: systemic lupus erythematosus, Kikuchi-Fujimoto syndrome, adult onset Still's disease, antiphospholipid syndrome, and hemophagocytic syndrome, among others, so she underwent an extensive medical investigation including two lymph node biopsies. She received treatment accordingly with steroids, methotrexate, and mofetil mycophenolate, with initial improvement of her symptoms, which recurred every time the dose was reduced. Two and a half years later the patient decided to retire the chin implant and afterwards all her systemic symptoms have disappeared. She remains in good health, without recurrence of any symptom and off medications until today. Albeit this patient fulfills proposed major ASIA criteria, to our knowledge it would be the first description of systemic features of autoinflammation in connection with a metal implant. PMID:26000140

  6. β2-adrenoceptor signaling reduction in dendritic cells is involved in the inflammatory response in adjuvant-induced arthritic rats

    PubMed Central

    Wu, Huaxun; Chen, Jingyu; Song, Shasha; Yuan, Pingfan; Liu, Lihua; Zhang, Yunfang; Zhou, Aiwu; Chang, Yan; Zhang, Lingling; Wei, Wei

    2016-01-01

    Rheumatoid arthritis (RA) is characterized by inflammation of the synovium, which leads to the progressive destruction of cartilage and bone. Adrenoreceptor (AR) signaling may play an important role in modulating dendritic cell (DC), which may be involved in the pathogenesis of RA. We examined the effect of the β-AR agonist isoprenaline (ISO) on DC function, the impact of the β2-AR agonist salbutamol on adjuvant-induced arthritic (AA) rats, and changes in β2-AR signaling in DCs during the course of AA. ISO inhibited the expression of the surface molecules CD86 and MHC-II, inhibited the stimulation of T lymphocyte proliferation by DC and TNF-α secretion, and promoted DC antigen uptake and IL-10 secretion. The effects of ISO on MHC-II expression, DC stimulation of T lymphocyte proliferation, and DC antigen uptake were mediated by β2-AR. Treatment with salbutamol ameliorated the severity of AA and histopathology of the joints and inhibited proliferation of thymus lymphocytes and FLS in vivo. β2-AR signaling was weaker in AA rats compared to the control. Elevated GRK2 and decreased β2-AR expression in DC cytomembranes were observed in AA and may have decreased the anti-inflammatory effect of β2-AR signaling. Decreased β2-AR signaling may be relevant to the exacerbation of arthritis inflammation. PMID:27079168

  7. Co-Administration of Molecular Adjuvants Expressing NF-Kappa B Subunit p65/RelA or Type-1 Transactivator T-bet Enhance Antigen Specific DNA Vaccine-Induced Immunity

    PubMed Central

    Shedlock, Devon J.; Tingey, Colleen; Mahadevan, Lavanya; Hutnick, Natalie; Reuschel, Emma L.; Kudchodkar, Sagar; Flingai, Seleeke; Yan, Jenny; Kim, Joseph J.; Ugen, Kenneth E.; Weiner, David B.; Muthumani, Kar

    2014-01-01

    DNA vaccine-induced immunity can be enhanced by the co-delivery of synthetic gene-encoding molecular adjuvants. Many of these adjuvants have included cytokines, chemokines or co-stimulatory molecules that have been demonstrated to enhance vaccine-induced immunity by increasing the magnitude or type of immune responses and/or protective efficacy. In this way, through the use of adjuvants, immune responses can be highly customizable and functionally tailored for optimal efficacy against pathogen specific (i.e., infectious agent) or non-pathogen (i.e., cancer) antigens. In the novel study presented here, we examined the use of cellular transcription factors as molecular adjuvants. Specifically the co-delivery of (a) RelA, a subunit of the NF-κB transcription complex or (b) T-bet, a Th1-specific T box transcription factor, along with a prototypical DNA vaccine expressing HIV-1 proteins was evaluated. As well, all of the vaccines and adjuvants were administered to mice using in vivo electroporation (EP), a technology demonstrated to dramatically increase plasmid DNA transfection and subsequent transgene expression with concomitant enhancement of vaccine induced immune responses. As such, this study demonstrated that co-delivery of either adjuvant resulted in enhanced T and B cell responses, specifically characterized by increased T cell numbers, IFN-γ production, as well as enhanced antibody responses. This study demonstrates the use of cellular transcription factors as adjuvants for enhancing DNA vaccine-induced immunity. PMID:26344618

  8. Co-Administration of Molecular Adjuvants Expressing NF-Kappa B Subunit p65/RelA or Type-1 Transactivator T-bet Enhance Antigen Specific DNA Vaccine-Induced Immunity.

    PubMed

    Shedlock, Devon J; Tingey, Colleen; Mahadevan, Lavanya; Hutnick, Natalie; Reuschel, Emma L; Kudchodkar, Sagar; Flingai, Seleeke; Yan, Jenny; Kim, Joseph J; Ugen, Kenneth E; Weiner, David B; Muthumani, Kar

    2014-01-01

    DNA vaccine-induced immunity can be enhanced by the co-delivery of synthetic gene-encoding molecular adjuvants. Many of these adjuvants have included cytokines, chemokines or co-stimulatory molecules that have been demonstrated to enhance vaccine-induced immunity by increasing the magnitude or type of immune responses and/or protective efficacy. In this way, through the use of adjuvants, immune responses can be highly customizable and functionally tailored for optimal efficacy against pathogen specific (i.e., infectious agent) or non-pathogen (i.e., cancer) antigens. In the novel study presented here, we examined the use of cellular transcription factors as molecular adjuvants. Specifically the co-delivery of (a) RelA, a subunit of the NF-κB transcription complex or (b) T-bet, a Th1-specific T box transcription factor, along with a prototypical DNA vaccine expressing HIV-1 proteins was evaluated. As well, all of the vaccines and adjuvants were administered to mice using in vivo electroporation (EP), a technology demonstrated to dramatically increase plasmid DNA transfection and subsequent transgene expression with concomitant enhancement of vaccine induced immune responses. As such, this study demonstrated that co-delivery of either adjuvant resulted in enhanced T and B cell responses, specifically characterized by increased T cell numbers, IFN-γ production, as well as enhanced antibody responses. This study demonstrates the use of cellular transcription factors as adjuvants for enhancing DNA vaccine-induced immunity. PMID:26344618

  9. Adjuvant treatment

    PubMed Central

    Sultana, Asma; Neoptolemos, John

    2006-01-01

    Exocrine pancreatic cancer (pancreatic ductal adenocarcinoma) is one of the leading causes of cancer deaths in the western world, accounting for 5% of all cancer-related deaths. Only a small percentage of patients with pancreatic cancer are able to undergo potentially curative resection, even in specialized centres, and prognosis remains poor after successful surgery. Over the last few years efforts have been directed towards the development of adjuvant therapies in attempts to improve outcome. The main trials of adjuvant chemotherapy, chemoradiotherapy and chemoradiotherapy with follow-on chemotherapy are described in this paper, followed by the results of the ESPAC-1 trial and the status of ESPAC-2 and -3 trials. PMID:18333088

  10. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Under physiological conditions the gut-associated lymphoid tissues not only prevent the induction of a local inflammatory immune response, but also induce systemic tolerance to fed antigens. A notable exception is coeliac disease, where genetically susceptible individuals expressing human leukocyte...

  11. Crystallization and preliminary X-ray diffraction analyses of several forms of the CfaB major subunit of enterotoxigenic Escherichia coli CFA/I fimbriae

    PubMed Central

    Li, Yong-Fu; Poole, Steven; Rasulova, Fatima; McVeigh, Annette L.; Savarino, Stephen J.; Xia, Di

    2009-01-01

    Enterotoxigenic Escherichia coli (ETEC), a major global cause of diarrhea, initiates the pathogenic process via fimbriae-mediated attachment to the small intestinal epithelium. A common prototypic ETEC fimbria, colo­nization factor antigen I (CFA/I), consists of a tip-localized minor adhesive subunit CfaE and the stalk-forming major subunit CfaB, both of which are necessary for fimbrial assembly. To elucidate the structure of CFA/I at atomic resolution, three recombinant proteins were generated consisting of fusions of the minor and major subunits (CfaEB) and of two (CfaBB) and three (CfaBBB) repeats of the major subunit. Crystals of CfaEB diffracted X-rays to 2.1 Å resolution and displayed the symmetry of space group P21. CfaBB exhibited a crystal diffraction limit of 2.3 Å resolution and had the symmetry of space group P21212. CfaBBB crystallized in the monoclinic space group C2 and diffracted X-­rays to 2.3 Å resolution. These structures were determined using the molecular-replacement method. PMID:19255474

  12. A gold glyco-nanoparticle carrying a Listeriolysin O peptide and formulated with Advax™ delta inulin adjuvant induces robust T-cell protection against listeria infection.

    PubMed

    Rodriguez-Del Rio, Estela; Marradi, Marco; Calderon-Gonzalez, Ricardo; Frande-Cabanes, Elisabet; Penadés, Soledad; Petrovsky, Nikolai; Alvarez-Dominguez, Carmen

    2015-03-17

    In the search for an effective vaccine against the human pathogen, Listeria monocytogenes (Listeria), gold glyconanoparticles (GNP) loaded with a listeriolysin O peptide LLO91-99 (GNP-LLO) were used to immunise mice, initially using a dendritic cell (DC) vaccine approach, but subsequently using a standard parenteral immunisation approach. To enhance vaccine immunogenicity a novel polysaccharide adjuvant based on delta inulin (Advax™) was also co-formulated with the GNP vaccine. Confirming previous results, DC loaded in vitro with GNP-LLO provided better protection against listeriosis than DC loaded in vitro using free LLO peptide. The immunogenicity of GNP-LLO loaded DC vaccines was further increased by addition of Advax™ adjuvant. However, as DC vaccines are expensive and impracticable for prophylactic use, we next asked whether the same GNP-LLO antigen could be used to directly target DC in vivo. Immunisation of mice with GNP-LLO plus Advax™ adjuvant induced LLO-specific T-cell immunity and protection against Listeria challenge. Protection correlated with an increased frequency of splenic CD4(+) and CD8(+) T cells, NK cells and CD8α(+) DC, and Th1 cytokine production (IL-12, IFN-γ, TNF-α, and MCP-1), post-challenge. Enhanced T-cell epitope recruitment post-challenge was seen in the groups that received Advax™ adjuvant. Immunisation with GNP-LLO91-99 plus Advax™ adjuvant provided equally robust Listeria protection as the best DC vaccine strategy but without the complexity and cost, making this a highly promising strategy for development of a prophylactic vaccine against listeriosis. PMID:25659269

  13. Adjuvant dendritic cell vaccination induces tumor-specific immune responses in the majority of stage III melanoma patients

    PubMed Central

    Boudewijns, Steve; Bol, Kalijn F.; Schreibelt, Gerty; Westdorp, Harm; Textor, Johannes C.; van Rossum, Michelle M.; Scharenborg, Nicole M.; de Boer, Annemiek J.; van de Rakt, Mandy W. M. M.; Pots, Jeanne M.; van Oorschot, Tom G. M.; Duiveman-de Boer, Tjitske; Olde Nordkamp, Michel A.; van Meeteren, Wilmy S. E. C.; van der Graaf, Winette T. A.; Bonenkamp, Johannes J.; de Wilt, Johannes H. W.; Aarntzen, Erik H. J. G.; Punt, Cornelis J. A.; Gerritsen, Winald R.; Figdor, Carl G.; de Vries, I. Jolanda M.

    2016-01-01

    ABSTRACT Purpose: To determine the effectiveness of adjuvant dendritic cell (DC) vaccination to induce tumor-specific immunological responses in stage III melanoma patients. Experimental design: Retrospective analysis of stage III melanoma patients, vaccinated with autologous monocyte-derived DC loaded with tumor-associated antigens (TAA) gp100 and tyrosinase after radical lymph node dissection. Skin-test infiltrating lymphocytes (SKILs) obtained from delayed-type hypersensitivity skin-test biopsies were analyzed for the presence of TAA-specific CD8+ T cells by tetrameric MHC-peptide complexes and by functional TAA-specific T cell assays, defined by peptide-recognition (T2 cells) and/or tumor-recognition (BLM and/or MEL624) with specific production of Th1 cytokines and no Th2 cytokines. Results: Ninety-seven patients were analyzed: 21 with stage IIIA, 34 with stage IIIB, and 42 had stage IIIC disease. Tetramer-positive CD8+ T cells were present in 68 patients (70%), and 24 of them showed a response against all 3 epitopes tested (gp100:154–162, gp100:280–288, and tyrosinase:369–377) at any point during vaccinations. A functional T cell response was found in 62 patients (64%). Rates of peptide-recognition of gp100:154–162, gp100:280–288, and tyrosinase:369–377 were 40%, 29%, and 45%, respectively. Median recurrence-free survival and distant metastasis-free survival of the whole study population were 23.0 mo and 36.8 mo, respectively. Conclusions: DC vaccination induces a functional TAA-specific T cell response in the majority of stage III melanoma patients, indicating it is more effective in stage III than in stage IV melanoma patients. Furthermore, performing multiple cycles of vaccinations enhances the chance of a broader immune response. PMID:27622047

  14. Vaccine adjuvants as potential cancer immunotherapeutics.

    PubMed

    Temizoz, Burcu; Kuroda, Etsushi; Ishii, Ken J

    2016-07-01

    Accumulated evidence obtained from various clinical trials and animal studies suggested that cancer vaccines need better adjuvants than those that are currently licensed, which include the most commonly used alum and incomplete Freund's adjuvant, because of either a lack of potent anti-tumor immunity or the induction of undesired immunity. Several clinical trials using immunostimulatory adjuvants, particularly agonistic as well as non-agonistic ligands for TLRs, C-type lectin receptors, retinoic acid-inducible gene I-like receptors and stimulator of interferon genes, have revealed their therapeutic potential not only as vaccine adjuvants but also as anti-tumor agents. Recently, combinations of such immunostimulatory or immunomodulatory adjuvants have shown superior efficacy over their singular use, suggesting that seeking optimal combinations of the currently available or well-characterized adjuvants may provide a better chance for the development of novel adjuvants for cancer immunotherapy. PMID:27006304

  15. Vaccine adjuvants as potential cancer immunotherapeutics

    PubMed Central

    Temizoz, Burcu; Kuroda, Etsushi

    2016-01-01

    Accumulated evidence obtained from various clinical trials and animal studies suggested that cancer vaccines need better adjuvants than those that are currently licensed, which include the most commonly used alum and incomplete Freund’s adjuvant, because of either a lack of potent anti-tumor immunity or the induction of undesired immunity. Several clinical trials using immunostimulatory adjuvants, particularly agonistic as well as non-agonistic ligands for TLRs, C-type lectin receptors, retinoic acid-inducible gene I-like receptors and stimulator of interferon genes, have revealed their therapeutic potential not only as vaccine adjuvants but also as anti-tumor agents. Recently, combinations of such immunostimulatory or immunomodulatory adjuvants have shown superior efficacy over their singular use, suggesting that seeking optimal combinations of the currently available or well-characterized adjuvants may provide a better chance for the development of novel adjuvants for cancer immunotherapy. PMID:27006304

  16. The bovine viral diarrhea virus E2 protein formulated with a novel adjuvant induces strong, balanced immune responses and provides protection from viral challenge in cattle.

    PubMed

    Snider, Marlene; Garg, Ravendra; Brownlie, Robert; van den Hurk, Jan V; van Drunen Littel-van den Hurk, Sylvia

    2014-11-28

    Bovine viral diarrhea virus (BVDV) is still one of the most serious pathogens in cattle, meriting the development of improved vaccines. Recently, we developed a new adjuvant consisting of poly[di(sodium carboxylatoethylphenoxy)]-phosphazene (PCEP), either CpG ODN or poly(I:C), and an immune defense regulator (IDR) peptide. As this adjuvant has been shown to mediate the induction of robust, balanced immune responses, it was evaluated in an E2 subunit vaccine against BVDV in lambs and calves. The BVDV type 2 E2 protein was produced at high levels in a mammalian expression system and purified. When formulated with either CpG ODN or poly(I:C), together with IDR and PCEP, the E2 protein elicited high antibody titers and production of IFN-γ secreting cells in lambs. As the immune responses were stronger when poly(I:C) was used, the E2 protein with poly(I:C), IDR and PCEP was subsequently tested in cattle. Robust virus neutralizing antibodies as well as cell-mediated immune responses, including CD8(+) cytotoxic T cell (CTL) responses, were induced. The fact that CTL responses were demonstrated in calves vaccinated with an E2 protein subunit vaccine indicates that this adjuvant formulation promotes cross-presentation. Furthermore, upon challenge with a high dose of virulent BVDV-2, the vaccinated calves showed almost no temperature response, weight loss, leukopenia or virus replication, in contrast to the control animals, which had severe clinical disease. These data suggest that this E2 subunit formulation induces significant protection from BVDV-2 challenge, and thus is a promising BVDV vaccine candidate; in addition, the adjuvant platform has applications in bovine vaccines in general. PMID:25454860

  17. Synthetic innate defense regulator peptide combination using CpG ODN as a novel adjuvant induces long‑lasting and balanced immune responses.

    PubMed

    Yu, Chao-Heng; Luo, Zi-Chao; Li, Meng; Lu, Lian; Li, Zhan; Wu, Xiao-Zhe; Fan, Ying-Zi; Zhang, Hai-Long; Zhou, Bai-Ling; Wan, Yang; Men, Ke; Tian, Yao-Mei; Chen, Shuang; Yuan, Feng-Jiao; Xiang, Rong; Yang, Li

    2016-01-01

    Vaccines are critical tools for the prevention and treatment of several diseases. Adjuvants have been traditionally used to enhance immunity to vaccines and experimental antigens. In the present study, the adjuvant combination of CpG oligodeoxynucleotides (CpG ODN) and the innate defense regulator (IDR) peptide, IDR‑HH2, was evaluated for its ability to enhance and modulate the immune response when formulated with alum and the recombinant hepatitis B surface antigen (HBsAg). The CpG‑HH2 complex enhanced the secretions of tumor necrosis factor‑α, monocyte chemotactic protein 1 and interferon‑γ by human peripheral blood mononuclear cells and promoted murine bone marrow dentritic cell maturation. In addition, the present study demonstrated that IDR‑HH2 was chemotactic for human neutrophils, THP‑1 cells and RAW264.7 cells at concentrations between 2.5 and 40 µg/ml. The present study also observed that significantly higher anti‑HBs antibody titers, which were sustained at high levels for as long as 35 weeks following the boost immunization, were induced by the combination adjuvant, even when co‑administered with a commercial hepatitis B vaccine at a low antigen dose (0.1 µg HBsAg). Notably, the level of IgG2a was almost equal to the level of IgG1, indicating that a balanced T helper (Th)1/Th2 immune response was elicited by the novel vaccine, which was consistent with the ELISpot results. These data suggest that the CpG‑HH2 complex may be a potential effective adjuvant, which facilitates a reduction in the dose of antigen and induces long‑lasting, balanced immune responses. PMID:26647852

  18. Comparative antigen-induced gene expression profiles unveil novel aspects of susceptibility/resistance to adjuvant arthritis in rats.

    PubMed

    Yu, Hua; Lu, Changwan; Tan, Ming T; Moudgil, Kamal D

    2013-12-01

    Lewis (LEW) and Wistar Kyoto (WKY) rats of the same major histocompatibility complex (MHC) haplotype (RT.1(l)) display differential susceptibility to adjuvant-induced arthritis (AIA). LEW are susceptible while WKY are resistant to AIA. To gain insights into the mechanistic basis of these disparate outcomes, we compared the gene expression profiles of the draining lymph node cells (LNC) of these two rat strains early (day 7) following a potentially arthritogenic challenge. LNC were tested both ex vivo and after restimulation with the disease-related antigen, mycobacterial heat-shock protein 65. Biotin-labeled fragment cRNA was generated from RNA of LNC and then hybridized with an oligonucleotide-based DNA microarray chip. The differentially expressed genes (DEG) were compared by limiting the false discovery rate to <5% and fold change ≥2.0, and their association with quantitative trait loci (QTL) was analyzed. This analysis revealed overall a more active immune response in WKY than LEW rats. Important differences were observed in the association of DEG with QTL in LEW vs. WKY rats. Both the number of upregulated DEG associated with rat arthritis-QTL and their level of expression were relatively higher in LEW when compared to WKY rat; however, the number of downregulated DEG-associated with rat arthritis-QTL as well as AIA-QTL were found to be higher in WKY than in LEW rats. In conclusion, distinct gene expression profiles define arthritis-susceptible versus resistant phenotype of MHC-compatible inbred rats. These results would advance our understanding of the pathogenesis of autoimmune arthritis and might also offer potential novel targets for therapeutic purposes. PMID:23911410

  19. Improved Poisson solver for cfa/magnetron simulation

    SciTech Connect

    Dombrowski, G.E.

    1996-12-31

    E{sub dc}, the static field of a device having vane-shaped anodes, has been determined by application of Hockney`s method, which in turn uses Buneman`s cyclic reduction. This result can be used for both cfa and magnetrons, but does not solve the general space-charge fields. As pointed out by Hockney, the matrix of coupling capacitive factors between the vane-defining mesh points can also be used to solve the Poisson equation for the entire cathode-anode domain. Space-charge fields of electrons between anode electrodes can now be determined. This technique also computes the Ramo function for the entire region. This method has been applied to the magnetron. Extension to the cfa with many different space-charge bunches does not appear to be practicable. Calculations for the type 4J50 magnetron by the various degrees of accuracy in solving the Poisson equation are compared with experimental measurements.

  20. Inactivated Eyedrop Influenza Vaccine Adjuvanted with Poly(I:C) Is Safe and Effective for Inducing Protective Systemic and Mucosal Immunity

    PubMed Central

    Kim, Eun-Do; Han, Soo Jung; Byun, Young-Ho; Yoon, Sang Chul; Choi, Kyoung Sub; Seong, Baik Lin; Seo, Kyoung Yul

    2015-01-01

    The eye route has been evaluated as an efficient vaccine delivery routes. However, in order to induce sufficient antibody production with inactivated vaccine, testing of the safety and efficacy of the use of inactivated antigen plus adjuvant is needed. Here, we assessed various types of adjuvants in eyedrop as an anti-influenza serum and mucosal Ab production-enhancer in BALB/c mice. Among the adjuvants, poly (I:C) showed as much enhancement in antigen-specific serum IgG and mucosal IgA antibody production as cholera toxin (CT) after vaccinations with trivalent hemagglutinin-subunits or split H1N1 vaccine antigen in mice. Vaccination with split H1N1 eyedrop vaccine antigen plus poly(I:C) showed a similar or slightly lower efficacy in inducing antibody production than intranasal vaccination; the eyedrop vaccine-induced immunity was enough to protect mice from lethal homologous influenza A/California/04/09 (H1N1) virus challenge. Additionally, ocular inoculation with poly(I:C) plus vaccine antigen generated no signs of inflammation within 24 hours: no increases in the mRNA expression levels of inflammatory cytokines nor in the infiltration of mononuclear cells to administration sites. In contrast, CT administration induced increased expression of IL-6 cytokine mRNA and mononuclear cell infiltration in the conjunctiva within 24 hours of vaccination. Moreover, inoculated visualizing materials by eyedrop did not contaminate the surface of the olfactory bulb in mice; meanwhile, intranasally administered materials defiled the surface of the brain. On the basis of these findings, we propose that the use of eyedrop inactivated influenza vaccine plus poly(I:C) is a safe and effective mucosal vaccine strategy for inducing protective anti-influenza immunity. PMID:26355295

  1. Extract of the Chinese herbal formula Huo Luo Xiao Ling Dan inhibited adjuvant arthritis in rats

    PubMed Central

    Zhang, Rui-Xin; Fan, Arthur Yin; Zhou, An-Nan; Moudgil, Kamal D.; Ma, Zhong-Ze; Lee, David Yue-Wei; Fong, Harry HS; Berman, Brian M.; Lao, Lixing

    2010-01-01

    Ethnopharmacological relevance The herbal formula Huo Luo Xiao Ling Dan (HLXL) and its modifications have been used in traditional Chinese medicine for about one hundred years to alleviate pain and inflammation. Aim To investigate the effects of HLXL on complete Freund’s adjuvant (CFA)-induced multiple-joint arthritis in rats. Materials and Methods Male Lewis rats, 190–210g, were immunized subcutaneously at the base of the tail with 200 µl of heat-killed M. tuberculosis in mineral oil (5 mg/ml). HLXL (2.30g/kg and 4.60g/kg) or vehicle control (n=8 per group) was administered orally (i.g.) once a day between days 16–25 post-CFA injection. The rats were observed for signs of arthritis with arthritic changes (erythema, edema, induration) being scored on a scale of 0 to 4 of increasing severity using a standard scoring system. The maximum arthritis score per rat was 16. A plethysmometer was used to measure edema volume in each paw. Adverse effects of HLXL were monitored by closely observing the animals for unusual behavioral changes. Levels of tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) in local tissue were measured by enzyme-linked immunosorbent assay on day 25 post-CFA. Results HLXL significantly decreased arthritis scores between days 23–25 in the 2.30g/kg group and 21–25 in the 4.60g/kg group (p<0.05). It reduced paw edema on days 22 and 24 in the 2.30g/kg group and on days 20, 22 and 24 in the 4.60g/kg group compared to control (p<0.05). Local tissue TNF-α and IL-1β levels on day 25 post-CFA injection were significantly (p<0.05) lower in rats treated with HLXL than in control rats. No observable adverse effects were found. Conclusion The data suggest that HLXL produces significant anti-arthritic effects that may be mediated by suppressing pro-inflammatory cytokines, and it appears to be safe. PMID:19100323

  2. BCG Vaccine-Induced Neuroprotection in a Mouse Model of Parkinson's Disease

    PubMed Central

    Yong, Jing; Lacan, Goran; Dang, Hoa; Hsieh, Terry; Middleton, Blake; Wasserfall, Clive; Tian, Jide; Melega, William P.; Kaufman, Daniel L.

    2011-01-01

    There is a growing interest in using vaccination with CNS antigens to induce autoreactive T cell responses that home to damaged areas in the CNS and ameliorate neurodegenerative disease. Neuroprotective vaccine studies have focused on administering oligodendrocyte antigens or Copaxone® in complete Freund's adjuvant (CFA). Theoretical considerations, however, suggest that vaccination with a neuronal antigen may induce more robust neuroprotective immune responses. We assessed the neuroprotective potential of vaccines containing tyrosine hydroxylase (a neuronal protein involved in dopamine synthesis) or Copaxone® in CFA in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Surprisingly, we observed that the main beneficial factor in these vaccines was the CFA. Since the major immunogenic component in CFA is Mycobacterium tuberculosis, which closely related to the bacille Calmette-Guérin (BCG) that is used in human vaccines, we tested BCG vaccination in the MPTP mouse model. We observed that BCG vaccination partially preserved markers of striatal dopamine system integrity and prevented an increase in activated microglia in the substantia nigra of MPTP-treated mice. These results support a new neuroprotective vaccine paradigm in which general (nonself-reactive) immune stimulation in the periphery can limit potentially deleterious microglial responses to a neuronal insult and exert a neurorestorative effect in the CNS. Accordingly, BCG vaccination may provide a new strategy to augment current treatments for a wide range of neuropathological conditions. PMID:21304945

  3. BCG vaccine-induced neuroprotection in a mouse model of Parkinson's disease.

    PubMed

    Yong, Jing; Lacan, Goran; Dang, Hoa; Hsieh, Terry; Middleton, Blake; Wasserfall, Clive; Tian, Jide; Melega, William P; Kaufman, Daniel L

    2011-01-01

    There is a growing interest in using vaccination with CNS antigens to induce autoreactive T cell responses that home to damaged areas in the CNS and ameliorate neurodegenerative disease. Neuroprotective vaccine studies have focused on administering oligodendrocyte antigens or Copaxone® in complete Freund's adjuvant (CFA). Theoretical considerations, however, suggest that vaccination with a neuronal antigen may induce more robust neuroprotective immune responses. We assessed the neuroprotective potential of vaccines containing tyrosine hydroxylase (a neuronal protein involved in dopamine synthesis) or Copaxone® in CFA in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Surprisingly, we observed that the main beneficial factor in these vaccines was the CFA. Since the major immunogenic component in CFA is Mycobacterium tuberculosis, which closely related to the bacille Calmette-Guérin (BCG) that is used in human vaccines, we tested BCG vaccination in the MPTP mouse model. We observed that BCG vaccination partially preserved markers of striatal dopamine system integrity and prevented an increase in activated microglia in the substantia nigra of MPTP-treated mice. These results support a new neuroprotective vaccine paradigm in which general (nonself-reactive) immune stimulation in the periphery can limit potentially deleterious microglial responses to a neuronal insult and exert a neurorestorative effect in the CNS. Accordingly, BCG vaccination may provide a new strategy to augment current treatments for a wide range of neuropathological conditions. PMID:21304945

  4. A Lipopolysaccharide from Pantoea Agglomerans Is a Promising Adjuvant for Sublingual Vaccines to Induce Systemic and Mucosal Immune Responses in Mice via TLR4 Pathway.

    PubMed

    Fukasaka, Masahiro; Asari, Daisuke; Kiyotoh, Eiji; Okazaki, Arimichi; Gomi, Yasuyuki; Tanimoto, Takeshi; Takeuchi, Osamu; Akira, Shizuo; Hori, Mitsuhiko

    2015-01-01

    A lipopolysaccharide from Pantoea agglomerans (LPSpa) has been applied to various fields for human use as a Toll-like receptor 4 ligand and its safety has been confirmed. Here, we showed for the first time the application of LPSpa as an effective mucosal adjuvant for activating vaccine-induced antigen specific immune responses. Mice sublingually immunized with influenza vaccine (HA split vaccine) with LPSpa induced both HA-specific IgG (systemic) and IgA (mucosal) antibody responses, which led to a significant increase in survival rate against lethal influenza virus challenge compared with subcutaneous vaccination. After sublingual administration of ovalbumin with LPSpa, ovalbumin-specific mucosal IgA responses were induced at both mucosal surfaces close to the immunized site and at remote mucosal surfaces. Sublingual administration of LPSpa evoked local antigen-uptake by dendritic cells in cervical lymph nodes. LPSpa induced cytokine production and the maturation and proliferation of innate immune cells via Toll-like receptor 4 in dendritic cells. Collectively, these results suggest that LPSpa can be used as an effective mucosal adjuvant to stimulate and activate local innate immune cells to improve and enhance mucosal vaccine potency against various pathogens. PMID:25978818

  5. A Lipopolysaccharide from Pantoea Agglomerans Is a Promising Adjuvant for Sublingual Vaccines to Induce Systemic and Mucosal Immune Responses in Mice via TLR4 Pathway

    PubMed Central

    Kiyotoh, Eiji; Okazaki, Arimichi; Gomi, Yasuyuki; Tanimoto, Takeshi; Takeuchi, Osamu; Akira, Shizuo; Hori, Mitsuhiko

    2015-01-01

    A lipopolysaccharide from Pantoea agglomerans (LPSpa) has been applied to various fields for human use as a Toll-like receptor 4 ligand and its safety has been confirmed. Here, we showed for the first time the application of LPSpa as an effective mucosal adjuvant for activating vaccine-induced antigen specific immune responses. Mice sublingually immunized with influenza vaccine (HA split vaccine) with LPSpa induced both HA-specific IgG (systemic) and IgA (mucosal) antibody responses, which led to a significant increase in survival rate against lethal influenza virus challenge compared with subcutaneous vaccination. After sublingual administration of ovalbumin with LPSpa, ovalbumin-specific mucosal IgA responses were induced at both mucosal surfaces close to the immunized site and at remote mucosal surfaces. Sublingual administration of LPSpa evoked local antigen-uptake by dendritic cells in cervical lymph nodes. LPSpa induced cytokine production and the maturation and proliferation of innate immune cells via Toll-like receptor 4 in dendritic cells. Collectively, these results suggest that LPSpa can be used as an effective mucosal adjuvant to stimulate and activate local innate immune cells to improve and enhance mucosal vaccine potency against various pathogens. PMID:25978818

  6. A Novel Prime and Boost Regimen of HIV Virus-Like Particles with TLR4 Adjuvant MPLA Induces Th1 Oriented Immune Responses against HIV.

    PubMed

    Poteet, Ethan; Lewis, Phoebe; Li, Feng; Zhang, Sheng; Gu, Jianhua; Chen, Changyi; Ho, Sam On; Do, Thai; Chiang, SuMing; Fujii, Gary; Yao, Qizhi

    2015-01-01

    HIV virus-like particles (VLPs) present the HIV envelope protein in its native conformation, providing an ideal vaccine antigen. To enhance the immunogenicity of the VLP vaccine, we sought to improve upon two components; the route of administration and the additional adjuvant. Using HIV VLPs, we evaluated sub-cheek as a novel route of vaccine administration when combined with other conventional routes of immunization. Of five combinations of distinct prime and boost sequences, which included sub-cheek, intranasal, and intradermal routes of administration, intranasal prime and sub-cheek boost (IN+SC) resulted in the highest HIV-specific IgG titers among the groups tested. Using the IN+SC regimen we tested the adjuvant VesiVax Conjugatable Adjuvant Lipid Vesicles (CALV) + monophosphoryl lipid A (MPLA) at MPLA concentrations of 0, 7.5, 12.5, and 25 μg/dose in combination with our VLPs. Mice that received 12.5 or 25 μg/dose MPLA had the highest concentrations of Env-specific IgG2c (20.7 and 18.4 μg/ml respectively), which represents a Th1 type of immune response in C57BL/6 mice. This was in sharp contrast to mice which received 0 or 7.5 μg MPLA adjuvant (6.05 and 5.68 μg/ml of IgG2c respectively). In contrast to IgG2c, MPLA had minor effects on Env-specific IgG1; therefore, 12.5 and 25 μg/dose of MPLA induced the optimal IgG1/IgG2c ratio of 1.3. Additionally, the percentage of germinal center B cells increased significantly from 15.4% in the control group to 31.9% in the CALV + 25 μg MPLA group. These mice also had significantly more IL-2 and less IL-4 Env-specific CD8+ T cells than controls, correlating with an increased percentage of Env-specific central memory CD4+ and CD8+ T cells. Our study shows the strong potential of IN+SC as an efficacious route of administration and the effectiveness of VLPs combined with MPLA adjuvant to induce Env specific Th1-oriented HIV-specific immune responses. PMID:26312747

  7. Crystallization and preliminary X-ray diffraction analysis of CfaE, the adhesive subunit of the CFA/I fimbriae from human enterotoxigenic Escherichia coli

    SciTech Connect

    Li, Yong-Fu; Poole, Steven; Rasulova, Fatima; Esser, Lothar; Savarino, Stephen J.; Xia, Di

    2006-02-01

    The adhesin CfaE of the CFA/I fimbriae from human enterotoxigenic E. coli has been crystallized. CfaE crystals diffracted X-rays to better than 2.4 Å and phasing was solved by the SIRAS method. Enterotoxigenic Escherichia coli (ETEC) represents a formidable food and waterborne diarrheal disease threat of global importance. The first step in ETEC pathogenesis is bacterial attachment to small-intestine epithelial cells via adhesive fimbriae, many of which are genetically related to the prototype colonization factor antigen I (CFA/I). The minor fimbrial subunit CfaE is required for initiation of CFA/I fimbrial assembly and mediates bacterial attachment to host cell-surface receptors. A donor-strand complemented variant of CfaE (dscCfaE) was expressed with a hexahistidine tag, purified to homogeneity and crystallized using the hanging-drop vapor-diffusion method. X-ray diffraction data sets were collected to 2.4 Å resolution for both native and derivatized crystals and showed the symmetry of space group P6{sub 2}22, with unit-cell parameters a = b = 142.9, c = 231.9 Å. Initial phases were derived from the SIRAS approach and electron density showed two molecules in the crystallographic asymmetric unit. Sequence assignments were aided by anomalous signals from the selenium of an SeMet-derivatized crystal and from S atoms of a native crystal.

  8. Polysaccharides: Candidates of promising vaccine adjuvants.

    PubMed

    Li, Pingli; Wang, Fengshan

    2015-04-01

    Aluminium-based adjuvants remain the only adjuvants approved for human use in the USA for over 80 years because of alum's simplicity, tolerability, safety and cost-efficiency. Recent development of vaccines, especially the increasing applications of recombinant subunit and synthetic vaccines, makes aluminium adjuvants cannot stimulate enough immunity to the antigens, since aluminium adjuvants can only induce Th2 type immune responses. So, novel adjuvants are urgent to make up the disadvantages of aluminium adjuvants. However, some major hurdles need to be overcome, not only the scientific knowledge of adjuvants but also unacceptable side-effects and toxicity. A number of carbohydrate-based polysaccharides from plant, bacterial, yeast and synthetic sources can act as pathogen-associated molecular patterns (PAMPs) and recognize pattern recognition receptors (PRRs) on immune cells, followed by triggering innate immunity and regulating adaptive immunity. What is more, polysaccharides are safe and biodegradable without tissue deposits as observed in aluminium adjuvants. Therefore, polysaccharide-based compounds and formulations are potential vaccine adjuvant candidates. Here, we mainly review polysaccharide-based adjuvants investigated in recent years. PMID:25994059

  9. Autoimmune/auto-inflammatory syndrome induced by adjuvants (ASIA) after quadrivalent human papillomavirus vaccination in Colombians: a call for personalised medicine.

    PubMed

    Anaya, Juan-Manuel; Reyes, Benjamin; Perdomo-Arciniegas, Ana M; Camacho-Rodríguez, Bernardo; Rojas-Villarraga, Adriana

    2015-01-01

    This was a case study in which 3 patients with autoimmune/auto-inflammatory syndrome induced by adjuvants (ASIA) after quadrivalent human papillomavirus vaccination (HPV) were evaluated and described. All the patients were women. Diagnosis consisted of HLA-B27 enthesitis related arthritis, rheumatoid arthritis and systemic lupus erythematous, respectively. Our results highlight the risk of developing ASIA after HPV vaccination and may serve to increase the awareness of such a complication. Factors that are predictive of developing autoimmune diseases should be examined at the population level in order to establish preventive measures in at-risk individuals for whom healthcare should be personalized and participatory. PMID:25962455

  10. When uncommon and common coalesce: adult onset Still's disease associated with breast augmentation as part of autoimmune syndrome induced by adjuvants (ASIA).

    PubMed

    Dagan, A; Kogan, M; Shoenfeld, Y; Segal, G

    2016-06-01

    Adult onset Still's disease (AOSD) is an uncommon, multisystemic, auto-inflammatory disorder, while breast augmentation is a very common cosmetic procedure. We describe a case in which these two coalesce, AOSD, manifested with pleuritis and pericarditis, developed after breast mammoplasty. The pathogenetic, missing link, behind the development of AOSD following mammoplasty, is thought to be the autoimmune (auto-inflammatory) syndrome induced by adjuvants (ASIA). We reviewed other cases of AOSD associated with breast mammoplasty published to date and the literature regarding AOSD and ASIA syndrome. The review is followed by a short debate of whether silicone implants should be explanted in similar, future cases. PMID:25604318

  11. Matrix MTM adjuvanted virosomal H5N1 vaccine induces balanced Th1/Th2 CD4+ T cell responses in man

    PubMed Central

    Pedersen, Gabriel K; Sjursen, Haakon; Nøstbakken, Jane K; Jul-Larsen, Åsne; Hoschler, Katja; Cox, Rebecca J

    2014-01-01

    T cellular responses play a significant role in mediating protective immune responses against influenza in humans. In the current study, we evaluated the ability of a candidate virosomal H5N1 vaccine adjuvanted with Matrix MTM to induce CD4+ and CD8+ T cell responses in a phase 1 clinical trial. We vaccinated 60 healthy adult volunteers (at days 0 and 21) with 30 μg haemagglutinin (HA) alone or 1.5, 7.5, or 30 μg HA formulated with Matrix MTM. To evaluate the T cellular responses, lymphocytes were stimulated in vitro with homologous (A/Vietnam/1194/2004 [H5N1]) and heterologous H5N1 (A/Anhui/1/05 or A/Bar-headed Goose/Qinghai/1A/05) antigens. The antigen-specific cytokine responses were measured by intracellular cytokine staining and by multiplex (Luminex) assays. An increase in CD4+ Th1 and Th2 cytokines was detected 21 days after the first vaccine dose. No increase in Th cytokine responses was observed after the second dose, although it is possible that the cytokine levels peaked earlier than sampling point at day 42. Formulation with the Matrix MTM adjuvant augmented both the homologous and cross-reactive cytokine response. Antigen-specific CD8+ T cell responses were detected only in a few vaccinated individuals. The concentrations of Th1 and to a lesser extent, Th2 cytokines at 21 days post-vaccination correlated moderately with subsequent days 35 and 180 serological responses as measured by the microneutralisation, haemagglutination inhibition, and single radial hemolysis assays. Results presented here show that the virosomal H5N1 vaccine induced balanced Th1/Th2 cytokine responses and that Matrix MTM is a promising adjuvant for future development of candidate pandemic influenza vaccines. PMID:25424948

  12. New pre-pandemic influenza vaccines: an egg- and adjuvant-independent human adenoviral vector strategy induces long-lasting protective immune responses in mice.

    PubMed

    Hoelscher, M A; Jayashankar, L; Garg, S; Veguilla, V; Lu, X; Singh, N; Katz, J M; Mittal, S K; Sambhara, S

    2007-12-01

    Highly pathogenic avian H5N1 influenza viruses that are currently circulating in southeast Asia may acquire the potential to cause the next influenza pandemic. A number of alternate approaches are being pursued to generate cross-protective, dose-sparing, safe, and effective vaccines, as traditional vaccine approaches, i.e., embryonated egg-grown, are not immunogenic. We developed a replication-incompetent adenoviral vector-based, adjuvant- and egg-independent pandemic influenza vaccine strategy as a potential alternative to conventional egg-derived vaccines. In this paper, we address suboptimal dose and longevity of vaccine-induced protective immunity and demonstrate that a vaccine dose as little as 1 x 10(6) plaque-forming unit (PFU) is sufficient to induce protective immune responses against a highly pathogenic H5N1 virus. Furthermore, the vaccine-induced humoral and cellular immune responses and protective immunity persisted at least for a year. PMID:17957181

  13. Human Anti-CD40 Antibody and Poly IC:LC Adjuvant Combination Induces Potent T Cell Responses in the Lung of Non-Human Primates1

    PubMed Central

    Thompson, Elizabeth A; Liang, Frank; Lindgren, Gustaf; Sandgren, Kerrie J; Quinn, Kylie M; Darrah, Patricia A; Koup, Richard A; Seder, Robert A; Kedl, Ross M; Loré, Karin

    2015-01-01

    Non-live vaccine platforms that induce potent cellular immune responses in mucosal tissue would have broad application for vaccines against infectious diseases and tumors. Induction of cellular immunity could be optimized by targeted activation of multiple innate and co-stimulatory signaling pathways, such as CD40 or toll-like receptors (TLRs). In this study, we evaluated immune activation and elicitation of T cell responses in non-human primates (NHPs) after immunization with peptide antigens adjuvanted with an agonistic αCD40Ab, with or without the TLR3 ligand poly IC:LC. We found that intravenous administration of the αCD40Ab induced rapid and transient innate activation characterized by IL-12 production and upregulated co-stimulatory and lymph node homing molecules on dendritic cells. Using fluorescently-labeled Abs for in vivo tracking, the αCD40Ab bound to all leucocytes, except T cells, and disseminated to multiple organs. CD4+ and CD8+ T cell responses were significantly enhanced when the αCD40Ab was co-administered with poly IC:LC compared to either adjuvant given alone and were almost exclusively compartmentalized to the lung. Notably, antigen-specific T cells in the bronchoalveolar lavage were sustained at ~5–10%. These data indicate that systemic administration of αCD40Ab may be particularly advantageous for vaccines and/or therapies requiring T cell immunity in the lung. PMID:26123354

  14. Human Anti-CD40 Antibody and Poly IC:LC Adjuvant Combination Induces Potent T Cell Responses in the Lung of Nonhuman Primates.

    PubMed

    Thompson, Elizabeth A; Liang, Frank; Lindgren, Gustaf; Sandgren, Kerrie J; Quinn, Kylie M; Darrah, Patricia A; Koup, Richard A; Seder, Robert A; Kedl, Ross M; Loré, Karin

    2015-08-01

    Nonlive vaccine platforms that induce potent cellular immune responses in mucosal tissue would have broad application for vaccines against infectious diseases and tumors. Induction of cellular immunity could be optimized by targeted activation of multiple innate and costimulatory signaling pathways, such as CD40 or TLRs. In this study, we evaluated immune activation and elicitation of T cell responses in nonhuman primates after immunization with peptide Ags adjuvanted with an agonistic anti-CD40Ab, with or without the TLR3 ligand poly IC:LC. We found that i.v. administration of the anti-CD40Ab induced rapid and transient innate activation characterized by IL-12 production and upregulated costimulatory and lymph node homing molecules on dendritic cells. Using fluorescently labeled Abs for in vivo tracking, we found that the anti-CD40Ab bound to all leukocytes, except T cells, and disseminated to multiple organs. CD4(+) and CD8(+) T cell responses were significantly enhanced when the anti-CD40Ab was coadministered with poly IC:LC compared with either adjuvant given alone and were almost exclusively compartmentalized to the lung. Notably, Ag-specific T cells in the bronchoalveolar lavage were sustained at ∼5-10%. These data indicate that systemic administration of anti-CD40Ab may be particularly advantageous for vaccines and/or therapies that require T cell immunity in the lung. PMID:26123354

  15. Anti-arthritic activity of luteolin in Freund's complete adjuvant-induced arthritis in rats by suppressing P2X4 pathway.

    PubMed

    Shi, Fengchao; Zhou, Dun; Ji, Zhongqiu; Xu, Zhaofeng; Yang, Huilin

    2015-01-25

    To investigate anti-arthritic activity of luteolin (Lut) in Freund's complete adjuvant (FCA)-induced arthritis (AA) in rats. AA was induced by injecting with Freund's complete adjuvant (FCA). Male rats were randomly divided into five groups with 10 mice in each group: (1) control group (saline), (2) AA group, (3) AA+Diclofenac Sodium (AA+DS, 5 mg/kg), (4) AA+Lut (20 mg/kg), (5) AA+Lut (40 mg/kg). Male SD rats were subjected to treatment with Lut at 10 and 20 mg/kg from days 18 to 24 after immunization. Arthritic scores, tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interleukin-17 (IL-17), paw histopathology and the proteins of P2X4 pathway were assessed at the end of the experiment. Lut reduced the severity of arthritic scores during the experimental period as compared with positive control (RA). Lut significantly suppressed TNF-α, IL-6, IL-1β and IL-17 as compared with RA group. Histopathological examination indicated that Lut alleviated infiltration of inflammatory cells and synovial hyperplasia as well as protected joint destruction. Lut significantly suppressed P2X4, NLRP1, ASC, and Caspase-1p10. Lut may be a potential preventive or therapeutic candidate for the treatment of inflammation and arthritis. PMID:25450234

  16. Enhancement of anti arthritic effect of quercetin using thioglycolic acid-capped cadmium telluride quantum dots as nanocarrier in adjuvant induced arthritic Wistar rats.

    PubMed

    Jeyadevi, R; Sivasudha, T; Rameshkumar, A; Ananth, D Arul; Aseervatham, G Smilin Bell; Kumaresan, K; Kumar, L Dinesh; Jagadeeswari, S; Renganathan, R

    2013-12-01

    In this present study, we investigated thio glycolic acid-capped cadmium telluride quantum dots (TGA-CdTe QDs) as nano carrier to study the antiarthritic activity of quercetin on adjuvant induced arthritic Wistar rats. The free radical scavenging activity of QDs-QE complex was evaluated by 2,2'-azinobis-3-ethylbenzothiazoline-6-sulphonic acid (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO) and superoxide anion scavenging assays. Fifteen days after adjuvant induction, arthritic rats received QDs-QE complex orally at the dose of 0.2 and 0.4mg/kg daily for 3 weeks. Diclofenac sodium (DF) was used as a reference drug. Administration of QDs-QE complex showed a significant reduction in inflammation and improvement in cartilage regeneration. Treatment with QDs-QE complex significantly (P<0.05) reduced the expressions lipid peroxidation and showed significant (P<0.05) increase in activities of antioxidant enzymes such as superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GPx) catalase (CAT) levels in paw tissue. C-reactive protein (CRP), rheumatoid factor (RF), red blood cells (RBC) and white blood cells (WBC) count and erythrocyte sedimentation rate (ESR) of experimental animals were also estimated. Histology of hind limb tissue in experimental groups confirmed the complete cartilage regeneration in arthritis induced rats treated with QDs-QE complex. Based on our findings, we suggest that the QDs act as nano carrier for the drugs used in the treatment of various degenerative diseases. PMID:23994749

  17. Void statistics of the CfA redshift survey

    NASA Technical Reports Server (NTRS)

    Vogeley, Michael S.; Geller, Margaret J.; Huchra, John P.

    1991-01-01

    Clustering properties of two samples from the CfA redshift survey, each containing about 2500 galaxies, are studied. A comparison of the velocity distributions via a K-S test reveals structure on scales comparable with the extent of the survey. The void probability function (VPF) is employed for these samples to examine the structure and to test for scaling relations in the galaxy distribution. The galaxy correlation function is calculated via moments of galaxy counts. The shape and amplitude of the correlation function roughly agree with previous determinations. The VPFs for distance-limited samples of the CfA survey do not match the scaling relation predicted by the hierarchical clustering models. On scales not greater than 10/h Mpc, the VPFs for these samples roughly follow the hierarchical pattern. A variant of the VPF which uses nearly all the data in magnitude-limited samples is introduced; it accounts for the variation of the sampling density with velocity in a magnitude-limited survey.

  18. Antinociceptive Effect of Tephrosia sinapou Extract in the Acetic Acid, Phenyl-p-benzoquinone, Formalin, and Complete Freund's Adjuvant Models of Overt Pain-Like Behavior in Mice

    PubMed Central

    Martinez, Renata M.; Zarpelon, Ana C.; Domiciano, Talita P.; Georgetti, Sandra R.; Baracat, Marcela M.; Moreira, Isabel C.; Andrei, Cesar C.; Verri, Waldiceu A.; Casagrande, Rubia

    2016-01-01

    Tephrosia toxicaria, which is currently known as Tephrosia sinapou (Buc'hoz) A. Chev. (Fabaceae), is a source of compounds such as flavonoids. T. sinapou has been used in Amazonian countries traditional medicine to alleviate pain and inflammation. The purpose of this study was to evaluate the analgesic effects of T. sinapou ethyl acetate extract in overt pain-like behavior models in mice by using writhing response and flinching/licking tests. We demonstrated in this study that T. sinapou extract inhibited, in a dose (1–100 mg/kg) dependent manner, acetic acid- and phenyl-p-benzoquinone- (PBQ-) induced writhing response. Furthermore, it was active via intraperitoneal, subcutaneous, and peroral routes of administration. T. sinapou extract also inhibited formalin- and complete Freund's adjuvant- (CFA-) induced flinching/licking at 100 mg/kg dose. In conclusion, these findings demonstrate that T. sinapou ethyl acetate extract reduces inflammatory pain in the acetic acid, PBQ, formalin, and CFA models of overt pain-like behavior. Therefore, the potential of analgesic activity of T. sinapou indicates that it deserves further investigation. PMID:27293981

  19. Topological analysis of the CfA redshift survey

    NASA Technical Reports Server (NTRS)

    Vogeley, Michael S.; Park, Changbom; Geller, Margaret J.; Huchra, John P.; Gott, J. Richard, III

    1994-01-01

    We study the topology of large-scale structure in the Center for Astrophysics Redshift Survey, which now includes approximately 12,000 galaxies with limiting magnitude m(sub B) is less than or equal to 15.5. The dense sampling and large volume of this survey allow us to compute the topology on smoothing scales from 6 to 20/h Mpc; we thus examine the topology of structure in both 'nonlinear' and 'linear' regimes. On smoothing scales less than or equal to 10/h Mpc this sample has 3 times the number of resolution elements of samples examined in previous studies. Isodensity surface of the smoothed galaxy density field demonstrate that coherent high-density structures and large voids dominate the galaxy distribution. We compute the genus-threshold density relation for isodensity surfaces of the CfA survey. To quantify phase correlation in these data, we compare the CfA genus with the genus of realizations of Gaussian random fields with the power spectrum measured for the CfA survey. On scales less than or equal to 10/h Mpc the observed genus amplitude is smaller than random phase (96% confidence level). This decrement reflects the degree of phase coherence in the observed galaxy distribution. In other words the genus amplitude on these scales is not good measure of the power spectrum slope. On scales greater than 10/h Mpc, where the galaxy distribution is rougly in the 'linear' regime, the genus ampitude is consistent with the random phase amplitude. The shape of the genus curve reflects the strong coherence in the observed structure; the observed genus curve appears broader than random phase (94% confidence level for smoothing scales less than or equal to 10/h Mpc) because the topolgoy is spongelike over a very large range of density threshold. This departre from random phase consistent with a distribution like a filamentary net of 'walls with holes.' On smoothing scales approaching approximately 20/h Mpc the shape of the CfA genus curve is consistent with random phase

  20. Combination of coenzyme Q10 with methotrexate suppresses Freund's complete adjuvant-induced synovial inflammation with reduced hepatotoxicity in rats: Effect on oxidative stress and inflammation.

    PubMed

    Tawfik, Mona K

    2015-01-01

    Methotrexate (MTX) is a cornerstone disease modifying anti-rheumatic drug. One of its major drawbacks is hepatotoxicity, resulting in poor compliance of therapy. Coenzyme Q10 (CoQ10) is an antioxidant and anti-inflammatory compound, possessing both anti-arthritic and hepatoprotective potential. The present study was carried out to evaluate the effect of CoQ10 (10mg/kg) alone and in combination with MTX (2mg/kg) on the progression of adjuvant-induced arthritis in rats, and to elucidate the potential properties of CoQ10 in ameliorating MTX-induced liver damage in rats. Rats were assigned to; normal, arthritic, MTX treated, CoQ10 treated or a combination of MTX and CoQ10. CoQ10 administration potentiated the antiarthritic effect of MTX. Moreover, the combination therapy was effective in attenuating the severity of MTX-induced liver damage displayed by the improvement in hepatospecific serum markers and confirmed by the histo-pathological evaluation. Additionally, it attenuated the hepatic oxidative stress and the intensity of inflammatory mediators associated with MTX administration as evident by the regulation of oxidant/anti-oxidant balance and the inhibitory effects on TNF-α and IL-6 levels. These results revealed that CoQ10 can serve as a useful adjuvant and promote the safe use of MTX in the management of arthritis, not only by potentiating the antiarthritic effect of MTX, but also by alleviating MTX-induced hepatocellular injury. PMID:25488045

  1. Propionibacterium acnes induces an adjuvant effect in B-1 cells and affects their phagocyte differentiation via a TLR2-mediated mechanism.

    PubMed

    Gambero, Monica; Teixeira, Daniela; Butin, Liane; Ishimura, Mayari Eika; Mariano, Mario; Popi, Ana Flavia; Longo-Maugéri, Ieda Maria

    2016-09-01

    B-1 lymphocytes are present in large numbers in the mouse peritoneal cavity, as are macrophages, and are responsible for natural IgM production. These lymphocytes migrate to inflammatory foci and are also involved in innate immunity. It was also demonstrated that B-1 cells are able to differentiated into phagocytes (B-1CDP), which is characterized by expression of F4/80 and increased phagocytic activity. B-1 cell responses to antigens and adjuvants are poorly characterized. It has been shown that Propionibacterium acnes suspensions induce immunomodulatory effects in both macrophages and B-2 lymphocytes. We recently demonstrated that this bacterium has the ability to increase B-1 cell populations both in vitro and in vivo. P. acnes induces B-1CDP differentiation, increases the expression of TLR2, TLR4 and TLR9 and augments the expression of CD80, CD86 and CD40 in B-1 and B-1CDP cells. Because P. acnes has been shown to modulate TLR expression, in this study, we investigated the role of TLR2 and TLR4 in B-1 cell population, including B-1CDP differentiation and phagocytic activity in vitro and in vivo. Interestingly, we have demonstrated that TLR2 signaling could be involved in the increase in the B-1 cell population induced by P. acnes. Furthermore, the early differentiation of B-1CDP is also dependent of TLR2. It was also observed that TLR signals also interfere in the phagocytic ability of B-1 cells and their phagocytes. According to these data, it is clear that P. acnes promotes an important adjuvant effect in B-1 cells by inducing them to differentiate into B-1CDP cells and modulates their phagocytic functions both in vivo and in vitro. Moreover, most of these effects are mediated primarily via TLR2. These data reinforce the findings that such bacterial suspensions have powerful adjuvant properties. The responses of B-1 cells to exogenous stimulation indicate that these cells are important to the innate immune response. PMID:27233619

  2. Protective effect of apigenin on Freund's complete adjuvant-induced arthritis in rats via inhibiting P2X7/NF-κB pathway.

    PubMed

    Chang, Xiayun; He, He; Zhu, Lingpeng; Gao, Jin; Wei, Tingting; Ma, Zhanqian; Yan, Tianhua

    2015-07-01

    To evaluate the effect of apigenin (AP) on arthritis in rats stimulated by Freund's complete adjuvant (FCA) was the main purpose of the investigation. Arthritis model was established by the administration of 0.1 ml FCA in the palmar surface. AP and diclofenac sodium (DS) were administered to explore and evidence the protective effects against adjuvant-induced arthritis (AA). Cytokines tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) were detected to assess the anti-inflammatory effect of AP. Besides, pathological conditions were examined in rat paws. Related-proteins of nuclear factor kappa B (NF-κB) signal pathway activated by P2X7 were investigated to determine the molecular mechanism of AP and their expressions were measured by western blot. The data showed that AP significantly suppressed the expressions of P2X7/NF-κB signal-related proteins and alleviated inflammatory reactions. Therefore, it was assumed that AP might be a potential therapeutic candidate to treat arthritis. PMID:25935278

  3. Sublingual vaccination with sonicated Salmonella proteins and mucosal adjuvant induces mucosal and systemic immunity and protects mice from lethal enteritis.

    PubMed

    Huang, Ching-Feng; Wu, Tzee-Chung; Wu, Chia-Chao; Lee, Chin-Cheng; Lo, Wen-Tsung; Hwang, Kwei-Shuai; Hsu, Mu-Ling; Peng, Ho-Jen

    2011-07-01

    Salmonella enteritidis is one of the most common pathogens of enteritis. Most experimental vaccines against Salmonella infection have been applied through injections. This is a new trial to explore the effect of sublingual administration of Salmonella vaccines on systemic and mucosal immunity. Adult BALB/c mice were sublingually vaccinated with sonicated Salmonella proteins (SSP) alone, or plus adjuvant CpG DNA (CpG) or cholera toxin (CT). They were boosted 2 weeks later. Saliva specific secretory IgA (SIgA) antibody responses were significantly stimulated in the mice vaccinated with SSP only or together with CpG or CT. Whereas the mice sublingually vaccinated with SSP and CpG had higher spleen cell IFN-γ production and serum specific IgG2a antibody responses, those receiving SSP and CT showed enhanced spleen cell IL-4, IL-5 and IL-6 production, and serum specific IgG1 antibody responses. After oral challenge with live S. enteritidis, the same strain of the source of SSP, immune protection in those sublingually vaccinated with SSP and CpG or CT was found to prevent intestinal necrosis and to render a higher survival rate. In conclusion, sublingual vaccination together with mucosal adjuvant CpG or CT is a simple but effective way against enteric bacterial pathogens. PMID:21635554

  4. Effect of polaprezinc on impaired healing of chronic gastric ulcers in adjuvant-induced arthritic rats--role of insulin-like growth factors (IGF)-1.

    PubMed

    Kato, S; Tanaka, A; Ogawa, Y; Kanatsu, K; Seto, K; Yoneda, T; Takeuchi, K

    2001-01-01

    Polaprezinc, N-(3-aminopropionyl)-L-histidinatozinc, has been shown to stimulate the production of insulin-like growth factor-1 (IGF-1) in mesenchymal cells, the polypeptide playing a role in the gastric epithelial wound repair. The present study was performed to examine the effect of polaprezinc on the impaired healing of chronic gastric ulcers in adjuvant-induced arthritic rats, in relation to IGF-1. Arthritis was induced in male Dark Agouti (DA) rats by a single injection of Freund's complete adjuvant (FCA), and the gastric ulcers were induced by thermal cauterization (70 degrees C for 30 sec) 7 days after FCA injection. Omeprazole (30 mg/kg) was administered p.o. once daily, while recombinant human IGF-1 (rhIGF-1) (30 micrograms/kg, s.c.) or polaprezinc (3-10 mg/kg, p.o.) was administered twice daily, starting from 3 days after ulceration for 14 days. The healing of gastric ulcers was significantly delayed in arthritic rats as compared to normal rats on day 10 and 17 following ulceration. The expression of IGF-1 mRNA was markedly increased in the ulcerated mucosa, but this response was apparently attenuated in arthritic rats. Repeated administration of polaprezinc accelerated the healing of gastric ulcers in both normal and arthritic rats, in a dose-dependent manner, and this effect was more pronounced in arthritic rats. Likewise, treatment with omeprazole also significantly promoted the healing of gastric ulcers in both normal and arthritic rats. On the other hand, rhIGF-1 significantly promoted the gastric ulcer healing in arthritic rats without any effect on that in normal rats. These results suggest that the impaired healing of chronic gastric ulcers in arthritic rats is, at least partly, accounted for by less expression of IGF-1, and the polaprezinc improves the delayed healing of gastric ulcers in arthritic rats, probably through an increase in IGF-1 production. PMID:11208487

  5. Intranasal immunization of mice with CpG DNA induces strong systemic and mucosal responses that are influenced by other mucosal adjuvants and antigen distribution.

    PubMed Central

    McCluskie, M. J.; Weeratna, R. D.; Davis, H. L.

    2000-01-01

    BACKGROUND: Synthetic oligodeoxynucleotides (ODN) containing immunostimulatory cytosine-guanine phosphate-linked dinucleotide (CpG) motifs are potent systemic and mucosal adjuvants in mice that have synergistic action with numerous other adjuvants, including alum and cholera toxin (CT). Herein, we evaluate CpG ODN with intranasal (IN) delivery of purified hepatitis B surface antigen (HBsAg), relative to and in combination with CT, Escherichia coli heat labile enterotoxin (LT), the B subunit of CT (CTB), and a nontoxic derivative of LT (LTK63). MATERIALS AND METHODS: BALB/c mice were immunized by IN administration of HBsAg, alone or combined with CT, LT, CTB, or LTK63, and/or CpG ODN, or non-CpG control ODN. In addition, the effect of low-or high-volume administration was assessed, in order to target upper respiratory or entire respiratory tract, respectively. HBsAg-specific systemic (immunoglobulins: IgG, IgG1, IgG2a in plasma) and mucosal (IgA in fecal, lung, vaginal, saliva, and gut samples) humoral responses, as well as cell-mediated immune responses including T-cell proliferation and cytokines (interleukins: IL-4, IL-5; interferon: IFN-gamma) were evaluated. RESULTS: CpG ODN, CT, and LT augmented anti-HBs titers equally, and more so than did CTB or LTK63. CpG ODN acted synergistically with CT and LT, but not CTB or LTK63 to enhance anti-HBs titers. Nevertheless, CpG ODN induced a more Th1-like response for all combinations, compared with the same formulation without CpG. Strength of induced systemic and mucosal immune responses was better with IN delivery of a large volume. A small volume required multiple administrations and higher doses of antigen and adjuvant for equal results. This suggests that delivery of antigen to the lung and/or diges-tive system is superior to delivery to the nasal cavity. CONCLUSIONS: Our results suggest that the synergy between CpG ODN and native toxins (CT, LT) may depend on their enzymatic activity and that the lack of synergy

  6. A2A Adenosine Receptors Are Differentially Modulated by Pharmacological Treatments in Rheumatoid Arthritis Patients and Their Stimulation Ameliorates Adjuvant-Induced Arthritis in Rats

    PubMed Central

    Vincenzi, Fabrizio; Padovan, Melissa; Targa, Martina; Corciulo, Carmen; Giacuzzo, Sarah; Merighi, Stefania; Gessi, Stefania; Govoni, Marcello; Borea, Pier Andrea; Varani, Katia

    2013-01-01

    A2A adenosine receptors (ARs) play a key role in the inhibition of the inflammatory process. The purpose of this study was to evaluate the modulation of A2AARs in rheumatoid arthritis (RA) patients after different pharmacological treatments and to investigate the effect of A2AAR stimulation in a rat model of arthritis. We investigated A2AAR density and functionality in RA progression by using a longitudinal study in RA patients before and after methotrexate (MTX), anti-TNFα agents or rituximab treatments. A2AARs were analyzed by saturation binding assays in lymphocytes from RA patients throughout the 24-month study timeframe. In an adjuvant-induced arthritis model in rats we showed the efficacy of the A2AAR agonist, CGS 21680 in comparison with standard therapies by means of paw volume assessment, radiographic and ultrasonographic imaging. Arthritic-associated pain was investigated in mechanical allodynia and thermal hyperalgesia tests. IL-10 release following A2AAR stimulation in lymphocytes from RA patients and in serum from arthritic rats was measured. In lymphocytes obtained from RA patients, the A2AAR up-regulation was gradually reduced in function of the treatment time and the stimulation of these receptors mediated a significant increase of IL-10 production. In the same cells, CGS 21680 did not affected cell viability and did not produced cytotoxic effects. The A2AAR agonist CGS 21680 was highly effective, as suggested by the marked reduction of clinical signs, in rat adjuvant-induced arthritis and associated pain. This study highlighted that A2AAR agonists represent a physiological-like therapeutic alternative for RA treatment as suggested by the anti-inflammatory role of A2AARs in lymphocytes from RA patients. The effectiveness of A2AAR stimulation in a rat model of arthritis supported the role of A2AAR agonists as potential pharmacological treatment for RA. PMID:23326596

  7. Carvedilol alleviates adjuvant-induced arthritis and subcutaneous air pouch edema: Modulation of oxidative stress and inflammatory mediators

    SciTech Connect

    Arab, Hany H.; El-Sawalhi, Maha M.

    2013-04-15

    Rheumatoid arthritis (RA) is a systemic inflammatory disease with cardiovascular complications as the leading cause of morbidity. Carvedilol is an adrenergic antagonist which has been safely used in treatment of several cardiovascular disorders. Given that carvedilol has powerful antioxidant/anti-inflammatory properties, we aimed to investigate its protective potential against arthritis that may add further benefits for its clinical usefulness especially in RA patients with concomitant cardiovascular disorders. Two models were studied in the same rat; adjuvant arthritis and subcutaneous air pouch edema. Carvedilol (10 mg/kg/day p.o. for 21 days) effectively suppressed inflammation in both models with comparable efficacy to the standard anti-inflammatory diclofenac (5 mg/kg/day p.o.). Notably, carvedilol inhibited paw edema and abrogated the leukocyte invasion to air pouch exudates. The latter observation was confirmed by the histopathological assessment of the pouch lining that revealed mitigation of immuno-inflammatory cell influx. Carvedilol reduced/normalized oxidative stress markers (lipid peroxides, nitric oxide and protein thiols) and lowered the release of inflammatory cytokines (TNF-α and IL-6), and eicosanoids (PGE{sub 2} and LTB{sub 4}) in sera and exudates of arthritic rats. Interestingly, carvedilol, per se, didn't present any effect on assessed biochemical parameters in normal rats. Together, the current study highlights evidences for the promising anti-arthritic effects of carvedilol that could be mediated through attenuation of leukocyte migration, alleviation of oxidative stress and suppression of proinflammatory cytokines and eicosanoids. - Highlights: ► Carvedilol possesses promising anti-arthritic properties. ► It markedly suppressed inflammation in adjuvant arthritis and air pouch edema. ► It abrogated the leukocyte invasion to air pouch exudates and linings. ► It reduced/normalized oxidative stress markers in sera and exudates of

  8. Effect of Different Adjuvants on Protection and Side-Effects Induced by Helicobacter suis Whole-Cell Lysate Vaccination

    PubMed Central

    Bosschem, Iris; Bayry, Jagadeesh; De Bruyne, Ellen; Van Deun, Kim; Smet, Annemieke; Vercauteren, Griet; Ducatelle, Richard; Haesebrouck, Freddy; Flahou, Bram

    2015-01-01

    Helicobacter suis (H. suis) is a widespread porcine gastric pathogen, which is also of zoonotic importance. The first goal of this study was to investigate the efficacy of several vaccine adjuvants (CpG-DNA, Curdlan, Freund’s Complete and Incomplete, Cholera toxin), administered either subcutaneously or intranasally along with H. suis whole-cell lysate, to protect against subsequent H. suis challenge in a BALB/c infection model. Subcutaneous immunization with Freund’s complete (FC)/lysate and intranasal immunization with Cholera toxin (CT)/lysate were shown to be the best options for vaccination against H. suis, as determined by the amount of colonizing H. suis bacteria in the stomach, although adverse effects such as post-immunization gastritis/pseudo-pyloric metaplasia and increased mortality were observed, respectively. Therefore, we decided to test alternative strategies, including sublingual vaccine administration, to reduce the unwanted side-effects. A CCR4 antagonist that transiently inhibits the migration of regulatory T cells was also included as a new adjuvant in this second study. Results confirmed that immunization with CT (intranasally or sublingually) is among the most effective vaccination protocols, but increased mortality was still observed. In the groups immunized subcutaneously with FC/lysate and CCR4 antagonist/lysate, a significant protection was observed. Compared to the FC/lysate immunized group, gastric pseudo-pyloric metaplasia was less severe or even absent in the CCR4 antagonist/lysate immunized group. In general, an inverse correlation was observed between IFN-γ, IL-4, IL-17, KC, MIP-2 and LIX mRNA expression and H. suis colonization density, whereas lower IL-10 expression levels were observed in partially protected animals. PMID:26115373

  9. Protective effects of L-carnitine and alpha-lipoic acid in rats with adjuvant arthritis.

    PubMed

    Tastekin, Nurettin; Aydogdu, Nurettin; Dokmeci, Dikmen; Usta, Ufuk; Birtane, Murat; Erbas, Hakan; Ture, Mevlut

    2007-10-01

    Free radicals play an important role in the pathophysiology of adjuvant arthritis. The purpose of this study was to assess the efficacy of L-carnitine (LC) and alpha-lipoic acid (alpha-LA) which are known to have antioxidant effects, in the treatment of adjuvant arthritis. Arthritis model was created by the administration of complete Freund's adjuvant (CFA) in 32 of 40 male Sprague-Dawley rats. The rats were divided into five groups. Rats in Group I served as controls and received 0.1 ml kg(-1) saline. Group II received only 0.1 ml of CFA and served as the CFA-control for the other groups. Groups III-V, after being injected with CFA, were treated with LC, alpha-LA or diclofenac, respectively. Levels of malondialdehyde (MDA) and glutathione (GSH) were measured in plasma samples. Enzyme activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) were measured. The paws of rats were evaluated histopathologically to investigate the anti-inflammatory effects. TNF-alpha levels were measured for the evaluation of inflammation. In Group II plasma MDA increased, levels of glutathione decreased, enzyme activities of SOD and GPx decreased. Histopathological damage increased in the paws of the rats in this group. MDA levels decreased in Groups III-V when compared with Group II. GSH levels significantly increased in Group III and IV than Group V. SOD activity of Group IV was higher than Group III and V. TNF-alpha levels were significantly lower in Group IV and V. LC and alpha-LA seemed to have protective effects against oxidative damage in adjuvant arthritis model. PMID:17826175

  10. Antibody responses induced by recombinant ALV-A gp85 protein vaccine combining with CpG-ODN adjuvant in breeder hens and the protection for their offspring against early infection.

    PubMed

    Zhang, Dandan; Li, Hongmei; Zhang, Zhongsheng; Sun, Shuhong; Cheng, Ziqiang; Liu, Jianzhu; Zhao, Peng; Ren, Qingya; Guo, Huijun

    2015-04-01

    To observe the antibody responses induced by recombinant A subgroup avian leukosis virus (ALV-A) gp85 protein vaccine plus CpG-ODN adjuvant and the protection of maternal antibodies (MAbs) for the hatched chickens against early infection, the gp85 gene was amplified from the proviral cDNA of ALV-A-SDAU09C1 strain using PCR and the recombinant plasmid containing target gene was constructed and expressed in EscherichiaColi. The expressed product was confirmed using SDS-PAGE and western blot that it is about 46KD of recombinant protein. The purified recombinant proteins combining with CpG-ODN adjuvant or Freund's adjuvant were inoculated into the breeder hens, the ALV-A antibodies in serum and in egg-yolk were detected; the fertilized eggs from the vaccinated hens with different titers of egg-yolk antibody were hatched and then challenged with 10(4.2)/0.1mL TCID50 of ALV-A-SDAU09C1 strain, all the hatched chickens were weekly detected for the viremias and the cloacal swab P27 antigen and pathological lesions; the neutralizing test of antisera in vitro was conducted. The results showed that the recombinant gp85 proteins combining with CpG-ODN adjuvant could induce the breeder hens to produce better antibody responses than gp85 protein with Freund's adjuvant or without adjuvant; the MAbs with higher titers induced by CpG-ODN+gp85 proteins could obviously decrease the ratios of viremias (13% vs 33%), cloacal detoxification (20% vs 67%) and death (0% vs 22%) caused by ALV-A infection than those by gp85 protein without adjuvant. The results of the neutralizing test indicated that the antisera from the hatched chickens could neutralize the ALV-A-SDAU09C1 strain in vitro, but which depends on the antibody titers. The results of IFA confirmed that the serum antibody could combine with the ALV in DF1 cells. It can be concluded that the prepared ALV-A gp85 subunit vaccine combining with CpG-ODN adjuvant could induce the breeder hens to produce better neutralizing antibody

  11. Streptococcal cell wall-induced arthritis and adjuvant arthritis in F344----Lewis and in Lewis----F344 bone marrow chimeras

    SciTech Connect

    van Bruggen, M.C.; van den Broek, M.F.; van den Berg, W.B. )

    1991-09-01

    Streptococcal cell wall (SCW)-induced arthritis and adjuvant arthritis (AA) are rat models for chronic, erosive polyarthritis. Both models can be induced in susceptible Lewis rats, whereas F344 rats are resistant. In AA as well as in SCW arthritis, antigen-specific T lymphocytes have been demonstrated to be crucial for chronic disease. In this communication the authors describe their studies to probe the cellular mechanism responsible for the difference in susceptibility of Lewis and F344, using bone marrow chimeras. By transplanting bone marrow cells from F344 into lethally irradiated Lewis recipients, Lewis rats were rendered resistant to SCW arthritis induction. F344 rats reconstituted with Lewis bone marrow, i.e., Lewis----F344 chimeras, develop an arthritis upon SCW injection. For AA comparable results were obtained. These data suggest that both resistance and susceptibility to bacterium-induced chronic arthritis are mediated by hemopoietic/immune cells and that the recipiental environment does not influence the susceptibility to chronic joint inflammation.

  12. Efficacy of Combined Ultrasound-and-Microbubbles-Mediated Diclofenac Gel Delivery to Enhance Transdermal Permeation in Adjuvant-Induced Rheumatoid Arthritis in the Rat.

    PubMed

    Liao, Ai-Ho; Chung, Huan-Yu; Chen, Wen-Shiang; Yeh, Ming-Kung

    2016-08-01

    A previous study that investigated the effect of ultrasound (US) on the transdermal permeation of the non-steroidal anti-inflammatory drug diclofenac found that therapeutic US can increase circulation in an inflamed joint and decrease arthritic pain. Transdermal drug delivery has recently been demonstrated by US combined with microbubbles (MB) contrast agent (henceforth referred to as "US-MB"). The present study evaluated the efficacy of US-MB-mediated diclofenac delivery for treating adjuvant-induced rheumatoid arthritis (RA) in rats. RA was induced by injecting 100 μL of complete Freund's adjuvant into the ankle joint of male Sprague-Dawley rats (250-300 g) that were randomly divided into five treatment groups: (i) carbopol gel alone (the control [group C]), (ii) diclofenac-carbopol gel (group D), (iii) US plus carbopol gel (group U), (iv) US plus diclofenac-carbopol gel (group DU) and (v) US-MB plus diclofenac-carbopol gel (group DUB). The ankle width was measured over 10 d using high-frequency (40-MHz) US B-mode and color Doppler-mode imaging, covering the period before and after treatment. Longitudinal US images of the induced RA showed synovitis and neovascularity. Only a small amount of neovascularity was observed after treatment. The recovery rate on day 10 was significantly higher in group DUB (97.7% ± 2.7%, mean ± standard deviation [SD]) than in groups C (1.0% ± 2.7%), D (37.5% ± 4.6%), U (75.5% ± 4.2%) and DU (87.3% ± 5.2%) (p < 0.05). The results obtained indicate that combining US and MB can increase the skin permeability and thereby enhance the delivery of diclofenac sodium gel and thereby inhibit inflammation of the tissues surrounding the arthritic ankle. Color Doppler-mode imaging revealed that US-MB treatment induced a rapid reduction in synovial neoangiogenesis in the arthritic area. PMID:27181685

  13. UP1304, a Botanical Composition Containing Two Standardized Extracts of Curcuma longa and Morus alba, Mitigates Pain and Inflammation in Adjuvant-induced Arthritic Rats

    PubMed Central

    Yimam, Mesfin; Lee, Young-Chul; Moore, Breanna; Jiao, Ping; Hong, Mei; Nam, Jeong-Bum; Kim, Mi-Ran; Kim, Tae-Woo; Kim, Hyun-Jin; Hyun, Eu-Jin; Chu, Min; Brownell, Lidia; Jia, Qi

    2016-01-01

    Background: Though, the initial etiologies of arthritis are multifactorial, clinically, patients share pain as the prime complaints. Present day pain relief therapeutics heavily relies on the use of prescription and over the counter nonsteroidal anti-inflammatory drugs as the first line of defense where their long-term usage causes gastrointestinal and cardiovascular-related side effects. Hence, the need for evidence-based safer and efficacious alternatives from natural sources to overcome the most prominent and disabling symptoms of arthritis is an overdue. Here, we evaluated the anti-inflammatory and analgesic effect of UP1304, a composition that contains a standardized blend of two extracts from the rhizome of Curcuma longa and the root bark of Morus alba in adjuvant-induced arthritis models in rats. Materials and Methods: The anti-inflammatory and analgesic effects of the botanical composition were demonstrated in adjuvant-induced arthritis models in rats with oral dose ranges of 50–200 mg/kg. Ibuprofen at a dose of 100 mg/kg was used as a reference compound. Ex vivo sulfated glycosaminoglycan inhibition assays were performed. Results: Statistically significant improvements in pain resistance, suppression of paw edema and ankle thickness were observed in animals treated with UP1304 compared to vehicle-treated diseased rats. These results were similar to those achieved by ibuprofen treatment. Inhibitions of proteoglycan degradation were observed in a range of 37.5–61.7% for concentration of UP1304 at 50–200 μg/mL when compared to interleukin-1α-exposed untreated explants. Conclusions: These data suggest that UP1304, for its analgesic and anti-inflammatory effects, could potentially be considered agent of botanical origin for the improvement of arthritis associated symptoms. SUMMARY Pain is one of the cardinal signs of arthritis.Long term applications of commonly used non-steroidal anti-inflammatory drugs for pain relief are associated with cardiovascular

  14. Recombinant baculovirus vaccine containing multiple M2e and adjuvant LTB induces T cell dependent, cross-clade protection against H5N1 influenza virus in mice.

    PubMed

    Zhang, Jie; Fan, Hui-Ying; Zhang, Zhen; Zhang, Juan; Zhang, Jiao; Huang, Jian-Ni; Ye, Yu; Liao, Ming

    2016-01-27

    H5N1, highly pathogenic avian influenza poses, a threat to animal and human health. Rapid changes in H5N1 viruses require periodic reformulation of the conventional strain-matched vaccines, thus emphasizing the need for a broadly protective influenza vaccine. Here, we constructed BV-Dual-3M2e-LTB, a recombinant baculovirus based on baculovirus display and BacMam technology. BV-Dual-3M2e-LTB harbors a gene cassette expressing three tandem copies of the highly conserved extracellular domain of influenza M2 protein (M2e) and the mucosal adjuvant, LTB. We showed that BV-Dual-3M2e-LTB displayed the target protein (M2e/LTB) on the baculoviral surface and expressed it in transduced mammalian cells. BV-Dual-3M2e-LTB, when delivered nasally in mice, was highly immunogenic and induced superior levels of anti-M2e IgA than the non-adjuvanted baculovirus (BV-Dual-3M2e). Importantly, after challenge with different H5N1 clades (clade 0, 2.3.2.1, 2.3.4 and 4), mice inoculated with BV-Dual-3M2e-LTB displayed improved survival and decreased lung virus shedding compared with mice inoculated with BV-Dual-3M2e. The enhanced protection from BV-Dual-3M2e-LTB is mediated by T cell immunity and is primarily based on CD8(+) T cells, while mucosal antibodies alone were insufficient for protection from lethal H5N1 challenge. These results suggest that BV-Dual-3M2e-LTB has potential to protect against a broad range of H5N1 strains thereby providing a novel direction for developing broadly protective vaccines based on cellular immunity. PMID:26724200

  15. The luminosity function of the CfA Redshift Survey

    NASA Technical Reports Server (NTRS)

    Marzke, R. O.; Huchra, J. P.; Geller, M. J.

    1994-01-01

    We use the CfA Reshift Survey of galaxies with m(sub z) less than or equal to 15.5 to calculate the galaxy luminosity function over the range -13 less than or equal to M(sub z) less than or equal to -22. The sample includes 9063 galaxies distributed over 2.1 sr. For galaxies with velocities cz greater or equal to 2500 km per sec, where the effects of peculiar velocities are small, the luminosity function is well represented by a Schechter function with parameters phi(sub star) = 0.04 +/- 0.01 per cu Mpc, M(sub star) = -18.8 +/- 0.3, and alpha = -1.0 +/- 0.2. When we include all galaxies with cz greater or equal to 500 km per sec, the number of galaxies in the range -16 less than or equal to M(sub z) less than or equal to -13 exceeds the extrapolation of the Schechter function by a factor of 3.1 +/- 0.5. This faint-end excess is not caused by the local peculiar velocity field but may be partially explained by small scale errors in the Zwicky magnitudes. Even with a scale error as large as 0.2 mag per mag, which is unlikely, the excess is still a factor of 1.8 +/- 0.3. If real, this excess affects the interpretation of deep counts of field galaxies.

  16. Crystallization and preliminary X-ray diffraction analysis of CfaE, the adhesive subunit of the CFA/I fimbriae from human enterotoxigenic Escherichia coli

    PubMed Central

    Li, Yong-Fu; Poole, Steven; Rasulova, Fatima; Esser, Lothar; Savarino, Stephen J.; Xia, Di

    2006-01-01

    Enterotoxigenic Escherichia coli (ETEC) represents a formidable food and waterborne diarrheal disease threat of global importance. The first step in ETEC pathogenesis is bacterial attachment to small-intestine epithelial cells via adhesive fimbriae, many of which are genetically related to the prototype colonization factor antigen I (CFA/I). The minor fimbrial subunit CfaE is required for initiation of CFA/I fimbrial assembly and mediates bacterial attachment to host cell-surface receptors. A donor-strand complemented variant of CfaE (dscCfaE) was expressed with a hexahistidine tag, purified to homogeneity and crystallized using the hanging-drop vapor-diffusion method. X-ray diffraction data sets were collected to 2.4 Å resolution for both native and derivatized crystals and showed the symmetry of space group P6222, with unit-cell parameters a = b = 142.9, c = 231.9 Å. Initial phases were derived from the SIRAS approach and electron density showed two molecules in the crystallographic asymmetric unit. Sequence assignments were aided by anomalous signals from the selenium of an SeMet-derivatized crystal and from S atoms of a native crystal. PMID:16511280

  17. Antibody and T-cell responses to a virosomal adjuvanted H9N2 avian influenza vaccine: impact of distinct additional adjuvants.

    PubMed

    Radosević, Katarina; Rodriguez, Ariane; Mintardjo, Ratna; Tax, Dennis; Bengtsson, Karin Lövgren; Thompson, Catherine; Zambon, Maria; Weverling, Gerrit Jan; Uytdehaag, Fons; Goudsmit, Jaap

    2008-07-01

    A highly efficacious vaccine is required to counteract a threat of an avian influenza pandemic. Increasing the potency of vaccines by adjuvation is essential not only to overcome generally low immunogenicity of pandemic strains, but also to allow dose sparing and as such to make it feasible to satisfy huge global production demands. In this study we evaluated the ability of four distinct adjuvants to further increase immune responses to a virosomal adjuvanted avian H9N2 influenza vaccine in mice. Currently registered adjuvants aluminium phosphate, aluminium hydroxide and MF59, as well as a novel promising adjuvant MATRIX-M were included in the study. Our results demonstrate that all adjuvants significantly increased the H9N2 haemagglutinin (HA) inhibition and ELISA antibody titers induced with the virosomal adjuvanted vaccine. The adjuvants exhibited different effect on the isotype of virus specific antibodies, with MATRIX-M inducing the most pronounced skewing to IgG2a, i.e. towards Th1 type of response. While the virosomal adjuvanted pandemic influenza vaccine efficiently induced CD4(+) T-cell response, with no further increase upon adjuvation, the CD8(+) T-cell responses induced with virosomal adjuvanted vaccine could be significantly improved upon additional adjuvation with MATRIX-M or MF59. All adjuvants demonstrated a dose sparing effect, i.e. in combination with the virosomal adjuvanted pandemic influenza vaccine they increased immune responses to comparable level independent of the tested vaccine dose. In conclusion, our results demonstrate that immune responses to a virosomal adjuvanted pandemic influenza vaccine can be further enhanced by add-on adjuvants, with MATRIX-M being overall the most potent adjuvant in combination with virosomes, followed by MF59 and finally aluminium-based adjuvants. PMID:18514980

  18. PKCα is required for inflammation-induced trafficking of extrasynaptic AMPA receptors in tonically firing lamina II dorsal horn neurons during the maintenance of persistent inflammatory pain

    PubMed Central

    Kopach, Olga; Viatchenko-Karpinski, Viacheslav; Atianjoh, Fidelis E.; Belan, Pavel; Tao, Yuan-Xiang; Voitenko, Nana

    2012-01-01

    Persistent inflammation promotes internalization of synaptic GluR2-containing Ca2+-impermeable AMPA receptors (AMPARs) and insertion of GluR1-containing Ca2+-permeable AMPARs at extrasynaptic sites in dorsal horn neurons. Previously we have shown that internalization of synaptic GluR2-containing AMPARs requires an activation of spinal cord protein kinase C alpha (PKCα), but molecular mechanisms that underlie altered trafficking of extrasynaptic AMPARs are still unclear. By utilizing the antisence oligodeoxynucleotides that specifically knockdown PKCα, we have found that a decrease in dorsal horn PKCα expression prevents complete Freund’s adjuvant (CFA)-induced increase in a functional expression of extrasynaptic Ca2+-permeable AMPARs in substantia gelatinosa (SG) neurons of the rat spinal cord. This was manifested as an abolishment of augmented AMPA-induced currents and associated [Ca2+]i transients, and as a reverse of the current rectification 1 d post-CFA. These changes were observed specifically in SG neurons characterized by intrinsic tonic firing properties, but not in those exhibiting strong adaptation. Finally, dorsal horn PKCα knockdown produced anti-nociceptive effect on CFA-induced thermal and mechanical hypersensitivity during the maintenance period of inflammatory pain, indicating a role for PKCα in persistent inflammatory pain maintenance. Altogether, our results indicate that inflammation-induced trafficking of extrasynaptic Ca2+-permeable AMPARs in tonically firing SG neurons depends on PKCα, and suggest that this PKCα-dependent trafficking may contribute to the persistent inflammatory pain maintenance. PMID:23374940

  19. Preliminary X-ray diffraction analysis of CfaA, a molecular chaperone essential for the assembly of CFA/I fimbriae of human enterotoxigenic Escherichia coli

    PubMed Central

    Bao, Rui; Esser, Lothar; Poole, Steven; McVeigh, Annette; Chen, Yu-xing; Savarino, Stephen J.; Xia, Di

    2014-01-01

    Understanding of pilus bioassembly in Gram-negative bacteria stems mainly from studies of P pili and type 1 fimbriae of uropathogenic Escherichia coli, which are mediated by the classic chaperone–usher pathway (CUP). However, CFA/I fimbriae, a class 5 fimbria and intestinal colonization factor for enterotoxigenic E. coli (ETEC), are proposed to assemble via the alternate chaperone pathway (ACP). Both CUP and ACP fimbrial bioassembly pathways require the function of a periplasmic chaperone, but their corresponding proteins share very low similarity in primary sequence. Here, the crystallization of the CFA/I periplasmic chaperone CfaA by the hanging-drop vapor-diffusion method is reported. X-ray diffraction data sets were collected from a native CfaA crystal to 2 Å resolution and to 1.8 and 2.8 Å resolution, respectively, from a lead and a platinum derivative. These crystals displayed the symmetry of space group C2, with unit-cell parameters a = 103.6, b = 28.68, c = 90.60 Å, β = 119.7°. Initial phases were derived from multiple isomorphous replacement with anomalous scattering experiments using the data from the platinum and lead derivatives. This resulted in an interpretable electron-density map showing one CfaA molecule in an asymmetric unit. Sequence assignments were aided by anomalous signals from the heavy-atom derivatives. Refinement of the atomic model of CfaA is ongoing, which is expected to further understanding of the essential aspects and allowable variations in tertiary structure of the greater family of chaperones involved in chaperone–usher mediated bioassembly. PMID:24637755

  20. Preliminary X-ray diffraction analysis of CfaA, a molecular chaperone essential for the assembly of CFA/I fimbriae of human enterotoxigenic Escherichia coli.

    PubMed

    Bao, Rui; Esser, Lothar; Poole, Steven; McVeigh, Annette; Chen, Yu Xing; Savarino, Stephen J; Xia, Di

    2014-02-01

    Understanding of pilus bioassembly in Gram-negative bacteria stems mainly from studies of P pili and type 1 fimbriae of uropathogenic Escherichia coli, which are mediated by the classic chaperone-usher pathway (CUP). However, CFA/I fimbriae, a class 5 fimbria and intestinal colonization factor for enterotoxigenic E. coli (ETEC), are proposed to assemble via the alternate chaperone pathway (ACP). Both CUP and ACP fimbrial bioassembly pathways require the function of a periplasmic chaperone, but their corresponding proteins share very low similarity in primary sequence. Here, the crystallization of the CFA/I periplasmic chaperone CfaA by the hanging-drop vapor-diffusion method is reported. X-ray diffraction data sets were collected from a native CfaA crystal to 2 Å resolution and to 1.8 and 2.8 Å resolution, respectively, from a lead and a platinum derivative. These crystals displayed the symmetry of space group C2, with unit-cell parameters a = 103.6, b = 28.68, c = 90.60 Å, β = 119.7°. Initial phases were derived from multiple isomorphous replacement with anomalous scattering experiments using the data from the platinum and lead derivatives. This resulted in an interpretable electron-density map showing one CfaA molecule in an asymmetric unit. Sequence assignments were aided by anomalous signals from the heavy-atom derivatives. Refinement of the atomic model of CfaA is ongoing, which is expected to further understanding of the essential aspects and allowable variations in tertiary structure of the greater family of chaperones involved in chaperone-usher mediated bioassembly. PMID:24637755

  1. Topical Anti-Inflammatory and Analgesic Effects of Multiple Applications of S(+)-Flurbiprofen Plaster (SFPP) in a Rat Adjuvant-Induced Arthritis Model.

    PubMed

    Sugimoto, Masanori; Toda, Yoshihisa; Hori, Miyuki; Mitani, Akiko; Ichihara, Takahiro; Sekine, Shingo; Kaku, Shinsuke; Otsuka, Noboru; Matsumoto, Hideo

    2016-06-01

    Preclinical Research The aim of this study was to evaluate the efficacy of multiple applications of S(+)-flurbiprofen plaster (SFPP), a novel Nonsteroidal anti-inflammatory drug (NSAID) patch, for the alleviation of inflammatory pain and edema in rat adjuvant-induced arthritis (AIA) model as compared to other NSAID patches. The AIA model was induced by the injection of Mycobacterium butyricum and rats were treated with a patch (1.0 cm × 0.88 cm) containing each NSAID (SFP, ketoprofen, loxoprofen, diclofenac, felbinac, flurbiprofen, or indomethacin) applied to the paw for 6 h per day for 5 days. The pain threshold was evaluated using a flexion test of the ankle joint, and the inflamed paw edema was evaluated using a plethysmometer. cyclooxygenase (COX)-1 and COX-2 inhibition was evaluated using human recombinant proteins. Multiple applications of SFPP exerted a significant analgesic effect from the first day of application as compared to the other NSAID patches. In terms of paw edema, SFPP decreased edema from the second day after application, Multiple applications of SFPP were superior to those of other NSAID patches, in terms of the analgesic effect with multiple applications. These results suggest that SFPP may be a beneficial patch for providing analgesic and anti-inflammatory effects clinically. Drug Dev Res 77 : 206-211, 2016. © 2016 The Authors Drug Development Research Published by Wiley Periodicals, Inc. PMID:27241582

  2. A Soft Coral-Derived Compound, 11-epi-Sinulariolide Acetate Suppresses Inflammatory Response and Bone Destruction in Adjuvant-Induced Arthritis

    PubMed Central

    Lee, Hsin-Pai; Chen, Wu-Fu; Sun, Yu-Min; Su, Jui-Hsin; Lu, Yi; Huang, Shi-Ying; Hung, Han-Chun; Sung, Ping-Jyun; Sheu, Jyh-Horng; Wen, Zhi-Hong

    2013-01-01

    In recent years, a significant number of metabolites with potent anti-inflammatory properties have been discovered from marine organisms, and several of these compounds are now under clinical trials. In the present study, we isolated 11-epi-sinulariolide acetate (Ya-s11), a cembrane-type compound with anti-inflammatory effects, from the Formosa soft coral Sinularia querciformis. Preliminary screening revealed that Ya-s11 significantly inhibited the expression of the proinflammatory proteins induced nitric oxide synthase and cyclooxygenase-2 in lipopolysaccharide-stimulated murine macrophages. We also examined the therapeutic effects of Ya-s11 on adjuvant-induced arthritis (AIA) in female Lewis rats, which demonstrate features similar to human rheumatoid arthritis (RA). Animal experiments revealed that Ya-s11 (subcutaneously 9 mg/kg once every 2 days from day 7 to day 28 postimmunization) significantly inhibited AIA characteristics. Moreover, Ya-s11 also attenuated protein expression of cathepsin K, matrix metalloproteinases-9 (MMP-9), tartrate-resistant acid phosphatase (TRAP), and tumor necrosis factor-α (TNF-α) in ankle tissues of AIA-rats. Based on its attenuation of the expression of proinflammatory proteins and disease progression in AIA rats, the marine-derived compound Ya-s11 may serve as a useful therapeutic agent for the treatment of RA. PMID:23675440

  3. Norisoboldine, an alkaloid compound isolated from Radix Linderae, inhibits synovial angiogenesis in adjuvant-induced arthritis rats by moderating Notch1 pathway-related endothelial tip cell phenotype.

    PubMed

    Lu, Qian; Lu, Shuai; Gao, Xinghua; Luo, Yubin; Tong, Bei; Wei, Zhifeng; Lu, Tao; Xia, Yufeng; Chou, Guixin; Wang, Zhengtao; Dai, Yue

    2012-08-01

    Synovial angiogenesis is well recognized as participating in the pathogenesis of rheumatoid arthritis (RA) and has been regarded as a potential target for RA therapy. Previously, we have shown that norisoboldine (NOR) can protect joints from destruction in mice with collagen II-induced arthritis (CIA). Here, we investigate the effect of NOR on synovial angiogenesis in adjuvant-induced arthritis (AA) rats, and clarify the mechanisms in vitro. NOR, administered orally, significantly reduced the number of blood vessels and expression of growth factors in the synovium of AA rats. In vitro, it markedly prevented the migration and sprouting of endothelial cells. Notably, the endothelial tip cell phenotype, which is essential for the migration of endothelial cells and subsequent angiogenesis, was significantly inhibited by NOR. This inhibitory effect was attenuated by pretreatment with N-{N-[2-(3,5-difluorophenyl) acetyl]-(S)-alanyl}-(S)-phenylglycine tert-butyl ester, a Notch1 inhibitor, suggesting that the action of NOR was related to the Notch1 pathway. A molecular docking study further confirmed that NOR was able to promote Notch1 activation by binding the Notch1 transcription complex. In conclusion, NOR was able to prevent synovial angiogenesis in AA rats, which is a putatively new mechanism responsible for its anti-rheumatoid effect. The anti-angiogenesis action of NOR was likely achieved by moderating the Notch1 pathway-related endothelial tip cell phenotype with a potential action target of the Notch1 transcription complex. PMID:22875342

  4. Activation-Induced TIM-4 Expression Identifies Differential Responsiveness of Intestinal CD103+ CD11b+ Dendritic Cells to a Mucosal Adjuvant

    PubMed Central

    Schmidt, Alfonso J.; Ronchese, Franca

    2016-01-01

    Macrophage and dendritic cell (DC) populations residing in the intestinal lamina propria (LP) are highly heterogeneous and have disparate yet collaborative roles in the promotion of adaptive immune responses towards intestinal antigen. Under steady-state conditions, macrophages are efficient at acquiring antigen but are non-migratory. In comparison, intestinal DC are inefficient at antigen uptake but migrate to the mesenteric lymph nodes (mLN) where they present antigen to T cells. Whether such distinction in the roles of DC and macrophages in the uptake and transport of antigen is maintained under immunostimulatory conditions is less clear. Here we show that the scavenger and phosphatidylserine receptor T cell Immunoglobulin and Mucin (TIM)-4 is expressed by the majority of LP macrophages at steady-state, whereas DC are TIM-4 negative. Oral treatment with the mucosal adjuvant cholera toxin (CT) induces expression of TIM-4 on a proportion of CD103+ CD11b+ DC in the LP. TIM-4+ DC selectively express high levels of co-stimulatory molecules after CT treatment and are detected in the mLN a short time after appearing in the LP. Importantly, intestinal macrophages and DC expressing TIM-4 are more efficient than their TIM-4 negative counterparts at taking up apoptotic cells and soluble antigen ex vivo. Taken together, our results show that CT induces phenotypic changes to migratory intestinal DC that may impact their ability to take up local antigens and in turn promote the priming of mucosal immunity. PMID:27379516

  5. Analgesic Effect of the Newly Developed S(+)-Flurbiprofen Plaster on Inflammatory Pain in a Rat Adjuvant-Induced Arthritis Model.

    PubMed

    Sugimoto, Masanori; Toda, Yoshihisa; Hori, Miyuki; Mitani, Akiko; Ichihara, Takahiro; Sekine, Shingo; Hirose, Takuya; Endo, Hiromi; Futaki, Nobuko; Kaku, Shinsuke; Otsuka, Noboru; Matsumoto, Hideo

    2016-02-01

    Preclinical Research This article describes the properties of a novel topical NSAID (Nonsteroidal anti-inflammatory drug) patch, SFPP (S(+)-flurbiprofen plaster), containing the potent cyclooxygenase (COX) inhibitor, S(+)-flurbiprofen (SFP). The present studies were conducted to confirm human COX inhibition and absorption of SFP and to evaluate the analgesic efficacy of SFPP in a rat adjuvant-induced arthritis (AIA) model. COX inhibition by SFP, ketoprofen and loxoprofen was evaluated using human recombinant COX proteins. Absorption of SFPP, ketoprofen and loxoprofen from patches through rat skin was assessed 24 h after application. The AIA model was induced by injecting Mycobacterium tuberculosis followed 20 days later by the evaluation of the prostaglandin PGE2 content of the inflamed paw and the pain threshold. SFP exhibited more potent inhibitory activity against COX-1 (IC50  = 8.97 nM) and COX-2 (IC50  = 2.94 nM) than the other NSAIDs evaluated. Absorption of SFP was 92.9%, greater than that of ketoprofen and loxoprofen from their respective patches. Application of SFPP decreased PGE2 content from 15 min to 6 h and reduced paw hyperalgesia compared with the control, ketoprofen and loxoprofen patches. SFPP showed analgesic efficacy, and was superior to the ketoprofen and loxoprofen patches, which could be through the potent COX inhibitory activity of SFP and greater skin absorption. The results suggested SFPP can be expected to exert analgesic effect clinically. PMID:26763139

  6. Therapeutic effects of total steroid saponin extracts from the rhizome of Dioscorea zingiberensis C.H.Wright in Freund’s complete adjuvant induced arthritis in rats

    PubMed Central

    Zhang, Xin-xin; Ito, Yoichiro; Liang, Jin-ru; Liu, Jian-li; He, Jiao; Sun, Wen-ji

    2014-01-01

    The aim of our present study is to explore the anti-arthritic potential effect of total steroid saponins (TSSN) extracted from the rhizome of Dioscorea zingiberensis C.H.Wright (DZW) and to investigate the underlying mechanisms. This work was performed using adjuvant-induced arthritis (AIA) rats in vivo and lipopolysaccharide (LPS) simulated 264.7 macrophage cells in vitro. In AIA-induced arthritic rats, TSSN significantly alleviated the arthritic progression through evaluating arthritic score, immune organ indexes, paw swelling, and body weight. This phenomenon was well correlated with significant suppression of the overproduction of inflammation cytokines (IL-1, IL-1β, IL-6, and TNF-α), oxidant stress makers (MDA and NO), eicosanoids (LTB4 and PGE2), and inflammatory enzymes (5-LOX and COX-2) versus the AIA rats without treatment. On the contrary, the release of SOD and IL-10 was profoundly increased. What’s more, TSSN could obviously ameliorate the translocation of NF-κB to the nucleus through phosphorylation of the p65 and IκBα in vivo and vitro. The current findings demonstrated that TSSN could protect the injured ankle joint from further deterioration and exert its satisfactory anti-arthritis properties through anti-inflammatory and anti-oxidant effects via inactivating NF-κB signal pathway. This research implies that DZW may be a useful therapeutic agent for the treatment of human arthritis. PMID:25066758

  7. Comparing interval estimates for small sample ordinal CFA models.

    PubMed

    Natesan, Prathiba

    2015-01-01

    Robust maximum likelihood (RML) and asymptotically generalized least squares (AGLS) methods have been recommended for fitting ordinal structural equation models. Studies show that some of these methods underestimate standard errors. However, these studies have not investigated the coverage and bias of interval estimates. An estimate with a reasonable standard error could still be severely biased. This can only be known by systematically investigating the interval estimates. The present study compares Bayesian, RML, and AGLS interval estimates of factor correlations in ordinal confirmatory factor analysis models (CFA) for small sample data. Six sample sizes, 3 factor correlations, and 2 factor score distributions (multivariate normal and multivariate mildly skewed) were studied. Two Bayesian prior specifications, informative and relatively less informative were studied. Undercoverage of confidence intervals and underestimation of standard errors was common in non-Bayesian methods. Underestimated standard errors may lead to inflated Type-I error rates. Non-Bayesian intervals were more positive biased than negatively biased, that is, most intervals that did not contain the true value were greater than the true value. Some non-Bayesian methods had non-converging and inadmissible solutions for small samples and non-normal data. Bayesian empirical standard error estimates for informative and relatively less informative priors were closer to the average standard errors of the estimates. The coverage of Bayesian credibility intervals was closer to what was expected with overcoverage in a few cases. Although some Bayesian credibility intervals were wider, they reflected the nature of statistical uncertainty that comes with the data (e.g., small sample). Bayesian point estimates were also more accurate than non-Bayesian estimates. The results illustrate the importance of analyzing coverage and bias of interval estimates, and how ignoring interval estimates can be misleading

  8. Comparing interval estimates for small sample ordinal CFA models

    PubMed Central

    Natesan, Prathiba

    2015-01-01

    Robust maximum likelihood (RML) and asymptotically generalized least squares (AGLS) methods have been recommended for fitting ordinal structural equation models. Studies show that some of these methods underestimate standard errors. However, these studies have not investigated the coverage and bias of interval estimates. An estimate with a reasonable standard error could still be severely biased. This can only be known by systematically investigating the interval estimates. The present study compares Bayesian, RML, and AGLS interval estimates of factor correlations in ordinal confirmatory factor analysis models (CFA) for small sample data. Six sample sizes, 3 factor correlations, and 2 factor score distributions (multivariate normal and multivariate mildly skewed) were studied. Two Bayesian prior specifications, informative and relatively less informative were studied. Undercoverage of confidence intervals and underestimation of standard errors was common in non-Bayesian methods. Underestimated standard errors may lead to inflated Type-I error rates. Non-Bayesian intervals were more positive biased than negatively biased, that is, most intervals that did not contain the true value were greater than the true value. Some non-Bayesian methods had non-converging and inadmissible solutions for small samples and non-normal data. Bayesian empirical standard error estimates for informative and relatively less informative priors were closer to the average standard errors of the estimates. The coverage of Bayesian credibility intervals was closer to what was expected with overcoverage in a few cases. Although some Bayesian credibility intervals were wider, they reflected the nature of statistical uncertainty that comes with the data (e.g., small sample). Bayesian point estimates were also more accurate than non-Bayesian estimates. The results illustrate the importance of analyzing coverage and bias of interval estimates, and how ignoring interval estimates can be misleading

  9. Tight Conformational Coupling between the Domains of the Enterotoxigenic Escherichia coli Fimbrial Adhesin CfaE Regulates Binding State Transition*

    PubMed Central

    Liu, Yang; Esser, Lothar; Interlandi, Gianluca; Kisiela, Dagmara I.; Tchesnokova, Veronika; Thomas, Wendy E.; Sokurenko, Evgeni; Xia, Di; Savarino, Stephen J.

    2013-01-01

    CfaE, the tip adhesin of enterotoxigenic Escherichia coli colonization factor antigen I fimbriae, initiates binding of this enteropathogen to the small intestine. It comprises stacked β-sandwich adhesin (AD) and pilin (PD) domains, with the putative receptor-binding pocket at one pole and an equatorial interdomain interface. CfaE binding to erythrocytes is enhanced by application of moderate shear stress. A G168D replacement along the AD facing the CfaE interdomain region was previously shown to decrease the dependence on shear by increasing binding at lower shear forces. To elucidate the structural basis for this functional change, we studied the properties of CfaE G168D (with a self-complemented donor strand) and solved its crystal structure at 2.6 Å resolution. Compared with native CfaE, CfaE G168D showed a downward shift in peak erythrocyte binding under shear stress and greater binding under static conditions. The thermal melting transition of CfaE G168D occurred 10 °C below that of CfaE. Compared with CfaE, the atomic structure of CfaE G168D revealed a 36% reduction in the buried surface area at the interdomain interface. Despite the location of this single modification in the AD, CfaE G168D exhibited structural derangements only in the adjoining PD compared with CfaE. In molecular dynamics simulations, the G168D mutation was associated with weakened interdomain interactions under tensile force. Taken together, these findings indicate that the AD and PD of CfaE are conformationally tightly coupled and support the hypothesis that opening of the interface plays a critical modulatory role in the allosteric activation of CfaE. PMID:23393133

  10. Tight conformational coupling between the domains of the enterotoxigenic Escherichia coli fimbrial adhesin CfaE regulates binding state transition.

    PubMed

    Liu, Yang; Esser, Lothar; Interlandi, Gianluca; Kisiela, Dagmara I; Tchesnokova, Veronika; Thomas, Wendy E; Sokurenko, Evgeni; Xia, Di; Savarino, Stephen J

    2013-04-01

    CfaE, the tip adhesin of enterotoxigenic Escherichia coli colonization factor antigen I fimbriae, initiates binding of this enteropathogen to the small intestine. It comprises stacked β-sandwich adhesin (AD) and pilin (PD) domains, with the putative receptor-binding pocket at one pole and an equatorial interdomain interface. CfaE binding to erythrocytes is enhanced by application of moderate shear stress. A G168D replacement along the AD facing the CfaE interdomain region was previously shown to decrease the dependence on shear by increasing binding at lower shear forces. To elucidate the structural basis for this functional change, we studied the properties of CfaE G168D (with a self-complemented donor strand) and solved its crystal structure at 2.6 Å resolution. Compared with native CfaE, CfaE G168D showed a downward shift in peak erythrocyte binding under shear stress and greater binding under static conditions. The thermal melting transition of CfaE G168D occurred 10 °C below that of CfaE. Compared with CfaE, the atomic structure of CfaE G168D revealed a 36% reduction in the buried surface area at the interdomain interface. Despite the location of this single modification in the AD, CfaE G168D exhibited structural derangements only in the adjoining PD compared with CfaE. In molecular dynamics simulations, the G168D mutation was associated with weakened interdomain interactions under tensile force. Taken together, these findings indicate that the AD and PD of CfaE are conformationally tightly coupled and support the hypothesis that opening of the interface plays a critical modulatory role in the allosteric activation of CfaE. PMID:23393133

  11. Targeting TNF-α and NF-κB Activation by Bee Venom: Role in Suppressing Adjuvant Induced Arthritis and Methotrexate Hepatotoxicity in Rats

    PubMed Central

    Darwish, Samar F.; El-Bakly, Wesam M.; Arafa, Hossam M.; El-Demerdash, Ebtehal

    2013-01-01

    Low dose methotrexate is the cornerstone for the treatment of rheumatoid arthritis. One of its major drawbacks is hepatotoxicity, resulting in poor compliance of therapy. Dissatisfied arthritis patients are likely to seek the option of complementary and alternative medicine such as bee venom. The combination of natural products with modern medicine poses the possibility of potential interaction between the two groups and needs investigation. The present study was aimed to investigate the modulatory effect of bee venom acupuncture on efficacy, toxicity, and pharmacokinetics and tissue disposition of methotrexate. Complete Freund's adjuvant induced arthritic rats were treated for 3 weeks with methotrexate and/or bee venom. Arthritic score, ankle diameter, paw volume and tissue expression of NF-κB and TNF-α were determined to assess anti-arthritic effects, while anti-nociceptive effects were assessed by gait score and thermal hyperalgesia. Methotrexate toxicity was assessed by measuring serum TNF-α, liver enzymes and expression of NF-κB in liver. Combination therapy of bee venom with methotrexate significantly improved arthritic parameters and analgesic effect as compared to methotrexate alone. Bee venom ameliorated serum TNF-α and liver enzymes elevations as well as over expression of NF-κB in liver induced by methotrexate. Histological examination supported the results. And for the first time bee venom acupuncture was approved to increase methotrexate bioavailability with a significant decrease in its elimination. Conclusion: bee venom potentiates the anti-arthritic effects of methotrexate, possibly by increasing its bioavailability. Also, it provides a potent anti-nociceptive effect. Furthermore, bee venom protects against methotrexate induced hepatotoxicity mostly due to its inhibitory effect on TNF-α and NF-κB. PMID:24278124

  12. Role of ERK1/2 activation on itch sensation induced by bradykinin B1 activation in inflamed skin

    PubMed Central

    Chen, Yuanzhen; Jiang, Shuyan; Liu, Yuying; Xiong, Jialing; Liang, Jiexian; Ji, Wenjin

    2016-01-01

    It has previously been demonstrated that bradykinin receptor B1 (B1R) agonists evoke an itch-related scratching response in inflamed skin via the B1 receptor; however, the mechanisms responsible for this abnormal itch sensation remain unclear. Therefore, the present study utilized a complete Freund's adjuvant (CFA)-induced mouse model of inflammation to elucidate the mechanisms responsible. Over a period of 30 min, scratching behavior was quantified by the number of hind limb scratches of the area surrounding the drug injection site on the neck. Furthermore, western blot analysis was used to investigate the potential role of extracellular signal-regulated kinase (ERK) 1/2 signaling as a mediator of itch in CFA-treated mice. The results demonstrated that CFA-induced inflammation at the back of the neck is associated with sustained enhancement of ERK1/2 activation in the spinal cord. Moreover, B1R agonist treatment resulted in increased expression of phosphorylated ERK1/2 in the spinal cord, which peaked at 45 min. Consistent with these findings, inhibition of either mitogen-activated protein/ERK kinase or ERK1/2, as well as inhibition of ERK1/2 activation following inflammation, attenuated B1 receptor-mediated scratching responses to a greater extent, as compared with control mice. Collectively, the results of the present study indicated that enhanced and persistent ERK1/2 activation in the spinal cord may be required to induce a scratching response to B1R agonists following CFA-induced inflammation. PMID:27446253

  13. Regulation of osteoclastogenesis by Simon extracts composed of caffeic acid and related compounds: successful suppression of bone destruction accompanied with adjuvant-induced arthritis in rats.

    PubMed

    Tang, Quan Yong; Kukita, Toshio; Ushijima, Yuki; Kukita, Akiko; Nagata, Kengo; Sandra, Ferry; Watanabe, Toshiyuki; Toh, Kazuko; Okuma, Yutaka; Kawasaki, Sadamichi; Rasubala, Linda; Teramachi, Junpei; Miyamoto, Ichiko; Wu, Zhou; Iijima, Tadahiko

    2006-03-01

    Simon extracts are vitamin K(1)-rich food materials extracted from the leaves of the Simon sweet potato. Although vitamin K is known to stimulate bone formation, we postulated that Simon extracts also contain unknown biological compounds having the ability to regulate bone resorption. Here we prepared the vitamin K-free fraction from the Simon extracts and investigated the ability of this fraction on the differentiation of osteoclasts. A remarkable inhibitory effect of osteoclastogenesis was observed when osteoclast precursors were treated with this fraction in rat bone marrow culture systems as well as in a pure differentiation system using murine osteoclast precursor cell line. The vitamin K-free Simon extracts markedly suppressed severe bone destruction mediated by abundant osteoclasts associated with adjuvant-induced arthritis in rats. High performance liquid chromatography (HPLC) analysis revealed that the vitamin K-free Simon extracts contained three types of low molecular weight inhibitors for osteoclastogenesis; caffeic acid, chlorogenic acids and isochlorogenic acids. Among these substances, caffeic acid showed the most powerful inhibitory effects on osteoclastogenesis. Caffeic acid significantly suppressed expression of NFATc1, a key transcription factor for the induction of osteoclastogenesis. Our current study enlightened a high utility of the Simon extracts and their chemical components as effective regulators for bone resorption accompanied with inflammation and metabolic bone diseases. PMID:16205940

  14. The role of Montanide ISA 70 as an adjuvant in immune responses against Leishmania major induced by thiol-specific antioxidant-based protein vaccine.

    PubMed

    Khabazzadeh Tehrani, Narges; Mahdavi, Mehdi; Maleki, Fatemeh; Zarrati, Somayeh; Tabatabaie, Fatemeh

    2016-09-01

    Leishmaniasis is a parasitic disease caused by several species of the genus Leishmania. Montanide ISA 70 is an adjuvant composed of a natural metabolizable oil and a very refined emulsifier from the manide monooleate family. The TSA (thiol-specific antioxidant) is a important antigen of Leishmania major. The purpose of this work was protein-vaccine efficacy as an protection and excellent candidate in the presence Montanide. The expression of recombinant protein was confirmed with SDS (sodium dodecyl sulfate) page and Western bloting. 48 BALB/c mice were divided into four groups (TSA/Freund,TSA/Alum + BCG, TSA/Montanide and PBS groups) and immunized with 20 μg of vaccine subcutaneously three times intervals on days 0, 14 and 28. The mice were challenged with parasite 21 days after final immunization. The lymphocyte proliferation was evaluated with Brdu method. Cytokines and also total antibody and subclasses were evaluated with ELISA method. The vaccine formulated with the recombinant TSA protein with Montanide induced lymphocytes proliferation cytokines and total antibody and subclasses as compared with the control group. PMID:27605780

  15. Anti-arthritic Activity of Dashanga Ghana (An Ayurvedic Compound Formulation) Against Freund's Adjuvant Induced Arthritis in Charles Foster Albino Rats

    PubMed Central

    Ruknuddin, Galib; Patgiri, B. J.; Prajapati, P. K.; Ashok, B. K.; Ravishankar, B.

    2015-01-01

    Introduction: Arthritis is the most common cause of disability, limiting the activities of adults throughout the world. Apart from the conventional treatment strategies using non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, and glucocorticoids, newer and safer drugs are continuously being searched, as long-term usage of these drugs have resulted in adverse effects. Besides this, currently a number of medicinal plants are under scientific evaluation to develop a promising remedy in these cases. There is a need to investigate the complete therapeutic potential of these herbals for providing newer and safer treatment options with minimum side effects. Considering this, a polyherbal Ayurvedic compound formulation (Dashanga Ghana) has been studied in experimental animals to evaluate anti-arthritic activity. Materials and Methods: Dashanga Ghana has been prepared in the laboratory by following standard guidelines. Charles Foster albino rats were used to evaluate the activity through Freund's adjuvant induced arthritis model. Results and Conclusions: Dashanga Ghana is found to possess significant anti-arthritic activity. Further studies are required to identify and characterize exact active phyto-constituents and to elucidate the exact mechanism of action, which is responsible for the observed pharmacological profile. PMID:26862275

  16. Synthetic B- and T-cell epitope peptides of porcine reproductive and respiratory syndrome virus with Gp96 as adjuvant induced humoral and cell-mediated immunity.

    PubMed

    Chen, Caiwei; Li, Jing; Bi, Yuhai; Yang, Limin; Meng, Shanshan; Zhou, Yuancheng; Jia, Xiaojuan; Meng, Songdong; Sun, Lei; Liu, Wenjun

    2013-04-01

    Highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) has recently caused huge economic losses in the pig industry worldwide. Commercial vaccines, including inactivated vaccines and attenuated live vaccines, are available but fail to provide sustainable protection, especially against genetically heterologous strains. Thus several approaches have been used to develop more effective PRRSV vaccines and/or immune modulators to accelerate and magnify immune responses to PRRSV vaccines. Heat shock protein Gp96 is one such modulator that enhances both the innate and adaptive immune responses. In the present study, two B-cell epitopes and seven T-cell epitopes from PRRSV and a Pan DR T-helper cell epitope were synthesized and mixed with the N-terminal 22-355 aa of Gp96 (Gp96N) as an adjuvant, and immune responses were evaluated. Our results show that Gp96N activated PRRSV-specific humoral immune responses elicited by BCE-peptides and promoted the PRRSV-specific cellular immunity induced by TCE-peptides. Moreover, higher levels of IL-12 and TNF-α and lower levels of IL-4 and IL-10 were observed in the serum of Gp96N-vaccinated piglets compared to piglets immunized with no Gp96N, displaying a predominant Th1 type of immune response induced by Gp96N. Following challenge with the virulent HP-PRRSV isolate JXwn06, piglets vaccinated with the mixture of peptides and Gp96N presented with milder clinical symptoms, lower viremia, and less pathological lesions in their lungs, however, this vaccine could not provide lasting and effective protection against HP-PRRSV infection. These data provide important bases for the development of PRRSV epitope-based synthetic peptide vaccines combined with Gp96N as attractive immunomodulators in swine. PMID:23395588

  17. Modern Vaccines/Adjuvants Formulation—Session 2 (Plenary II)

    PubMed Central

    Collin, Nicolas

    2013-01-01

    On the 15–17th May 2013, the Fourth International Conference on Modern Vaccines/Adjuvants Formulation was organized in Lausanne, Switzerland, and gathered stakeholders from academics and from the industry to discuss several challenges, advances and promises in the field of vaccine adjuvants. Plenary session 2 of the meeting was composed of four different presentations covering: (1) the recent set-up of an adjuvant technology transfer and training platform in Switzerland, (2) the proposition to revisit existing paradigms of modern vaccinology, (3) the properties of polyethyleneimine as potential new vaccine adjuvant, and (4) the progresses in the design of HIV vaccine candidates able to induce broadly neutralizing antibodies. PMID:23966098

  18. Dysregulated microRNA Clusters in Response to Retinoic Acid and CYP26B1 Inhibitor Induced Testicular Function in Dogs

    PubMed Central

    Kasimanickam, Vanmathy R.; Kasimanickam, Ramanathan K.; Dernell, William S.

    2014-01-01

    Spermatogenesis is a multistep synchronized process. Diploid spermatogonia differentiate into haploid spermatozoa following mitosis, meiosis and spermiogenesis. Division and differentiation of male germ cells is achieved through the sequential expression of several genes. Numerous mRNAs in the differentiating germ cells undergo post-transcriptional and translational regulation. MiRNAs are powerful negative regulators of mRNA transcription, stability, and translation and recognize their mRNA targets through base-pairing. Retinoic acid (RA) signaling is essential for spermatogenesis and testicular function. Testicular RA level is critical for RA signal transduction. This study investigated the miRNAs modulation in an RA- induced testicular environment following the administration of all-trans RA (2 µM) and CYP26B1- inhibitor (1 µM) compared to control. Eighty four canine mature miRNAs were analyzed and their expression signatures were distinguished using real-time PCR based array technology. Of the miRNAs analyzed, miRNA families such as miR-200 (cfa-miR-200a, cfa-miR-200b and cfa-miR-200c), Mirlet-7 (cfa-let-7a, cfa-let-7b, cfa-let-7c, cfa-let-7g and cfa-let-7f), miR-125 (cfa-miR-125a and cfa-miR-125b), miR-146 (cfa-miR-146a and cfa-miR-146b), miR-34 (cfa-miR-34a, cfa-miR-34b and cfa-miR-34c), miR-23 (cfa-miR-23a and cfa-miR-23b), cfa-miR-184, cfa-miR-214 and cfa-miR-141 were significantly up-regulated with testicular RA intervention via administration of CYP26B1 inhibitor and all-trans-RA and species of miRNA such as cfa-miR-19a, cfa-miR-29b, cfa-miR-29c, cfa-miR-101 and cfa-miR-137 were significantly down-regulated. This study explored information regarding chromosome distribution, human orthologous sequences and the interaction of target genes of miRNA families significantly distinguished in this study using prediction algorithms. This study importantly identified dysregulated miRNA species resulting from RA-induced spermatogenesis. The present contribution

  19. Induction of lupus autoantibodies by adjuvants

    USGS Publications Warehouse

    Satoh, M.; Kuroda, Y.; Yoshida, H.; Behney, K.M.; Mizutani, A.; Akaogi, J.; Nacionales, D.C.; Lorenson, T.D.; Rosenbauer, R.J.; Reeves, W.H.

    2003-01-01

    Exposure to the hydrocarbon oil pristane induces lupus specific autoantibodies in non-autoimmune mice. We investigated whether the capacity to induce lupus-like autoimmunity is a unique property of pristane or is shared by other adjuvant oils. Seven groups of 3-month-old female BALB/cJ mice received a single intraperitoneal injection of pristane, squalene (used in the adjuvant MF59), incomplete Freund's adjuvant (IFA), three different medicinal mineral oils, or saline, respectively. Serum autoantibodies and peritoneal cytokine production were measured. In addition to pristane, the mineral oil Bayol F (IFA) and the endogenous hydrocarbon squalene both induced anti-nRNP/Sm and -Su autoantibodies (20% and 25% of mice, respectively). All of these hydrocarbons had prolonged effects on cytokine production by peritoneal APCs. However, high levels of IL-6, IL-12, and TNF?? production 2-3 months after intraperitoneal injection appeared to be associated with the ability to induce lupus autoantibodies. The ability to induce lupus autoantibodies is shared by several hydrocarbons and is not unique to pristane. It correlates with stimulation of the production of IL-12 and other cytokines, suggesting a relationship with a hydrocarbon's adjuvanticity. The potential to induce autoimmunity may complicate the use of oil adjuvants in human and veterinary vaccines. ?? 2003 Elsevier Ltd. All rights reserved.

  20. In vitro interactions between macrophages and aluminum-containing adjuvants.

    PubMed

    Rimaniol, Anne-Cécile; Gras, Gabriel; Clayette, Pascal

    2007-09-17

    Intramuscular administration of aluminum-adjuvanted vaccines induces an infiltration of aluminum-containing macrophages between muscle fibers. In vitro stimulation of human monocyte-derived macrophages with aluminum hydroxide (AlOOH) induces similar intracellular crystalline inclusions as well as phenotypical and functional modifications. We compared in this study the ability of other adjuvants to exert similar changes in macrophages in vitro. All mineral salts, i.e. aluminic (AlOOH, AlPO(4)) and non-aluminic mineral adjuvants (CaPO(4), FePO(4)) but not emulsion were able to increase macrophages capacity to potentiate autologous memory T lymphocyte proliferation, while only aluminic adjuvants induced CD83 expression and increased CD86 on macrophages. All together, this suggests that aluminic and non-aluminic adjuvants exerted their immunoactivities by distinct mechanisms on macrophages. PMID:17689842

  1. Immune-stimulating complexes as adjuvants for inducing local and systemic immunity after oral immunization with protein antigens.

    PubMed Central

    Mowat, A M; Maloy, K J; Donachie, A M

    1993-01-01

    Orally active synthetic vaccines containing purified antigens would have many benefits for immunizing against systemic and mucosal diseases. However, several factors have limited the development of such vaccines, including the poor immunogenicity of purified proteins and their usual ability to induce tolerance when given orally. Here, we show that incorporation of ovalbumin (OVA) into immune-stimulating complexes (ISCOMS) containing saponin prevents the induction of oral tolerance in mice. In parallel, the spleen and mesenteric lymph node of mice fed OVA ISCOMS are primed for class I major histocompatibility complex (MHC)-restricted cytotoxic T-cell activity which recognizes physiologically processed epitopes on OVA. Oral immunization with OVA ISCOMS also stimulates high secretory IgA antibody responses in the intestine itself, as well as serum IgG antibodies. None of these active immune responses are detectable in mice fed OVA alone. Despite the potent priming of mucosal priming by OVA ISCOMS, re-exposure to antigen does not induce the intestinal immunopathology found in other systems after the breakdown of oral tolerance. Thus, ISCOMS have several unique properties as vectors for oral immunization and could provide a basis for future mucosal vaccines. PMID:7508416

  2. The Three-Dimensional Structure of CFA/I Adhesion Pili

    PubMed Central

    Mu, Xiang-Qi; Savarino, Stephen J.; Bullitt, Esther

    2008-01-01

    Summary To survive the harsh environment of a churning intestinal tract, bacteria attach to the host epithelium via thin fibers called pili (or fimbriae). Enterotoxigenic Escherichia coli expressing CFA/I pili and related pili are the most common known bacterial cause of diarrheal disease, including traveler’s diarrhea. CFA/I pili, assembled via the alternate chaperone pathway, are essential for binding and colonization of the small bowel by these pathogenic bacteria. We elucidate unique structural features of CFA/I pili that appear to optimize their function as bacterial tethers in the intestinal tract. Using transmission electron microscopy of negatively stained sample in combination with iterative three-dimensional helical reconstruction methods for image processing, we have determined the structure of the CFA/I pilus filament. Our results indicate that strong end-to-end protein interactions and weak interactions between the coils of a sturdy spring-like helix provide the combination of strength, stability, and flexibility required to sustain bacterial adhesion and incite intestinal disease. We propose that CFA/I pili behave like a spring to survive the harsh environment of a churning intestinal tract, thereby persisting long enough for these bacteria to colonize the host epithelium and cause enteric disease. PMID:18166195

  3. Effect of Two Different Doses of Dexmedetomidine as Adjuvant in Bupivacaine Induced Subarachnoid Block for Elective Abdominal Hysterectomy Operations: A Prospective, Double-blind, Randomized Controlled Study

    PubMed Central

    Das, Anjan; Halder, Susanta; Chattopadhyay, Surajit; Mandal, Parthajit; Chhaule, Subinay; Banu, Rezina

    2015-01-01

    Objectives Improvements in perioperative pain management for lower abdominal operations has been shown to reduce morbidity, induce early ambulation, and improve patients’ long-term outcomes. Dexmedetomidine, a selective alpha-2 agonist, has recently been used intrathecally as adjuvant to spinal anesthesia to prolong its efficacy. We compared two different doses of dexmedetomidine added to hyperbaric bupivacaine for spinal anesthesia. The primary endpoints were the onset and duration of sensory and motor block, and duration of analgesia.   Methods A total of 100 patients, aged 35–60 years old, assigned to have elective abdominal hysterectomy under spinal anesthesia were divided into two equally sized groups (D5 and D10) in a randomized, double-blind fashion. The D5 group was intrathecally administered 3ml 0.5% hyperbaric bupivacaine with 5µg dexmedetomidine in 0.5ml of normal saline and the D10 group 3ml 0.5% bupivacaine with 10µg dexmedetomidine in 0.5ml of normal saline. For each patient, sensory and motor block onset times, block durations, time to first analgesic use, total analgesic need, postoperative visual analogue scale (VAS) scores, hemodynamics, and side effects were recorded.   Results Although both groups had a similar demographic profile, sensory and motor block in the D10 group (p<0.050) was earlier than the D5 group. Sensory and motor block duration and time to first analgesic use were significantly longer and the need for rescue analgesics was lower in the D10 group than the D5 group. The 24-hour VAS score was significantly lower in the D10 group (p<0.050). Intergroup hemodynamics were comparable (p>0.050) without any appreciable side effects.   Conclusion Spinal dexmedetomidine increases the sensory and motor block duration and time to first analgesic use, and decreases analgesic consumption in a dose-dependent manner. PMID:26366259

  4. Self-adjuvanted mRNA vaccines induce local innate immune responses that lead to a potent and boostable adaptive immunity.

    PubMed

    Kowalczyk, Aleksandra; Doener, Fatma; Zanzinger, Kai; Noth, Janine; Baumhof, Patrick; Fotin-Mleczek, Mariola; Heidenreich, Regina

    2016-07-19

    mRNA represents a new platform for the development of therapeutic and prophylactic vaccines with high flexibility with respect to production and application. We have previously shown that our two component self-adjuvanted mRNA-based vaccines (termed RNActive® vaccines) induce balanced immune responses comprising both humoral and cellular effector as well as memory responses. Here, we evaluated the early events upon intradermal application to gain more detailed insights into the underlying mode of action of our mRNA-based vaccine. We showed that the vaccine is taken up in the skin by both non-leukocytic and leukocytic cells, the latter being mostly represented by antigen presenting cells (APCs). mRNA was then transported to the draining lymph nodes (dLNs) by migratory dendritic cells. Moreover, the encoded protein was expressed and efficiently presented by APCs within the dLNs as shown by T cell proliferation and immune cell activation, followed by the induction of the adaptive immunity. Importantly, the immunostimulation was limited to the injection site and lymphoid organs as no proinflammatory cytokines were detected in the sera of the immunized mice indicating a favorable safety profile of the mRNA-based vaccines. Notably, a substantial boostability of the immune responses was observed, indicating that mRNA can be used effectively in repetitive immunization schedules. The evaluation of the immunostimulation following prime and boost vaccination revealed no signs of exhaustion as demonstrated by comparable levels of cytokine production at the injection site and immune cell activation within dLNs. In summary, our data provide mechanistic insight into the mode of action and a rational for the use of mRNA-based vaccines as a promising immunization platform. PMID:27269061

  5. Exposure of brown Norway rats to diesel exhaust particles prior to ovalbumin (OVA) sensitization elicits IgE adjuvant activity but attenuates OVA-induced airway inflammation.

    PubMed

    Dong, Caroline C; Yin, Xuejun J; Ma, Jane Y C; Millecchia, Lyndell; Barger, Mark W; Roberts, Jenny R; Zhang, Xing-Dong; Antonini, James M; Ma, Joseph K H

    2005-11-01

    Exposure to diesel exhaust particles (DEP) during the sensitization process has been shown to increase antigen-specific IgE production and aggravate allergic airway inflammation in human and animal models. In this study, we evaluated the effect of short-term DEP exposure on ovalbumin (OVA)-mediated responses using a post-sensitization model. Brown Norway rats were first exposed to filtered air or DEP (20.6 +/- 2.7 mg/m3) for 4 h/day for five consecutive days. One day after the final air or DEP exposure (day 1), rats were sensitized with aerosolized OVA (40.5 +/- 6.3 mg/m3), and then again on days 8 and 15, challenged with OVA on day 29, and sacrificed on days 9 or 30, 24 h after the second OVA exposure or the final OVA challenge, respectively. Control animals received aerosolized saline instead of OVA. DEP were shown to elicit an adjuvant effect on the production of antigen-specific IgE and IgG on day 30. At both time points, no significant airway inflammatory responses and lung injury were found for DEP exposure alone. However, the OVA-induced inflammatory cell infiltration, acellular lactate dehydrogenase activity and albumin content in bronchoalveolar lavage (BAL) fluid, and numbers of T cells and their CD4+ and CD8+ subsets in lung-draining lymph nodes were markedly reduced by DEP on day 30 compared with the air-plus-OVA exposure group. The OVA-induced nitric oxide (NO) in the BAL fluid and production of NO, interleukin (IL)-10, and IL-12 by alveolar macrophages (AM) were also significantly lowered by DEP on day 30 as well as day 9. DEP or OVA alone decreased intracellular glutathione (GSH) in AM and lymphocytes on days 9 and 30. The combined DEP and OVA exposure resulted in further depletion of GSH in both cell types. These results show that short-term DEP exposure prior to sensitization had a delayed effect on enhancement of the sensitization in terms of allergen-specific IgE and IgG production, but caused an attenuation of the allergen-induced airway

  6. CFA-7: an interpenetrated metal-organic framework of the MFU-4 family.

    PubMed

    Schmieder, Phillip; Grzywa, Maciej; Denysenko, Dmytro; Hambach, Manuel; Volkmer, Dirk

    2015-08-01

    The novel interpenetrated metal-organic framework CFA-7 (Coordination Framework Augsburg University-7), [Zn5Cl4(tqpt)3], has been synthesized containing the organic linker {H2-tqpt = 6,6,14,14-tetramethyl-6,14-dihydroquinoxalino[2,3-b]phenazinebistriazole}. Reaction of H2-tqpt and anhydrous ZnCl2 in N,N-dimethylformamide (DMF) yields CFA-7 as pseudo-cubic crystals. CFA-7 serves as precursor for the synthesis of isostructural frameworks with redox-active metal centers, which is demonstrated by postsynthetic metal exchange of Zn(2+) by different M(2+) (M = Co, Ni, Cu) ions. The novel framework is robust upon solvent removal and has been structurally characterized by single-crystal X-ray diffraction, TGA and IR spectroscopy, as well as gas sorption (Ar, CO2 and H2). PMID:26103597

  7. Prognostic Effects of Adjuvant Chemotherapy-Induced Amenorrhea and Subsequent Resumption of Menstruation for Premenopausal Breast Cancer Patients.

    PubMed

    Jeon, Se Jeong; Lee, Jae Il; Jeon, Myung Jae; Lee, Maria

    2016-04-01

    Chemotherapy-induced amenorrhea (CIA) is a side effect that occurs in patients with breast cancer (BC) as a result of chemotherapy. These patients require special treatments to avoid infertility and menopause. However, the factors controlling CIA, resumption of menstruation (RM), and persistence of menstruation after chemotherapy are unknown. The long-term prognosis for premenopausal patients with BC and the prognostic factors associated with CIA and RM are subject to debate. We performed a retrospective study by reviewing the medical records of 249 patients with BC (stage I to stage III) who were treated with cytotoxic chemotherapy. The median patient age was 43 (range, 26-55 years) and the median duration of follow-up was 64 months (range, 28-100 months). The medical records indicated that 219 patients (88.0%) scored as positive for the hormone receptor (HR); the majority of these patients completed chemotherapy and then received additional therapy of tamoxifen. Our analyses revealed that 88.0% (n = 219) of patients experienced CIA, and the percentage of RM during follow-up was 48.6% (n = 121). A total of 30 patients (12.0%) did not experience CIA. Disease-free survival (DFS) was affected by several factors, including tumour size ≥2 cm, node positivity, HR negative status, and body mass index ≥23 kg/m. Multivariate analysis indicated that tumour size ≥2 cm remained as a significant factor for DFS (hazard ratio = 3.3, P = 0.034). In summary, this study finds that the majority of premenopausal patients with BC (stage I to stage III) who receive chemotherapy experience CIA and subsequent RM. Although tumour size ≥2 cm is negatively associated with DFS, RM after CIA is not associated with poor prognosis. PMID:27057900

  8. A structural basis for sustained bacterial adhesion: biomechanical properties of CFA/I pili.

    PubMed

    Andersson, Magnus; Björnham, Oscar; Svantesson, Mats; Badahdah, Arwa; Uhlin, Bernt Eric; Bullitt, Esther

    2012-02-01

    Enterotoxigenic Escherichia coli (ETEC) are a major cause of diarrheal disease worldwide. Adhesion pili (or fimbriae), such as the CFA/I (colonization factor antigen I) organelles that enable ETEC to attach efficiently to the host intestinal tract epithelium, are critical virulence factors for initiation of infection. We characterized the intrinsic biomechanical properties and kinetics of individual CFA/I pili at the single-organelle level, demonstrating that weak external forces (7.5 pN) are sufficient to unwind the intact helical filament of this prototypical ETEC pilus and that it quickly regains its original structure when the force is removed. While the general relationship between exertion of force and an increase in the filament length for CFA/I pili associated with diarrheal disease is analogous to that of P pili and type 1 pili, associated with urinary tract and other infections, the biomechanical properties of these different pili differ in key quantitative details. Unique features of CFA/I pili, including the significantly lower force required for unwinding, the higher extension speed at which the pili enter a dynamic range of unwinding, and the appearance of sudden force drops during unwinding, can be attributed to morphological features of CFA/I pili including weak layer-to-layer interactions between subunits on adjacent turns of the helix and the approximately horizontal orientation of pilin subunits with respect to the filament axis. Our results indicate that ETEC CFA/I pili are flexible organelles optimized to withstand harsh motion without breaking, resulting in continued attachment to the intestinal epithelium by the pathogenic bacteria that express these pili. PMID:22178477

  9. Mechanisms of Action of Adjuvants

    PubMed Central

    Awate, Sunita; Babiuk, Lorne A.; Mutwiri, George

    2013-01-01

    Adjuvants are used in many vaccines, but their mechanisms of action are not fully understood. Studies from the past decade on adjuvant mechanisms are slowly revealing the secrets of adjuvant activity. In this review, we have summarized the recent progress in our understanding of the mechanisms of action of adjuvants. Adjuvants may act by a combination of various mechanisms including formation of depot, induction of cytokines and chemokines, recruitment of immune cells, enhancement of antigen uptake and presentation, and promoting antigen transport to draining lymph nodes. It appears that adjuvants activate innate immune responses to create a local immuno-competent environment at the injection site. Depending on the type of innate responses activated, adjuvants can alter the quality and quantity of adaptive immune responses. Understanding the mechanisms of action of adjuvants will provide critical information on how innate immunity influences the development of adaptive immunity, help in rational design of vaccines against various diseases, and can inform on adjuvant safety. PMID:23720661

  10. An Adjuvanted, Tetravalent Dengue Virus Purified Inactivated Vaccine Candidate Induces Long-Lasting and Protective Antibody Responses Against Dengue Challenge in Rhesus Macaques

    PubMed Central

    Fernandez, Stefan; Thomas, Stephen J.; De La Barrera, Rafael; Im-erbsin, Rawiwan; Jarman, Richard G.; Baras, Benoît; Toussaint, Jean-François; Mossman, Sally; Innis, Bruce L.; Schmidt, Alexander; Malice, Marie-Pierre; Festraets, Pascale; Warter, Lucile; Putnak, J. Robert; Eckels, Kenneth H.

    2015-01-01

    The immunogenicity and protective efficacy of a candidate tetravalent dengue virus purified inactivated vaccine (TDENV PIV) formulated with alum or an Adjuvant System (AS01, AS03 tested at three different dose levels, or AS04) was evaluated in a 0, 1-month vaccination schedule in rhesus macaques. One month after dose 2, all adjuvanted formulations elicited robust and persisting neutralizing antibody titers against all four dengue virus serotypes. Most of the formulations tested prevented viremia after challenge, with the dengue serotype 1 and 2 virus strains administered at 40 and 32 weeks post-dose 2, respectively. This study shows that inactivated dengue vaccines, when formulated with alum or an Adjuvant System, are candidates for further development. PMID:25646261

  11. B subunits of cholera toxin and thermolabile enterotoxin of Escherichia coli have similar adjuvant effect as whole molecules on rotavirus 2/6-VLP specific antibody responses and induce a Th17-like response after intrarectal immunization.

    PubMed

    Thiam, Fatou; Charpilienne, Annie; Poncet, Didier; Kohli, Evelyne; Basset, Christelle

    2015-12-01

    The purpose of this study was to evaluate the adjuvant effect of the B subunits of cholera toxin (CT) and the thermolabile enterotoxin of Escherichia coli (LT) by the intrarectal route of immunization and compare them to the whole molecules CT and LT-R192G, a non toxic mutant of LT, using 2/6-VLP as an antigen, in mice. All molecules induced similar antigen specific antibody titers in serum and feces, whereas different T cell profiles were observed. CTB and LTB, conversely to CT and LT-R192G, did not induce detectable production of IL-2 by antigen specific T cells. Moreover, CTB, conversely to LT-R192G, CT and LTB, did not induce antigen specific CD4+CD25+Foxp3- and Foxp3+ T cells, thus showing different effects between the B subunits themselves. However, all molecules induced an antigen specific Th17 response. In conclusion, B subunits are potent adjuvants on B cell responses by the intrarectal route. Although their impact on T cell responses are different, all molecules induce a 2/6-VLP-specific Th17 T cell response that may play a major role in helping B cell responses and thus in adjuvanticity and protection. PMID:26318874

  12. Prolactin-induced protein as a potential therapy response marker of adjuvant chemotherapy in breast cancer patients

    PubMed Central

    Jablonska, Karolina; Grzegrzolka, Jedrzej; Podhorska-Okolow, Marzenna; Stasiolek, Mariusz; Pula, Bartosz; Olbromski, Mateusz; Gomulkiewicz, Agnieszka; Piotrowska, Aleksandra; Rys, Janusz; Ambicka, Aleksandra; Ong, Siew Hwa; Zabel, Maciej; Dziegiel, Piotr

    2016-01-01

    Many studies are dedicated to exploring the molecular mechanisms of chemotherapy-resistance in breast cancer (BC). Some of them are focused on searching for candidate genes responsible for this process. The aim of this study was typing the candidate genes associated with the response to standard chemotherapy in the case of invasive ductal carcinoma. Frozen material from 28 biopsies obtained from IDC patients with different responses to chemotherapy were examined using gene expression microarray, Real-Time PCR (RT-PCR) and Western blot (WB). Based on the microarray results, further analysis of candidate gene expression was evaluated in 120 IDC cases by RT-PCR and in 224 IDC cases by immunohistochemistry (IHC). The results were correlated with clinical outcome and molecular subtype of the BC. Gene expression microarray revealed Prolactin-Induced Peptide (PIP) as a single gene differentially expressed in BC therapy responder or non-responder patients (p <0.05). The level of PIP expression was significantly higher in the BC therapy responder group than in the non-responder group at mRNA (p=0.0092) and protein level (p=0.0256). Expression of PIP mRNA was the highest in estrogen receptor positive (ER+) BC cases (p=0.0254) and it was the lowest in triple negative breast cancer (TNBC) (p=0.0336). Higher PIP mRNA expression was characterized by significantly longer disease free survival (DFS, p=0.0093), as well as metastasis free survival (MFS, p=0.0144). Additionally, PIP mRNA and PIP protein expression levels were significantly higher in luminal A than in other molecular subtypes and TNBC. Moreover significantly higher PIP expression was observed in G1, G2 vs. G3 cases (p=0.0027 and p=0.0013, respectively). Microarray analysis characterized PIP gene as a candidate for BC standard chemotherapy response marker. Analysis of clinical data suggests that PIP may be a good prognostic and predictive marker in IDC patients. Higher levels of PIP were related to longer DFS and MFS

  13. A rabies vaccine adjuvanted with saponins from leaves of the soap tree (Quillaja brasiliensis) induces specific immune responses and protects against lethal challenge.

    PubMed

    Yendo, Anna Carolina A; de Costa, Fernanda; Cibulski, Samuel P; Teixeira, Thais F; Colling, Luana C; Mastrogiovanni, Mauricio; Soulé, Silvia; Roehe, Paulo M; Gosmann, Grace; Ferreira, Fernando A; Fett-Neto, Arthur G

    2016-04-29

    Quillaja brasiliensis (Quillajaceae) is a saponin producing species native from southern Brazil and Uruguay. Its saponins are remarkably similar to those of Q. saponaria, which provides most of the saponins used as immunoadjuvants in vaccines. The immunostimulating capacities of aqueous extract (AE) and purified saponin fraction (QB-90) obtained from leaves of Q. brasiliensis were favorably comparable to those of a commercial saponin-based adjuvant preparation (Quil-A) in experimental vaccines against bovine herpesvirus type 1 and 5, poliovirus and bovine viral diarrhea virus in mice model. Herein, the immunogenicity and protection efficacy of rabies vaccines adjuvanted with Q. brasiliensis AE and its saponin fractions were compared with vaccines adjuvanted with either commercial Quil-A or Alum. Mice were vaccinated with one or two doses (on days 0 and 14) of one of the different vaccines and serum levels of total IgG, IgG1 and IgG2a were quantified over time. A challenge experiment with a lethal dose of rabies virus was carried out with the formulations. Viral RNA detection in the brain of mice was performed by qPCR, and RNA copy-numbers were quantified using a standard curve of in vitro transcribed RNA. All Q. brasiliensis saponin-adjuvanted vaccines significantly enhanced levels of specific IgG isotypes when compared with the no adjuvant group (P ≤ 0.05). Overall, one or two doses of saponin-based vaccine were efficient to protect against the lethal rabies exposure. Both AE and saponin fractions from Q. brasiliensis leaves proved potent immunological adjuvants in vaccines against a lethal challenge with a major livestock pathogen, hence confirming their value as competitive or complementary sustainable alternatives to saponins of Q. saponaria. PMID:27032516

  14. The luminosity function for different morphological types in the CfA Redshift Survey

    NASA Technical Reports Server (NTRS)

    Marzke, Ronald O.; Geller, Margaret J.; Huchra, John P.; Corwin, Harold G., Jr.

    1994-01-01

    We derive the luminosity function for different morphological types in the original CfA Redshift Survey (CfA1) and in the first two slices of the CfA Redshift Survey Extension (CfA2). CfA1 is a complete sample containing 2397 galaxies distributed over 2.7 steradians with m(sub z) less than or equal 14.5. The first two complete slices of CfA2 contain 1862 galaxies distributed over 0.42 steradians with m(sub z)=15.5. The shapes of the E-S0 and spiral luminosity functions (LF) are indistinguishable. We do not confirm the steeply decreasing faint end in the E-S0 luminosity function found by Loveday et al. for an independent sample in the southern hemisphere. We demonstrate that incomplete classification in deep redshift surveys can lead to underestimates of the faint end of the elliptical luminosity function and could be partially responsible for the difference between the CfA survey and other local field surveys. The faint end of the LF for the Magellanic spirals and irregulars is very steep. The Sm-Im luminosity function is well fit by a Schechter function with M*=-18.79, alpha=-1.87, and phi*=0.6x10(exp -3) for M(sub z) less than or equal to -13. These galaxies are largely responsible for the excess at the faint end of the general CfA luminosity function. The abundance of intrinsically faint, blue galaxies nearby affects the interpretation of deep number counts. The dwarf population increases the expected counts at B=25 in a no-evolution, q(sub 0)=0.05 model by a factor of two over standard no-evolution estimates. These dwarfs change the expected median redshift in deep redshift surveys by less than 10 percent . Thus the steep Sm-Im LF may contribute to the reconciliation of deep number counts with deep redshift surveys.

  15. [18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity.

    PubMed

    Kim, Woosuk; Le, Thuc M; Wei, Liu; Poddar, Soumya; Bazzy, Jimmy; Wang, Xuemeng; Uong, Nhu T; Abt, Evan R; Capri, Joseph R; Austin, Wayne R; Van Valkenburgh, Juno S; Steele, Dalton; Gipson, Raymond M; Slavik, Roger; Cabebe, Anthony E; Taechariyakul, Thotsophon; Yaghoubi, Shahriar S; Lee, Jason T; Sadeghi, Saman; Lavie, Arnon; Faull, Kym F; Witte, Owen N; Donahue, Timothy R; Phelps, Michael E; Herschman, Harvey R; Herrmann, Ken; Czernin, Johannes; Radu, Caius G

    2016-04-12

    Deoxycytidine kinase (dCK), a rate-limiting enzyme in the cytosolic deoxyribonucleoside (dN) salvage pathway, is an important therapeutic and positron emission tomography (PET) imaging target in cancer. PET probes for dCK have been developed and are effective in mice but have suboptimal specificity and sensitivity in humans. To identify a more suitable probe for clinical dCK PET imaging, we compared the selectivity of two candidate compounds-[(18)F]Clofarabine; 2-chloro-2'-deoxy-2'-[(18)F]fluoro-9-β-d-arabinofuranosyl-adenine ([(18)F]CFA) and 2'-deoxy-2'-[(18)F]fluoro-9-β-d-arabinofuranosyl-guanine ([(18)F]F-AraG)-for dCK and deoxyguanosine kinase (dGK), a dCK-related mitochondrial enzyme. We demonstrate that, in the tracer concentration range used for PET imaging, [(18)F]CFA is primarily a substrate for dCK, with minimal cross-reactivity. In contrast, [(18)F]F-AraG is a better substrate for dGK than for dCK. [(18)F]CFA accumulation in leukemia cells correlated with dCK expression and was abrogated by treatment with a dCK inhibitor. Although [(18)F]CFA uptake was reduced by deoxycytidine (dC) competition, this inhibition required high dC concentrations present in murine, but not human, plasma. Expression of cytidine deaminase, a dC-catabolizing enzyme, in leukemia cells both in cell culture and in mice reduced the competition between dC and [(18)F]CFA, leading to increased dCK-dependent probe accumulation. First-in-human, to our knowledge, [(18)F]CFA PET/CT studies showed probe accumulation in tissues with high dCK expression: e.g., hematopoietic bone marrow and secondary lymphoid organs. The selectivity of [(18)F]CFA for dCK and its favorable biodistribution in humans justify further studies to validate [(18)F]CFA PET as a new cancer biomarker for treatment stratification and monitoring. PMID:27035974

  16. Dexamethasone as Adjuvant to Bupivacaine Prolongs the Duration of Thermal Antinociception and Prevents Bupivacaine-Induced Rebound Hyperalgesia via Regional Mechanism in a Mouse Sciatic Nerve Block Model

    PubMed Central

    An, Ke; Elkassabany, Nabil M.; Liu, Jiabin

    2015-01-01

    Background Dexamethasone has been studied as an effective adjuvant to prolong the analgesia duration of local anesthetics in peripheral nerve block. However, the route of action for dexamethasone and its potential neurotoxicity are still unclear. Methods A mouse sciatic nerve block model was used. The sciatic nerve was injected with 60ul of combinations of various medications, including dexamethasone and/or bupivacaine. Neurobehavioral changes were observed for 2 days prior to injection, and then continuously for up to 7 days after injection. In addition, the sciatic nerves were harvested at either 2 days or 7 days after injection. Toluidine blue dyeing and immunohistochemistry test were performed to study the short-term and long-term histopathological changes of the sciatic nerves. There were six study groups: normal saline control, bupivacaine (10mg/kg) only, dexamethasone (0.5mg/kg) only, bupivacaine (10mg/kg) combined with low-dose (0.14mg/kg) dexamethasone, bupivacaine (10mg/kg) combined with high-dose (0.5mg/kg) dexamethasone, and bupivacaine (10mg/kg) combined with intramuscular dexamethasone (0.5mg/kg). Results High-dose perineural dexamethasone, but not systemic dexamethasone, combined with bupivacaine prolonged the duration of both sensory and motor block of mouse sciatic nerve. There was no significant difference on the onset time of the sciatic nerve block. There was “rebound hyperalgesia” to thermal stimulus after the resolution of plain bupivacaine sciatic nerve block. Interestingly, both low and high dose perineural dexamethasone prevented bupivacaine-induced hyperalgesia. There was an early phase of axon degeneration and Schwann cell response as represented by S-100 expression as well as the percentage of demyelinated axon and nucleus in the plain bupivacaine group compared with the bupivacaine plus dexamethasone groups on post-injection day 2, which resolved on post-injection day 7. Furthermore, we demonstrated that perineural dexamethasone

  17. Swertiamarin attenuates inflammation mediators via modulating NF-κB/I κB and JAK2/STAT3 transcription factors in adjuvant induced arthritis.

    PubMed

    Saravanan, S; Islam, V I Hairul; Babu, N Prakash; Pandikumar, P; Thirugnanasambantham, K; Chellappandian, M; Raj, C Simon Durai; Paulraj, M Gabriel; Ignacimuthu, S

    2014-06-01

    Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease that leads to pannus formation followed by severe joint destruction, characterized by synovial hyperplasia, inflammation and angiogenesis. Swertiamarin is a secoiridoid glycoside that is used as an anti-inflammatory compound, mainly found in Enicostema axillare (Lam) A. Raynal, a medicinal plant used in Indian system of traditional medicine. In the present study, the effect of swertiamarin was evlauated in experimental adjuvant arthritis animal model by the estimation of biochemical (paw thickness, lysosomal enzymes, and urinary degradative products) parameters, proinflammatory cytokines and enzymes along with histopathological and radiographic observations. The proteins of phosphorylated NF-κB/IκB and JAK2/STAT3 transcription factors were also quantified from experimental animals as well as LPS induced RAW 264.7 macrophage cells. In in silico analysis, swertiamarin was docked with proinflammatory enzymes to confirm its potential. The administration of swertiamarin (2, 5, 10mg/kg bw) significantly (P⩽0.05) inhibited the levels of paw thickness, lysosomal enzymes and increased the body weight of experimental animals in a dose dependent manner. In molecular analysis, the treatment decreased the release of proinflammatory cytokines (IL1, TNF, IL-6) and proangiogenic enzymes (MMPs, iNOS, PGE2, PPARγ and COX-2); and also significantly (P⩽0.05) increased the levels of antiinflammatory proteins (IL-10, IL-4) when compared to the disease groups. The swertiamarin treatment significantly (P⩽0.05) inhibited the release of NF-κB p65, p-IκBα, p-JAK2 and p-STAT3 signaling proteins levels on both experimental animals and LPS induced cells. Histopathological and radiological analysis evidenced the curative effect of swertiamarin on bone destruction. The docking studies of swertiamarin on proinflammatory enzymes supported the results from the in vivo experiments. Thus the swertiamarin inhibited

  18. A novel adjuvanted capsule based strategy for oral vaccination against infectious diarrhoeal pathogens.

    PubMed

    Davitt, Christopher J H; McNeela, Edel A; Longet, Stephanie; Tobias, Joshua; Aversa, Vincenzo; McEntee, Craig P; Rosa, Monica; Coulter, Ivan S; Holmgren, Jan; Lavelle, Ed C

    2016-07-10

    Diarrhoeal infections are a major cause of morbidity and mortality with enterotoxigenic Escherichia coli (ETEC) and cholera imposing a significant global burden. There is currently no licensed vaccine for ETEC. Development of new nonliving oral vaccines has proven difficult due to the physicochemical and immunological challenges associated with the oral route. This demands innovative delivery solutions to protect antigens, control their release and build in immune-stimulatory activity. We describe the Single Multiple Pill® (SmPill®) vaccine formulation which combines the benefits of enteric polymer coating to protect against low gastric pH, a dispersed phase to control release and aid the solubility of non-polar components and an optimized combination of adjuvant and antigen to promote mucosal immunity. We demonstrate the effectiveness of this system with whole cell killed E. coli overexpressing colonization factor antigen I (CFA/I), JT-49. Alpha-galactosylceramide was identified as a potent adjuvant within SmPill® that enhanced the immunogenicity of JT-49. The bacteria associated with the dispersed phase were retained within the capsules at gastric pH but released at intestinal pH. Vaccination with an optimized SmPill® formulation promoted CFA/I-specific immunoglobulin A (IgA) responses in the intestinal mucosa in addition to serum IgG and a solubilized adjuvant was indispensable for efficacy. PMID:27157995

  19. Delivery of an inactivated avian influenza virus vaccine adjuvanted with poly(D,L-lactic-co-glycolic acid) encapsulated CpG ODN induces protective immune responses in chickens.

    PubMed

    Singh, Shirene M; Alkie, Tamiru N; Nagy, Éva; Kulkarni, Raveendra R; Hodgins, Douglas C; Sharif, Shayan

    2016-09-14

    In poultry, systemic administration of commercial vaccines consisting of inactivated avian influenza virus (AIV) requires the simultaneous delivery of an adjuvant (water-in-oil emulsion). These vaccines are often limited in their ability to induce quantitatively better local (mucosal) antibody responses capable of curtailing virus shedding. Therefore, more efficacious adjuvants with the ability to provide enhanced immunogenicity and protective anti-AIV immunity in chickens are needed. While the Toll-like receptor (TLR) 21 agonist, CpG oligodeoxynucleotides (ODNs) has been recognized as a potential vaccine adjuvant in chickens, poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, successfully tested as vaccine delivery systems in other species, have not been extensively explored. The present study, therefore, assessed both systemic and mucosal antibody-mediated responses following intramuscular vaccination (administered at 7 and 21days post-hatch) of chickens with PLGA encapsulated H9N2 AIV plus encapsulated CpG ODN 2007 (CpG 2007), and nonencapsulated AIV plus PLGA encapsulated CpG 2007 vaccine formulations. Virus challenge was performed at 2weeks post-secondary vaccination using the oculo-nasal route. Our results showed that chickens vaccinated with the nonencapsulated AIV vaccine plus PLGA encapsulated CpG 2007 developed significantly higher systemic IgY and local (mucosal) IgY antibodies as well as haemagglutination inhibition antibody titres compared to PLGA encapsulated AIV plus encapsulated CpG 2007 vaccinated chickens. Furthermore, chickens that received CpG 2007 as an adjuvant in the vaccine formulation had antibodies exhibiting higher avidity indicating that the TLR21-mediated pathway may enhance antibody affinity maturation qualitatively. Collectively, our data indicate that vaccination of chickens with nonencapsulated AIV plus PLGA encapsulated CpG 2007 results in qualitatively and quantitatively augmented antibody responses leading to a reduction in

  20. Novel adjuvant systems.

    PubMed

    McCluskie, M J; Weeratna, R D

    2001-11-01

    Vaccination remains the single most valuable tool in the prevention of infectious disease. Nevertheless, there exists a need to improve the performance of existing vaccines such that fewer boosts are needed or to develop novel vaccines. For the development of effective vaccines for humans, a great need exists for safe and effective adjuvants. A number of novel adjuvants have been reported in recent years including: i) bacterial toxins such as cholera toxin, CT, and the Escherichia coli heat-labile enterotoxin, LT; ii) less toxic derivatives of CT and LT; iii) endogenous human immunomodulators, such as IL-2, IL-12, GM-CSF; iv) hormones; v) lipopeptides; vi) saponins, such as QS-21; vii) synthetic oligonucleotides containing CpG motifs (CpG ODN); viii) lipid 'A derivatives, such as monophosphoryl lipid A, MPL, and ix) muramyl dipeptide (MDP) derivatives. Herein, we will review recent findings using these novel adjuvant systems. PMID:12455400

  1. Vaccine Adjuvants: from 1920 to 2015 and Beyond

    PubMed Central

    Di Pasquale, Alberta; Preiss, Scott; Tavares Da Silva, Fernanda; Garçon, Nathalie

    2015-01-01

    The concept of stimulating the body’s immune response is the basis underlying vaccination. Vaccines act by initiating the innate immune response and activating antigen presenting cells (APCs), thereby inducing a protective adaptive immune response to a pathogen antigen. Adjuvants are substances added to vaccines to enhance the immunogenicity of highly purified antigens that have insufficient immunostimulatory capabilities, and have been used in human vaccines for more than 90 years. While early adjuvants (aluminum, oil-in-water emulsions) were used empirically, rapidly increasing knowledge on how the immune system interacts with pathogens means that there is increased understanding of the role of adjuvants and how the formulation of modern vaccines can be better tailored towards the desired clinical benefit. Continuing safety evaluation of licensed vaccines containing adjuvants/adjuvant systems suggests that their individual benefit-risk profile remains favorable. Adjuvants contribute to the initiation of the innate immune response induced by antigens; exemplified by inflammatory responses at the injection site, with mostly localized and short-lived effects. Activated effectors (such as APCs) then move to draining lymph nodes where they direct the type, magnitude and quality of the adaptive immune response. Thus, the right match of antigens and adjuvants can potentiate downstream adaptive immune responses, enabling the development of new efficacious vaccines. Many infectious diseases of worldwide significance are not currently preventable by vaccination. Adjuvants are the most advanced new technology in the search for new vaccines against challenging pathogens and for vulnerable populations that respond poorly to traditional vaccines. PMID:26343190

  2. Matrix-M Adjuvated Seasonal Virosomal Influenza Vaccine Induces Partial Protection in Mice and Ferrets against Avian H5 and H7 Challenge.

    PubMed

    Cox, Freek; Roos, Anna; Hafkemeijer, Nicole; Baart, Matthijs; Tolboom, Jeroen; Dekking, Liesbeth; Stittelaar, Koert; Goudsmit, Jaap; Radošević, Katarina; Saeland, Eirikur

    2015-01-01

    There is a constant threat of zoonotic influenza viruses causing a pandemic outbreak in humans. It is virtually impossible to predict which virus strain will cause the next pandemic and it takes a considerable amount of time before a safe and effective vaccine will be available once a pandemic occurs. In addition, development of pandemic vaccines is hampered by the generally poor immunogenicity of avian influenza viruses in humans. An effective pre-pandemic vaccine is therefore required as a first line of defense. Broadening of the protective efficacy of current seasonal vaccines by adding an adjuvant may be a way to provide such first line of defense. Here we evaluate whether a seasonal trivalent virosomal vaccine (TVV) adjuvated with the saponin-based adjuvant Matrix-M (MM) can confer protection against avian influenza H5 and H7 virus strains in mice and ferrets. We demonstrate that mice were protected from death against challenges with H5N1 and H7N7, but that the protection was not complete as evidenced by severe clinical signs. In ferrets, protection against H7N9 was not observed. In contrast, reduced upper and lower respiratory tract viral loads and reduced lung pathology, was achieved in H5N1 challenged ferrets. Together these results suggest that, at least to some extent, Matrix-M adjuvated seasonal virosomal influenza vaccine can serve as an interim measure to decrease morbidity and mortality associated with a pandemic outbreak. PMID:26402787

  3. Matrix-M Adjuvated Seasonal Virosomal Influenza Vaccine Induces Partial Protection in Mice and Ferrets against Avian H5 and H7 Challenge

    PubMed Central

    Hafkemeijer, Nicole; Baart, Matthijs; Tolboom, Jeroen; Dekking, Liesbeth; Stittelaar, Koert; Goudsmit, Jaap; Radošević, Katarina; Saeland, Eirikur

    2015-01-01

    There is a constant threat of zoonotic influenza viruses causing a pandemic outbreak in humans. It is virtually impossible to predict which virus strain will cause the next pandemic and it takes a considerable amount of time before a safe and effective vaccine will be available once a pandemic occurs. In addition, development of pandemic vaccines is hampered by the generally poor immunogenicity of avian influenza viruses in humans. An effective pre-pandemic vaccine is therefore required as a first line of defense. Broadening of the protective efficacy of current seasonal vaccines by adding an adjuvant may be a way to provide such first line of defense. Here we evaluate whether a seasonal trivalent virosomal vaccine (TVV) adjuvated with the saponin-based adjuvant Matrix-M (MM) can confer protection against avian influenza H5 and H7 virus strains in mice and ferrets. We demonstrate that mice were protected from death against challenges with H5N1 and H7N7, but that the protection was not complete as evidenced by severe clinical signs. In ferrets, protection against H7N9 was not observed. In contrast, reduced upper and lower respiratory tract viral loads and reduced lung pathology, was achieved in H5N1 challenged ferrets. Together these results suggest that, at least to some extent, Matrix-M adjuvated seasonal virosomal influenza vaccine can serve as an interim measure to decrease morbidity and mortality associated with a pandemic outbreak. PMID:26402787

  4. Porphyromonas gingivalis oral infection exacerbates the development and severity of collagen-induced arthritis

    PubMed Central

    2013-01-01

    Introduction Clinical studies suggest a direct influence of periodontal disease (PD) on serum inflammatory markers and disease assessment of patients with established rheumatoid arthritis (RA). However, the influence of PD on arthritis development remains unclear. This investigation was undertaken to determine the contribution of chronic PD to immune activation and development of joint inflammation using the collagen-induced arthritis (CIA) model. Methods DBA1/J mice orally infected with Porphyromonas gingivalis were administered with collagen II (CII) emulsified in complete Freund’s adjuvant (CFA) or incomplete Freund’s adjuvant (IFA) to induce arthritis. Arthritis development was assessed by visual scoring of paw swelling, caliper measurement of the paws, mRNA expression, paw micro-computed tomography (micro-CT) analysis, histology, and tartrate resistant acid phosphatase for osteoclast detection (TRAP)-positive immunohistochemistry. Serum and reactivated splenocytes were evaluated for cytokine expression. Results Mice induced for PD and/or arthritis developed periodontal disease, shown by decreased alveolar bone and alteration of mRNA expression in gingival tissues and submandibular lymph nodes compared to vehicle. P. gingivalis oral infection increased paw swelling and osteoclast numbers in mice immunized with CFA/CII. Arthritis incidence and severity were increased by P. gingivalis in mice that received IFA/CII immunizations. Increased synovitis, bone erosions, and osteoclast numbers in the paws were observed following IFA/CII immunizations in mice infected with P gingivalis. Furthermore, cytokine analysis showed a trend toward increased serum Th17/Th1 ratios when P. gingivalis infection was present in mice receiving either CFA/CII or IFA/CII immunizations. Significant cytokine increases induced by P. gingivalis oral infection were mostly associated to Th17-related cytokines of reactivated splenic cells, including IL-1β, IL-6, and IL-22 in the CFA

  5. AS03-Adjuvanted, Very-Low-Dose Influenza Vaccines Induce Distinctive Immune Responses Compared to Unadjuvanted High-Dose Vaccines in BALB/c Mice

    PubMed Central

    Yam, Karen K.; Gupta, Jyotsana; Winter, Kaitlin; Allen, Elizabeth; Brewer, Angela; Beaulieu, Édith; Mallett, Corey P.; Burt, David S.; Ward, Brian J.

    2015-01-01

    During the 2009–2010 influenza pandemic, an adjuvanted, dose-sparing vaccine was recommended for most Canadians. We hypothesize that differences exist in the responses to AS03-adjuvanted, low antigen (Ag) dose versus unadjuvanted, full-dose vaccines. We investigated the relationship between Ag dose and the oil-in-water emulsion Adjuvant System AS03. BALB/c mice received two IM doses of AS03A or AS03B with exaggerated dilutions of A/Uruguay/716/2007 H3N2 split virion vaccine Ag. Immune responses were assessed 3 weeks after the booster. Unadjuvanted “high” (3 μg) and low-dose (0.03–0.003 μg) vaccines generated similar serum antibody titers and cytokine secretion patterns in restimulated splenocytes. Compared to unadjuvanted “high-dose” vaccination, both AS03A and AS03B-adjuvanted low-dose vaccines tended to elicit higher serum antibody titers, broader induction of cytokine secretion and generated more influenza-specific antibody secreting cells and cytokine-secreting CD4 and CD8 T cells in splenocytes. We show that varying Ag and/or AS03 dose in this influenza vaccination mouse model can strongly influence both the magnitude and pattern of the immune response elicited. These findings are highly relevant given the likelihood of expanded use of adjuvanted, dose-sparing vaccines and raise questions about the use of “standard” doses of vaccines in pre-clinical vaccine studies. PMID:25972874

  6. Some Comments on Analytic Traditions in EFA As against CFA: An Analysis of Selected Research Reports.

    ERIC Educational Resources Information Center

    Kieffer, Kevin M.

    Factor analysis has historically been used for myriad purposes in the social and behavioral sciences, but an especially important application of this technique has been to evaluate construct validity. Since in the present milieu both exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) are readily available to the researcher,…

  7. Exploratory Structural Equation Modeling, Integrating CFA and EFA: Application to Students' Evaluations of University Teaching

    ERIC Educational Resources Information Center

    Marsh, Herbert W.; Muthen, Bengt; Asparouhov, Tihomir; Ludtke, Oliver; Robitzsch, Alexander; Morin, Alexandre J. S.; Trautwein, Ulrich

    2009-01-01

    This study is a methodological-substantive synergy, demonstrating the power and flexibility of exploratory structural equation modeling (ESEM) methods that integrate confirmatory and exploratory factor analyses (CFA and EFA), as applied to substantively important questions based on multidimentional students' evaluations of university teaching…

  8. Clinical trial to evaluate safety and immunogenicity of an oral inactivated enterotoxigenic Escherichia coli prototype vaccine containing CFA/I overexpressing bacteria and recombinantly produced LTB/CTB hybrid protein.

    PubMed

    Lundgren, A; Leach, S; Tobias, J; Carlin, N; Gustafsson, B; Jertborn, M; Bourgeois, L; Walker, R; Holmgren, J; Svennerholm, A-M

    2013-02-01

    We have developed a new oral vaccine against enterotoxigenic Escherichia coli (ETEC) diarrhea containing killed recombinant E. coli bacteria expressing increased levels of ETEC colonization factors (CFs) and a recombinant protein (LCTBA), i.e. a hybrid between the binding subunits of E. coli heat labile toxin (LTB) and cholera toxin (CTB). We describe a randomized, comparator controlled, double-blind phase I trial in 60 adult Swedish volunteers of a prototype of this vaccine. The safety and immunogenicity of the prototype vaccine, containing LCTBA and an E. coli strain overexpressing the colonization factor CFA/I, was compared to a previously developed oral ETEC vaccine, consisting of CTB and inactivated wild type ETEC bacteria expressing CFA/I (reference vaccine). Groups of volunteers were given two oral doses of either the prototype or the reference vaccine; the prototype vaccine was administered at the same or a fourfold higher dosage than the reference vaccine. The prototype vaccine was found to be safe and equally well-tolerated as the reference vaccine at either dosage tested. The prototype vaccine induced mucosal IgA (fecal secretory IgA and intestine-derived IgA antibody secreting cell) responses to both LTB and CFA/I, as well as serum IgA and IgG antibody responses to LTB. Immunization with LCTBA resulted in about twofold higher mucosal and systemic IgA responses against LTB than a comparable dose of CTB. The higher dose of the prototype vaccine induced significantly higher fecal and systemic IgA responses to LTB and fecal IgA responses to CFA/I than the reference vaccine. These results demonstrate that CF over-expression and inclusion of the LCTBA hybrid protein in an oral inactivated ETEC vaccine does not change the safety profile when compared to a previous generation of such a vaccine and that the prototype vaccine induces significant dose dependent mucosal immune responses against CFA/I and LTB. PMID:23306362

  9. Effect of different adjuvant formulations on the immunogenicity and protective effect of a live Mycoplasma hyopneumoniae vaccine after intramuscular inoculation.

    PubMed

    Xiong, Qiyan; Wei, Yanna; Xie, Haidong; Feng, Zhixin; Gan, Yuan; Wang, Chunlai; Liu, Maojun; Bai, Fangfang; Xie, Fang; Shao, Guoqing

    2014-06-01

    Mycoplasma hyopneumoniae (M. hyopneumoniae) vaccine strain 168 is an intrapulmonically injected attenuated live vaccine that is available in the Chinese market. The aim of this study was to develop suitable adjuvants for this live vaccine to provide effective protection after intramuscular inoculation. Several adjuvant components were screened to assess their toxicity for the live vaccine, and various adjuvant formulations were then designed and prepared. Vaccines supplemented with these adjuvants were used to immunize mice intramuscularly to assess the capacity of the adjuvants to induce a specific immune response. The screened formulations were then evaluated in pigs. Seven of the eight adjuvant components did not affect the viability of the live vaccine, and seven different adjuvant formulations were then designed. In mice, the ISCOM-matrix adjuvant and the levamisole-chitosan mixture adjuvant significantly enhanced serum IgG responses against M. hyopneumoniae, while lymphocyte proliferation was enhanced by the ISCOM-matrix adjuvant, the carbomer-astragalus polysaccharide mixture adjuvant and an oil-in-water emulsion adjuvant. These four adjuvants were evaluated in pigs. Enhancement of specific lymphocyte proliferation responses was observed in the groups vaccinated with the ISCOM-matrix adjuvant and the carbomer-astragalus polysaccharide mixture adjuvant. Significant enhancement of serum IgG antibody production was observed before challenge in pigs vaccinated with the carbomer-astragalus polysaccharide mixture adjuvant and the levamisole-chitosan mixture adjuvant, while after challenge, all of the animals that received vaccines containing adjuvants had higher antibody concentrations against M. hyopneumoniae than unvaccinated animals. Animals inoculated with a vaccine containing the ISCOM-matrix adjuvant (median score 3.57) or the carbomer-astragalus polysaccharide mixture adjuvant (median score 5.28) had reduced lesion scores compared to unvaccinated animals

  10. Structural characterization of CFA/III and Longus type IVb pili from enterotoxigenic Escherichia coli.

    PubMed

    Kolappan, Subramaniapillai; Roos, Justin; Yuen, Alex S W; Pierce, Owen M; Craig, Lisa

    2012-05-01

    The type IV pili are helical filaments found on many Gram-negative pathogenic bacteria, with multiple diverse roles in pathogenesis, including microcolony formation, adhesion, and twitching motility. Many pathogenic enterotoxigenic Escherichia coli (ETEC) isolates express one of two type IV pili belonging to the type IVb subclass: CFA/III or Longus. Here we show a direct correlation between CFA/III expression and ETEC aggregation, suggesting that these pili, like the Vibrio cholerae toxin-coregulated pili (TCP), mediate microcolony formation. We report a 1.26-Å resolution crystal structure of CofA, the major pilin subunit from CFA/III. CofA is very similar in structure to V. cholerae TcpA but possesses a 10-amino-acid insertion that replaces part of the α2-helix with an irregular loop containing a 3(10)-helix. Homology modeling suggests a very similar structure for the Longus LngA pilin. A model for the CFA/III pilus filament was generated using the TCP electron microscopy reconstruction as a template. The unique 3(10)-helix insert fits perfectly within the gap between CofA globular domains. This insert, together with differences in surface-exposed residues, produces a filament that is smoother and more negatively charged than TCP. To explore the specificity of the type IV pilus assembly apparatus, CofA was expressed heterologously in V. cholerae by replacing the tcpA gene with that of cofA within the tcp operon. Although CofA was synthesized and processed by V. cholerae, no CFA/III filaments were detected, suggesting that the components of the type IVb pilus assembly system are highly specific to their pilin substrates. PMID:22447901

  11. Near-Infrared Laser Adjuvant for Influenza Vaccine

    PubMed Central

    Kashiwagi, Satoshi; Yuan, Jianping; Forbes, Benjamin; Hibert, Mathew L.; Lee, Eugene L. Q.; Whicher, Laura; Goudie, Calum; Yang, Yuan; Chen, Tao; Edelblute, Beth; Collette, Brian; Edington, Laurel; Trussler, James; Nezivar, Jean; Leblanc, Pierre; Bronson, Roderick; Tsukada, Kosuke; Suematsu, Makoto; Dover, Jeffrey; Brauns, Timothy; Gelfand, Jeffrey; Poznansky, Mark C.

    2013-01-01

    Safe and effective immunologic adjuvants are often essential for vaccines. However, the choice of adjuvant for licensed vaccines is limited, especially for those that are administered intradermally. We show that non-tissue damaging, near-infrared (NIR) laser light given in short exposures to small areas of skin, without the use of additional chemical or biological agents, significantly increases immune responses to intradermal influenza vaccination without augmenting IgE. The NIR laser-adjuvanted vaccine confers increased protection in a murine influenza lethal challenge model as compared to unadjuvanted vaccine. We show that NIR laser treatment induces the expression of specific chemokines in the skin resulting in recruitment and activation of dendritic cells and is safe to use in both mice and humans. The NIR laser adjuvant technology provides a novel, safe, low-cost, simple-to-use, potentially broadly applicable and clinically feasible approach to enhancing vaccine efficacy as an alternative to chemical and biological adjuvants. PMID:24349390

  12. Adjuvant Therapy for Melanoma

    PubMed Central

    Davar, Diwakar; Tarhini, Ahmad A.

    2012-01-01

    Estimates from the U.S. Surveillance, Epidemiology, and End Results (SEER) registry suggest that melanoma incidence will reach 70,230 in 2011, of which 8,790 will die. The rising incidence and predilection for young individuals makes this tumor a leading source of lost productive years in the society. High-dose interferon-α2b is the only agent approved for adjuvant therapy of melanoma; the improvement in relapse-free survival has been observed across nearly all published studies and meta-analyses. However toxicity affects compliance and current research is focusing upon biomarkers that may allow selection of patients with greater likelihood of response, and exploring new agents either singly or in combination that may improve upon the benefit of IFN. In this article, we review the data for the adjuvant therapy of malignant melanoma - focusing on the results obtained with various regimens testing the several formulations of interferon-α2, and the adjuvant studies of vaccines and radiotherapy. Recent advances in the treatment of metastatic disease have established a role for CTLA-4 blockade and BRAF-inhibition, and raising hopes that these agents may have a role in the adjuvant setting. At present, several trials investigating combinations of novel agents with existing immunomodulators are underway. PMID:22453021

  13. Laser vaccine adjuvants

    PubMed Central

    Kashiwagi, Satoshi; Brauns, Timothy; Gelfand, Jeffrey; Poznansky, Mark C

    2014-01-01

    Immunologic adjuvants are essential for current vaccines to maximize their efficacy. Unfortunately, few have been found to be sufficiently effective and safe for regulatory authorities to permit their use in vaccines for humans and none have been approved for use with intradermal vaccines. The development of new adjuvants with the potential to be both efficacious and safe constitutes a significant need in modern vaccine practice. The use of non-damaging laser light represents a markedly different approach to enhancing immune responses to a vaccine antigen, particularly with intradermal vaccination. This approach, which was initially explored in Russia and further developed in the US, appears to significantly improve responses to both prophylactic and therapeutic vaccines administered to the laser-exposed tissue, particularly the skin. Although different types of lasers have been used for this purpose and the precise molecular mechanism(s) of action remain unknown, several approaches appear to modulate dendritic cell trafficking and/or activation at the irradiation site via the release of specific signaling molecules from epithelial cells. The most recent study, performed by the authors of this review, utilized a continuous wave near-infrared laser that may open the path for the development of a safe, effective, low-cost, simple-to-use laser vaccine adjuvant that could be used in lieu of conventional adjuvants, particularly with intradermal vaccines. In this review, we summarize the initial Russian studies that have given rise to this approach and comment upon recent advances in the use of non-tissue damaging lasers as novel physical adjuvants for vaccines. PMID:25424797

  14. MF59- and Al(OH)3-Adjuvanted Staphylococcus aureus (4C-Staph) Vaccines Induce Sustained Protective Humoral and Cellular Immune Responses, with a Critical Role for Effector CD4 T Cells at Low Antibody Titers

    PubMed Central

    Monaci, Elisabetta; Mancini, Francesca; Lofano, Giuseppe; Bacconi, Marta; Tavarini, Simona; Sammicheli, Chiara; Arcidiacono, Letizia; Giraldi, Monica; Galletti, Bruno; Rossi Paccani, Silvia; Torre, Antonina; Fontana, Maria Rita; Grandi, Guido; de Gregorio, Ennio; Bensi, Giuliano; Chiarot, Emiliano; Nuti, Sandra; Bagnoli, Fabio; Soldaini, Elisabetta; Bertholet, Sylvie

    2015-01-01

    Staphylococcus aureus (S. aureus) is an important opportunistic pathogen that may cause invasive life-threatening infections, like sepsis and pneumonia. Due to the increasing antibiotic resistance, the development of an effective vaccine against S. aureus is needed. Although a correlate of protection against staphylococcal diseases is not yet established, several findings suggest that both antibodies and CD4 T cells might contribute to optimal immunity. In this study, we show that adjuvanting a multivalent vaccine (4C-Staph) with MF59, an oil-in-water emulsion licensed in human vaccines, further potentiated antigen-specific IgG titers and CD4 T-cell responses compared to alum and conferred protection in the peritonitis model of S. aureus infection. Moreover, we showed that MF59- and alum-adjuvanted 4C-Staph vaccines induced persistent antigen-specific humoral and T-cell responses, and protected mice from infection up to 4 months after immunization. Furthermore, 4C-Staph formulated with MF59 was used to investigate which immune compartment is involved in vaccine-induced protection. Using CD4 T cell-depleted mice or B cell-deficient mice, we demonstrated that both T and B-cell responses contributed to 4C-Staph vaccine-mediated protective immunity. However, the role of CD4 T cells seemed more evident in the presence of low-antibody responses. This study provides preclinical data further supporting the use of the adjuvanted 4C-Staph vaccines against S. aureus diseases, and provides critical insights on the correlates of protective immunity necessary to combat this pathogen. PMID:26441955

  15. Alga-produced malaria transmission-blocking vaccine candidate Pfs25 formulated with a human use-compatible potent adjuvant induces high-affinity antibodies that block Plasmodium falciparum infection of mosquitoes.

    PubMed

    Patra, Kailash P; Li, Fengwu; Carter, Darrick; Gregory, James A; Baga, Sheyenne; Reed, Steven G; Mayfield, Stephen P; Vinetz, Joseph M

    2015-05-01

    A vaccine to prevent the transmission of malaria parasites from infected humans to mosquitoes is an important component for the elimination of malaria in the 21st century, yet it remains neglected as a priority of malaria vaccine development. The lead candidate for Plasmodium falciparum transmission-blocking vaccine development, Pfs25, is a sexual stage surface protein that has been produced for vaccine testing in a variety of heterologous expression systems. Any realistic malaria vaccine will need to optimize proper folding balanced against cost of production, yield, and potentially reactogenic contaminants. Here Chlamydomonas reinhardtii microalga-produced recombinant Pfs25 protein was formulated with four different human-compatible adjuvants (alum, Toll-like receptor 4 [TLR-4] agonist glucopyranosal lipid A [GLA] plus alum, squalene-oil-in-water emulsion, and GLA plus squalene-oil-in-water emulsion) and compared for their ability to induce malaria transmission-blocking antibodies. Alga-produced recombinant Pfs25 plus GLA plus squalene-oil-in-water adjuvant induced the highest titer and avidity in IgG antibodies, measured using alga-produced recombinant Pfs25 as the enzyme-linked immunosorbent assay (ELISA) antigen. These antibodies specifically reacted with the surface of P. falciparum macrogametes and zygotes and effectively prevented parasites from developing within the mosquito vector in standard membrane feeding assays. Alga-produced Pfs25 in combination with a human-compatible adjuvant composed of a TLR-4 agonist in a squalene-oil-in-water emulsion is an attractive new vaccine candidate that merits head-to-head comparison with other modalities of vaccine production and administration. PMID:25690099

  16. Alga-Produced Malaria Transmission-Blocking Vaccine Candidate Pfs25 Formulated with a Human Use-Compatible Potent Adjuvant Induces High-Affinity Antibodies That Block Plasmodium falciparum Infection of Mosquitoes

    PubMed Central

    Patra, Kailash P.; Li, Fengwu; Carter, Darrick; Gregory, James A.; Baga, Sheyenne; Reed, Steven G.; Mayfield, Stephen P.

    2015-01-01

    A vaccine to prevent the transmission of malaria parasites from infected humans to mosquitoes is an important component for the elimination of malaria in the 21st century, yet it remains neglected as a priority of malaria vaccine development. The lead candidate for Plasmodium falciparum transmission-blocking vaccine development, Pfs25, is a sexual stage surface protein that has been produced for vaccine testing in a variety of heterologous expression systems. Any realistic malaria vaccine will need to optimize proper folding balanced against cost of production, yield, and potentially reactogenic contaminants. Here Chlamydomonas reinhardtii microalga-produced recombinant Pfs25 protein was formulated with four different human-compatible adjuvants (alum, Toll-like receptor 4 [TLR-4] agonist glucopyranosal lipid A [GLA] plus alum, squalene–oil-in-water emulsion, and GLA plus squalene–oil-in-water emulsion) and compared for their ability to induce malaria transmission-blocking antibodies. Alga-produced recombinant Pfs25 plus GLA plus squalene–oil-in-water adjuvant induced the highest titer and avidity in IgG antibodies, measured using alga-produced recombinant Pfs25 as the enzyme-linked immunosorbent assay (ELISA) antigen. These antibodies specifically reacted with the surface of P. falciparum macrogametes and zygotes and effectively prevented parasites from developing within the mosquito vector in standard membrane feeding assays. Alga-produced Pfs25 in combination with a human-compatible adjuvant composed of a TLR-4 agonist in a squalene–oil-in-water emulsion is an attractive new vaccine candidate that merits head-to-head comparison with other modalities of vaccine production and administration. PMID:25690099

  17. Chronic pain induces anxiety with concomitant changes in opioidergic function in the amygdala.

    PubMed

    Narita, Minoru; Kaneko, Chihiro; Miyoshi, Kan; Nagumo, Yasuyuki; Kuzumaki, Naoko; Nakajima, Mayumi; Nanjo, Kana; Matsuzawa, Kiyomi; Yamazaki, Mitsuaki; Suzuki, Tsutomu

    2006-04-01

    Clinically, it has been reported that chronic pain induces depression, anxiety, and reduced quality of life. The endogenous opioid system has been implicated in nociception, anxiety, and stress. The present study was undertaken to investigate whether chronic pain could induce anxiogenic effects and changes in the opioidergic function in the amygdala in mice. We found that either injection of complete Freund's adjuvant (CFA) or neuropathic pain induced by sciatic nerve ligation produced a significant anxiogenic effect at 4 weeks after the injection or surgery. Under these conditions, the selective mu-opioid receptor agonist [D-Ala2,N-MePhe4,Gly5-ol]-enkephalin (DAMGO)- and the selective delta-opioid receptor agonist (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80)-stimulated [35S]GTPgammaS binding in membranes of the amygdala was significantly suppressed by CFA injection or nerve ligation. CFA injection was associated with a significant increase in the kappa-opioid receptor agonist 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl]acetamide hydrochloride (ICI199,441)-stimulated [35S]GTPgammaS binding in membranes of the amygdala. The intracerebroventricular administration and microinjection of a selective mu-opioid receptor antagonist, a selective delta-opioid receptor antagonist, and the endogenous kappa-opioid receptor ligand dynorphin A caused a significant anxiogenic effect in mice. We also found that thermal hyperalgesia induced by sciatic nerve ligation was reversed at 8 weeks after surgery. In the light-dark test, the time spent in the lit compartment was not changed at 8 weeks after surgery. Collectively, the present data constitute the first evidence that chronic pain has an anxiogenic effect in mice. This phenomenon may be associated with changes in opioidergic function in the amygdala. PMID:16123756

  18. Unlipidated Outer Membrane Protein Omp16 (U-Omp16) from Brucella spp. as Nasal Adjuvant Induces a Th1 Immune Response and Modulates the Th2 Allergic Response to Cow’s Milk Proteins

    PubMed Central

    Ibañez, Andrés E.; Smaldini, Paola; Coria, Lorena M.; Delpino, María V.; Pacífico, Lucila G. G.; Oliveira, Sergio C.; Risso, Gabriela S.; Pasquevich, Karina A.; Fossati, Carlos Alberto; Giambartolomei, Guillermo H.; Docena, Guillermo H.; Cassataro, Juliana

    2013-01-01

    The discovery of novel mucosal adjuvants will help to develop new formulations to control infectious and allergic diseases. In this work we demonstrate that U-Omp16 from Brucella spp. delivered by the nasal route (i.n.) induced an inflammatory immune response in bronchoalveolar lavage (BAL) and lung tissues. Nasal co-administration of U-Omp16 with the model antigen (Ag) ovalbumin (OVA) increased the amount of Ag in lung tissues and induced OVA-specific systemic IgG and T helper (Th) 1 immune responses. The usefulness of U-Omp16 was also assessed in a mouse model of food allergy. U-Omp16 i.n. administration during sensitization ameliorated the hypersensitivity responses of sensitized mice upon oral exposure to Cow’s Milk Protein (CMP), decreased clinical signs, reduced anti-CMP IgE serum antibodies and modulated the Th2 response in favor of Th1 immunity. Thus, U-Omp16 could be used as a broad Th1 mucosal adjuvant for different Ag formulations. PMID:23861971

  19. Long-term booster schedules with AS03A-adjuvanted heterologous H5N1 vaccines induces rapid and broad immune responses in Asian adults

    PubMed Central

    2014-01-01

    Background The pandemic potential of avian influenza A/H5N1 should not be overlooked, and the continued development of vaccines against these highly pathogenic viruses is a public health priority. Methods This open-label extension booster study followed a Phase III study of 1206 adults who had received two 3.75 μg doses of primary AS03A-adjuvanted or non-adjuvanted H5N1 split-virus vaccine (A/Vietnam/1194/2004; clade 1) (NCT00449670). The aim of the extension study was to evaluate different timings for heterologous AS03A-adjuvanted booster vaccination (A/Indonesia/5/2005; clade 2.1) given at Month 6, 12, or 36 post-primary vaccination. Immunogenicity was assessed 21 days after each booster vaccination and the persistence of immune responses against the primary vaccine strain (A/Vietnam) and the booster strain (A/Indonesia) was evaluated up to Month 48 post-primary vaccination. Reactogenicity and safety were also assessed. Results After booster vaccination given at Month 6, HI antibody responses to primary vaccine, and booster vaccine strains were markedly higher with one dose of AS03A-H5N1 booster vaccine in the AS03A-adjuvanted primary vaccine group compared with two doses of booster vaccine in the non-adjuvanted primary vaccine group. HI antibody responses were robust against the primary and booster vaccine strains 21 days after boosting at Month 12 or 36. At Month 48, in subjects boosted at Month 6, 12, or 36, HI antibody titers of ≥1:40 against the booster strain persisted in 39.2%, 61.2%, and 95.6% of subjects, respectively. Neutralizing antibody responses and cell-mediated immune responses also showed that AS03A-H5N1 heterologous booster vaccination elicited robust immune responses within 21 days of boosting at Month 6, 12, or 36 post-primary vaccination. The booster vaccine was well tolerated, and no safety concerns were raised. Conclusions In Asian adults primed with two doses of AS03A-adjuvanted H5N1 pandemic influenza vaccine, strong cross

  20. Adjuvant poly(N-isopropylacrylamide) generates more efficient monoclonal antibodies against truncated recombinant histidine-rich protein2 of Plasmodium falciparum for malaria diagnosis.

    PubMed

    Verma, Reena; Ravichandran, Ramakrishnan; Jayaprakash, Naatamai S; Kumar, Ashok; Vijayalakshmi, Mookambeswaran A; Venkataraman, Krishnan

    2015-05-01

    Adjuvants play an important role in eliciting immune responses and subsequent generation of antibodies with high specificity. Recently, poly(N-isopropylacrylamide) (PNiPAAm), also known as a "smart" polymer, has been proposed as a potential adjuvant for making antibodies and vaccines. This material exhibits efficient delivery, protection against degradation, and preservation of antigen epitopes. In this work, we used both CFA and smart polymer to develop a highly specific murine monoclonal antibody (mAb) against recombinant truncated histidine rich protein2 (HRP2) of Plasmodium falciparum. Our results indicate that the mAbs developed using these adjuvants were able to recognize recombinant HRP2 and native PfHRP2 protein from spent medium. The mAbs generated against recombinant truncated HRP2 showed better sensitivity to the antigen and importantly mAbs generated using PNiPAAm adjuvant were in the range of 10(8)-10(9) M(-1). The mAbs generated using PNiPAAm are very efficient and sensitive in detecting HRP2. To the best of our knowledge, this is the first report of such comparison having been made between these two adjuvants and we propose that the smart polymer has huge potential as an alternative to CFA. Additionally, we discuss the utility of the mAbs generated through PNiPAAm for specific diagnosis of malaria caused by P. falciparum. PMID:25641957

  1. A pan-inhibitor of DASH family enzymes induces immune-mediated regression of murine sarcoma and is a potent adjuvant to dendritic cell vaccination and adoptive T-cell therapy.

    PubMed

    Duncan, Brynn B; Highfill, Steven L; Qin, Haiying; Bouchkouj, Najat; Larabee, Shannon; Zhao, Peng; Woznica, Iwona; Liu, Yuxin; Li, Youhua; Wu, Wengen; Lai, Jack H; Jones, Barry; Mackall, Crystal L; Bachovchin, William W; Fry, Terry J

    2013-10-01

    Multimodality therapy consisting of surgery, chemotherapy, and radiation will fail in approximately 40% of patients with pediatric sarcomas and result in substantial long-term morbidity in those who are cured. Immunotherapeutic regimens for the treatment of solid tumors typically generate antigen-specific responses too weak to overcome considerable tumor burden and tumor suppressive mechanisms and are in need of adjuvant assistance. Previous work suggests that inhibitors of DASH (dipeptidyl peptidase IV activity and/or structural homologs) enzymes can mediate tumor regression by immune-mediated mechanisms. Herein, we demonstrate that the DASH inhibitor, ARI-4175, can induce regression and eradication of well-established solid tumors, both as a single agent and as an adjuvant to a dendritic cell (DC) vaccine and adoptive cell therapy (ACT) in mice implanted with the M3-9-M rhabdomyosarcoma cell line. Treatment with effective doses of ARI-4175 correlated with recruitment of myeloid (CD11b) cells, particularly myeloid DCs, to secondary lymphoid tissues and with reduced frequency of intratumoral monocytic (CD11bLy6-CLy6-G) myeloid-derived suppressor cells. In immunocompetent mice, combining ARI-4175 with a DC vaccine or ACT with tumor-primed T cells produced significant improvements in tumor responses against well-established M3-9-M tumors. In M3-9-M-bearing immunodeficient (Rag1) mice, ACT combined with ARI-4175 produced greater tumor responses and significantly improved survival compared with either treatment alone. These studies warrant the clinical investigation of ARI-4175 for treatment of sarcomas and other malignancies, particularly as an adjuvant to tumor vaccines and ACT. PMID:23994886

  2. A pan-inhibitor of DASH family enzymes induces immune-mediated regression of murine sarcoma and is a potent adjuvant to dendritic cell vaccination and adoptive T-cell therapy

    PubMed Central

    Duncan, Brynn B.; Highfill, Steven L.; Qin, Haiying; Bouchkouj, Najat; Larabee, Shannon; Zhao, Peng; Woznica, Iwona; Liu, Yuxin; Li, Youhua; Wu, Wengen; Lai, Jack H.; Jones, Barry; Mackall, Crystal L.; Bachovchin, William W.; Fry, Terry J.

    2013-01-01

    Current multimodality therapy consisting of surgery, chemotherapy and radiation will fail in approximately 40% of patients with pediatric sarcomas and results in substantial long-term morbidity in those who are cured. Immunotherapeutic regimens for the treatment of solid tumors typically generate antigen-specific responses too weak to overcome considerable tumor burden and tumor suppressive mechanisms and are in need of adjuvant assistance. Previous work suggests that inhibitors of DASH (Dipeptidyl peptidase IV activity and/or structural homologues) enzymes can mediate tumor regression via immune-mediated mechanisms. Here we demonstrate that the DASH inhibitor, ARI-4175, can induce regression and eradication of well-established solid tumors, both as a single agent and as an adjuvant to a dendritic cell (DC) vaccine and adoptive cell therapy (ACT) in mice implanted with the M3-9-M rhabdomyosarcoma (RMS) cell line. Treatment with effective doses of ARI-4175 correlated with recruitment of myeloid (CD11b+) cells, particularly myeloid dendritic cells (DCs), to secondary lymphoid tissues and with reduced frequency of intratumoral monocytic (CD11b+Ly6-ChiLy6-Glo) myeloid-derived suppressor cells. In immunocompetent mice, combining ARI-4175 with a DC vaccine or ACT with tumor-primed T cells produced significant improvements in tumor responses against well-established M3-9-M tumors. In M3-9-M-bearing immunodeficient (Rag1-/-) mice, ACT combined with ARI-4175 produced greater tumor responses and significantly improved survival compared to either treatment alone. These studies warrant the clinical investigation of ARI-4175 for treatment of sarcomas and other malignancies particularly as an adjuvant to tumor vaccines and ACT. PMID:23994886

  3. IRAS galaxies and the large-scale structure in the CfA slice

    SciTech Connect

    Babul, A.; Postman, M. Space Telescope Science Institute, Baltimore, MD )

    1990-08-01

    The spatial distributions of the IRAS and the optical galaxies in the first CfA slice are compared. The IRAS galaxies are generally less clustered than optical ones, but their distribution is essentially identical to that of late-type optical galaxies. The discrepancy between the clustering properties of the IRAS and optical samples in the CfA slice region is found to be entirely due to the paucity of IRAS galaxies in the core of the Coma cluster. The spatial distributions of the IRAS and the optical galaxies, both late and early types, outside the dense core of the Coma cluster are entirely consistent with each other. This conflicts with the prediction of the linear biasing scenario. 39 refs.

  4. IRAS galaxies and the large-scale structure in the CfA slice

    NASA Technical Reports Server (NTRS)

    Babul, Arif; Postman, Marc

    1990-01-01

    The spatial distributions of the IRAS and the optical galaxies in the first CfA slice are compared. The IRAS galaxies are generally less clustered than optical ones, but their distribution is essentially identical to that of late-type optical galaxies. The discrepancy between the clustering properties of the IRAS and optical samples in the CfA slice region is found to be entirely due to the paucity of IRAS galaxies in the core of the Coma cluster. The spatial distributions of the IRAS and the optical galaxies, both late and early types, outside the dense core of the Coma cluster are entirely consistent with each other. This conflicts with the prediction of the linear biasing scenario.

  5. Interleukin-1beta partially alleviates cyclosporin A-induced suppression of IgG1 isotype response to thyroglobulin in BALB/c mice in vivo.

    PubMed Central

    Dalai, S K; Miriyala, B; Kar, S K

    1998-01-01

    Cyclosporin A (CsA) at 120 mg/kg body weight when injected subcutaneously into BALB/c mice along with thyroglobulin emulsified in incomplete Freund's adjuvant (IFA) was found to suppress antigen-specific IgG titre by 86%. Isotyping revealed that both IgG1 and IgG2a titres were suppressed by 87% and 57%, respectively. But under identical conditions when complete Freund's adjuvant (CFA) was used, the suppression of antigen-specific IgG, IgG1 and IgG2a titres was 50%, 51% and 55%, respectively. Injection of anti-IL-1beta-neutralizing hamster monoclonal antibodies along with thyroglobulin and CsA emulsified in CFA increased the suppression of antigen-specific IgG titre. Under such conditions the IgG1 titre was suppressed more than the IgG2a titre. Recombinant human interleukin-1 receptor antagonist (rhuIL-1ra) also enhanced the suppression caused by CsA in the presence of CFA but control hamster immunoglobulin had no such effect. Recombinant human IL-1beta, when administered along with thyroglobulin and CsA emulsified in IFA, alleviated the suppression of antigen-specific IgG titre and the IgG1 titre was alleviated more than the IgG2a titre. Under identical conditions, rhuIL-1ra did not alleviate CsA-induced suppression. Lymphocytes from the lymph nodes of thyroglobulin-sensitized BALB/c mice when stimulated in vitro by thyroglobulin in the presence of CsA, secreted very little interferon-gamma (IFN-gamma) and IL-4, but on addition of an optimal dose of rhuIL-1beta, IFN-gamma and IL-4 secretion was partially restored. PMID:9767461

  6. Aluminum vaccine adjuvants: are they safe?

    PubMed

    Tomljenovic, L; Shaw, C A

    2011-01-01

    Aluminum is an experimentally demonstrated neurotoxin and the most commonly used vaccine adjuvant. Despite almost 90 years of widespread use of aluminum adjuvants, medical science's understanding about their mechanisms of action is still remarkably poor. There is also a concerning scarcity of data on toxicology and pharmacokinetics of these compounds. In spite of this, the notion that aluminum in vaccines is safe appears to be widely accepted. Experimental research, however, clearly shows that aluminum adjuvants have a potential to induce serious immunological disorders in humans. In particular, aluminum in adjuvant form carries a risk for autoimmunity, long-term brain inflammation and associated neurological complications and may thus have profound and widespread adverse health consequences. In our opinion, the possibility that vaccine benefits may have been overrated and the risk of potential adverse effects underestimated, has not been rigorously evaluated in the medical and scientific community. We hope that the present paper will provide a framework for a much needed and long overdue assessment of this highly contentious medical issue. PMID:21568886

  7. Redshifts for a sample of fainter galaxies in the first CfA survey slice

    SciTech Connect

    Thorstensen, J.R.; Wegner, G.A.; Hamwey, R.; Boley, F.; Geller, M.J. Harvard-Smithsonian Center for Astrophysics, Cambridge, MA )

    1989-10-01

    Redshifts were measured for 93 of the 94 galaxies in the Zwicky-Nilson merged catalog with the value of m(B/01) between 15.5 and 15.7 and with right ascension alpha between 8(h) and 17(h) and declination delta between 29 and 30 deg. This region is within the one covered by the first slice of the CfA (Center for Astrophysics) survey. The galaxies reinforce features already visible in the earlier survey. 19 refs.

  8. Redshifts for a sample of fainter galaxies in the first CfA survey slice

    NASA Technical Reports Server (NTRS)

    Thorstensen, J. R.; Wegner, G. A.; Hamwey, R.; Boley, F.; Geller, M. J.

    1989-01-01

    Redshifts were measured for 93 of the 94 galaxies in the Zwicky-Nilson merged catalog with the value of m(B/01) between 15.5 and 15.7 and with right ascension alpha between 8(h) and 17(h) and declination delta between 29 and 30 deg. This region is within the one covered by the first slice of the CfA (Center for Astrophysics) survey. The galaxies reinforce features already visible in the earlier survey.

  9. Immunization with Recombinant Brucella Species Outer Membrane Protein Omp16 or Omp19 in Adjuvant Induces Specific CD4+ and CD8+ T Cells as Well as Systemic and Oral Protection against Brucella abortus Infection▿

    PubMed Central

    Pasquevich, Karina A.; Estein, Silvia M.; Samartino, Clara García; Zwerdling, Astrid; Coria, Lorena M.; Barrionuevo, Paula; Fossati, Carlos A.; Giambartolomei, Guillermo H.; Cassataro, Juliana

    2009-01-01

    Available vaccines against Brucella spp. are live attenuated Brucella strains. In order to engineer a better vaccine to be used in animals and humans, our laboratory aims to develop an innocuous subunit vaccine. Particularly, we are interested in the outer membrane proteins (OMPs) of B. abortus: Omp16 and Omp19. In this study, we assessed the use of these proteins as vaccines against Brucella in BALB/c mice. Immunization with lipidated Omp16 (L-Omp16) or L-Omp19 in incomplete Freund's adjuvant (IFA) conferred significant protection against B. abortus infection. Vaccination with unlipidated Omp16 (U-Omp16) or U-Omp19 in IFA induced a higher degree of protection than the respective lipidated versions. Moreover, the level of protection induced after U-Omp16 or U-Omp19 immunization in IFA was similar to that elicited by live B. abortus S19 immunization. Flow cytometric analysis showed that immunization with U-Omp16 or U-Omp19 induced antigen-specific CD4+ as well as CD8+ T cells producing gamma interferon. In vivo depletion of CD4+ or CD8+ T cells in mice immunized with U-Omp16 or U-Omp19 plus IFA resulted in a loss of the elicited protection, indicating that both cell types are mediating immune protection. U-Omp16 or U-Omp19 vaccination induced a T helper 1 response, systemic protection in aluminum hydroxide formulation, and oral protection with cholera toxin adjuvant against B. abortus infection. Both immunization routes exhibited a similar degree of protection to attenuated Brucella vaccines (S19 and RB51, respectively). Overall these results indicate that U-Omp16 or U-Omp19 would be a useful candidate for a subunit vaccine against human and animal brucellosis. PMID:18981242

  10. Immunization with recombinant Brucella species outer membrane protein Omp16 or Omp19 in adjuvant induces specific CD4+ and CD8+ T cells as well as systemic and oral protection against Brucella abortus infection.

    PubMed

    Pasquevich, Karina A; Estein, Silvia M; García Samartino, Clara; Samartino, Clara García; Zwerdling, Astrid; Coria, Lorena M; Barrionuevo, Paula; Fossati, Carlos A; Giambartolomei, Guillermo H; Cassataro, Juliana

    2009-01-01

    Available vaccines against Brucella spp. are live attenuated Brucella strains. In order to engineer a better vaccine to be used in animals and humans, our laboratory aims to develop an innocuous subunit vaccine. Particularly, we are interested in the outer membrane proteins (OMPs) of B. abortus: Omp16 and Omp19. In this study, we assessed the use of these proteins as vaccines against Brucella in BALB/c mice. Immunization with lipidated Omp16 (L-Omp16) or L-Omp19 in incomplete Freund's adjuvant (IFA) conferred significant protection against B. abortus infection. Vaccination with unlipidated Omp16 (U-Omp16) or U-Omp19 in IFA induced a higher degree of protection than the respective lipidated versions. Moreover, the level of protection induced after U-Omp16 or U-Omp19 immunization in IFA was similar to that elicited by live B. abortus S19 immunization. Flow cytometric analysis showed that immunization with U-Omp16 or U-Omp19 induced antigen-specific CD4(+) as well as CD8(+) T cells producing gamma interferon. In vivo depletion of CD4(+) or CD8(+) T cells in mice immunized with U-Omp16 or U-Omp19 plus IFA resulted in a loss of the elicited protection, indicating that both cell types are mediating immune protection. U-Omp16 or U-Omp19 vaccination induced a T helper 1 response, systemic protection in aluminum hydroxide formulation, and oral protection with cholera toxin adjuvant against B. abortus infection. Both immunization routes exhibited a similar degree of protection to attenuated Brucella vaccines (S19 and RB51, respectively). Overall these results indicate that U-Omp16 or U-Omp19 would be a useful candidate for a subunit vaccine against human and animal brucellosis. PMID:18981242

  11. Immunoprotective activity of a Salmonid Alphavirus Vaccine: comparison of the immune responses induced by inactivated whole virus antigen formulations based on CpG class B oligonucleotides and poly I:C alone or combined with an oil adjuvant.

    PubMed

    Thim, Hanna L; Iliev, Dimitar B; Christie, Karen E; Villoing, Stéphane; McLoughlin, Marian F; Strandskog, Guro; Jørgensen, Jorunn B

    2012-07-01

    CpG oligonucleotides and polyinosinic:polycytidylic acid (poly I:C) are toll-like receptor (TLR) agonists that mimic the immunostimulatory properties of bacterial DNA and double-stranded viral RNA respectively, and which have exhibited potential to serve as vaccine adjuvants in previous experiments. Here, a combination of CpGs and poly I:C together with water- or oil-formulated Salmonid Alphavirus (SAV) antigen preparations has been used for a vaccine in Atlantic salmon and tested for protection in SAV challenge trial. The results demonstrate that vaccination with a high dose of the SAV antigen induced protection against challenge with SAV which correlated with production of neutralizing antibodies (NAbs). As the high antigen dose alone induced full protection, no beneficial effect from the addition of CpG and poly I:C could be observed. Nevertheless, these TLR ligands significantly enhanced the levels of NAbs in serum of vaccinated fish. Interestingly, gene expression analysis demonstrated that while addition of oil suppressed the CpG/poly I:C-induced expression of IFN-γ, the upregulation of IFNa1 was substantially enhanced. A low dose of the SAV antigen combined with oil did not induce any detectable levels of NAbs either with or without TLR ligands present, however the addition of CpG and poly I:C to the low SAV antigen dose formulation significantly enhanced the protection against SAV suggesting that CpG/poly I:C may have enhanced a cytotoxic response - a process which is dependent on the up-regulation of type I IFN. These results highlight the immunostimulatory properties of the tested TLR ligands and will serve as a ground for further, more detailed studies aimed to investigate their capacity to serve as adjuvants in vaccine formulations for Atlantic salmon. PMID:22634299

  12. Chronic oral or intraarticular administration of docosahexaenoic acid reduces nociception and knee edema and improves functional outcomes in a mouse model of Complete Freund’s Adjuvant–induced knee arthritis

    PubMed Central

    2014-01-01

    Introduction Clinical and preclinical studies have shown that supplementation with ω-3 polyunsaturated fatty acids (ω-3 PUFAs) reduce joint destruction and inflammation present in rheumatoid arthritis (RA). However, the effects of individual ω-3 PUFAs on chronic arthritic pain have not been evaluated to date. Thus, our aim in this study was to examine whether purified docosahexaenoic acid (DHA, an ω-3 PUFA) reduces spontaneous pain-related behavior and knee edema and improves functional outcomes in a mouse model of knee arthritis. Methods Unilateral arthritis was induced by multiple injections of Complete Freund’s Adjuvant (CFA) into the right knee joints of male ICR adult mice. Mice that received CFA injections were then chronically treated from day 15 until day 25 post–initial CFA injection with oral DHA (10, 30 and 100 mg/kg daily) or intraarticular DHA (25 and 50 μg/joint twice weekly). Spontaneous flinching of the injected extremity (considered as spontaneous pain-related behavior), vertical rearing and horizontal exploratory activity (considered as functional outcomes) and knee edema were assessed. To determine whether an endogenous opioid mechanism was involved in the therapeutic effect of DHA, naloxone (NLX, an opioid receptor antagonist, 3 mg/kg subcutaneously) was administered in arthritic mice chronically treated with DHA (30 mg/kg by mouth) at day 25 post–CFA injection. Results The intraarticular CFA injections resulted in increasing spontaneous flinching and knee edema of the ipsilateral extremity as well as worsening functional outcomes as time progressed. Chronic administration of DHA, given either orally or intraarticularly, significantly improved horizontal exploratory activity and reduced flinching behavior and knee edema in a dose-dependent manner. Administration of NLX did not reverse the antinociceptive effect of DHA. Conclusions To the best of our knowledge, this report is the first to demonstrate DHA’s antinociceptive and

  13. Review of Bayer pattern CFA demosaicing with new quality assessment algorithms

    NASA Astrophysics Data System (ADS)

    Maschal, Robert A., Jr.; Young, S. Susan; Reynolds, Joe; Krapels, Keith; Fanning, Jonathan; Corbin, Ted

    2010-04-01

    Given the frequent lack of a reference image or ground truth when performance testing Bayer pattern color filter array (CFA) demosaicing algorithms, two new no-reference quality assessment algorithms are proposed. These new quality assessment algorithms give a relative comparison of two demosaicing algorithms by measuring the presence of two common artifacts in their output images. For this purpose, various demosaicing algorithms are reviewed, especially adaptive color plane, gradient based methods, and median filtering, with particular attention paid to the false color and edge blurring artifacts common to all demosaicing algorithms. Classic quality assessment methods which require a reference image, such as MSE, PSNR, and ΔE, are reviewed, their typical usage characterized, and their associated pitfalls identified. With this information in mind, the motivations for no-reference quality assessment are discussed. The new quality assessment algorithms are then designed for a relative comparison of two images demosaiced from the same CFA data by measuring the sharpness of the edges and determining the presence of false colors. Demosaicing algorithms described earlier are evaluated and ranked using these new algorithms. A large quantity of real images is given for review. These images are also used to justify those rankings suggested by the new quality assessment algorithms. This work provides a path forward for future research investigating possible relationships between CFA demosaicing and color image super-resolution.

  14. Measures of large-scale structure in the CfA redshift survey slices

    NASA Technical Reports Server (NTRS)

    De Lapparent, Valerie; Geller, Margaret J.; Huchra, John P.

    1991-01-01

    Variations of the counts-in-cells with cell size are used here to define two statistical measures of large-scale clustering in three 6 deg slices of the CfA redshift survey. A percolation criterion is used to estimate the filling factor which measures the fraction of the total volume in the survey occupied by the large-scale structures. For the full 18 deg slice of the CfA redshift survey, f is about 0.25 + or - 0.05. After removing groups with more than five members from two of the slices, variations of the counts in occupied cells with cell size have a power-law behavior with a slope beta about 2.2 on scales from 1-10/h Mpc. Application of both this statistic and the percolation analysis to simulations suggests that a network of two-dimensional structures is a better description of the geometry of the clustering in the CfA slices than a network of one-dimensional structures. Counts-in-cells are also used to estimate at 0.3 galaxy h-squared/Mpc the average galaxy surface density in sheets like the Great Wall.

  15. Measures of large-scale structure in the CfA redshift survey slices

    SciTech Connect

    De Lapparent, V.; Geller, M.J.; Huchra, J.P. Harvard-Smithsonian Center for Astrophysics, Cambridge, MA )

    1991-03-01

    Variations of the counts-in-cells with cell size are used here to define two statistical measures of large-scale clustering in three 6 deg slices of the CfA redshift survey. A percolation criterion is used to estimate the filling factor which measures the fraction of the total volume in the survey occupied by the large-scale structures. For the full 18 deg slice of the CfA redshift survey, f is about 0.25 + or - 0.05. After removing groups with more than five members from two of the slices, variations of the counts in occupied cells with cell size have a power-law behavior with a slope beta about 2.2 on scales from 1-10/h Mpc. Application of both this statistic and the percolation analysis to simulations suggests that a network of two-dimensional structures is a better description of the geometry of the clustering in the CfA slices than a network of one-dimensional structures. Counts-in-cells are also used to estimate at 0.3 galaxy h-squared/Mpc the average galaxy surface density in sheets like the Great Wall. 46 refs.

  16. Simulation of a distributed current source in a linear format CFA

    NASA Astrophysics Data System (ADS)

    Pearlman, Marcus; Browning, Jim

    2015-11-01

    A fundamental limit on Crossed-Field Amplifiers (CFA) gain is beam to RF power ratio. With too much beam power, the RF signal on the slow wave circuit is ``swamped.'' It is proposed here that a controllable, distributed cathode source can be used to tailor current injection and optimize gain. In this work a linear format CFA with a meander line slow wave circuit is tested experimentally and numerically using Vsim. Simulations of the original design, which operates at 900 MHz, shows < 1dB gain at beam currents >100 mA. This beam current is higher than the capabilities of the Field Emitter Array cathodes available to the group; therefore no experimental gain was observed. To be able to compare simulation to experiment, the CFA model under study was changed to the experiment used at Northeastern University in 1991, which also uses a meander line circuit and an injected beam configuration. Direct comparisons between the simulation and this experiment are performed to validate the model. Additional simulations study the effect of different current distributions on gain, bandwidth, and efficiency. Practical considerations such as how to control the energy of the beam separately from the sole potential in order to minimize lost current to sole are also examined. This research was supported by the Air Force Office of Scientific Research and the department of Electrical and Computer Engineering at Boise State University.

  17. Adjuvants for vaccines to drugs of abuse and addiction.

    PubMed

    Alving, Carl R; Matyas, Gary R; Torres, Oscar; Jalah, Rashmi; Beck, Zoltan

    2014-09-22

    Immunotherapeutic vaccines to drugs of abuse, including nicotine, cocaine, heroin, oxycodone, methamphetamine, and others are being developed. The theoretical basis of such vaccines is to induce antibodies that sequester the drug in the blood in the form of antibody-bound drug that cannot cross the blood brain barrier, thereby preventing psychoactive effects. Because the drugs are haptens a successful vaccine relies on development of appropriate hapten-protein carrier conjugates. However, because induction of high and prolonged levels of antibodies is required for an effective vaccine, and because injection of T-independent haptenic drugs of abuse does not induce memory recall responses, the role of adjuvants during immunization plays a critical role. As reviewed herein, preclinical studies often use strong adjuvants such as complete and incomplete Freund's adjuvant and others that cannot be, or in the case of many newer adjuvants, have never been, employed in humans. Balanced against this, the only adjuvant that has been included in candidate vaccines in human clinical trials to nicotine and cocaine has been aluminum hydroxide gel. While aluminum salts have been widely utilized worldwide in numerous licensed vaccines, the experience with human responses to aluminum salt-adjuvanted vaccines to haptenic drugs of abuse has suggested that the immune responses are too weak to allow development of a successful vaccine. What is needed is an adjuvant or combination of adjuvants that are safe, potent, widely available, easily manufactured, and cost-effective. Based on our review of the field we recommend the following adjuvant combinations either for research or for product development for human use: aluminum salt with adsorbed monophosphoryl lipid A (MPLA); liposomes containing MPLA [L(MPLA)]; L(MPLA) adsorbed to aluminum salt; oil-in-water emulsion; or oil-in-water emulsion containing MPLA. PMID:25111169

  18. New Surface-Associated Heat-Labile Colonization Factor Antigen (CFA/II) Produced by Enterotoxigenic Escherichia coli of Serogroups O6 and O8

    PubMed Central

    Evans, Dolores G.; Evans, Doyle J.

    1978-01-01

    Enterotoxigenic Escherichia coli (ETEC) belonging to serogroups O6 and O8 do not possess the H-10407-type colonization factor antigen (CFA/I). However, these frequently isolated ETEC were found to possess a second and distinct heat-labile surface-associated colonization factor antigen, termed CFA/II. Whereas CFA/I mediates mannose-resistant hemagglutination of human group A erythrocytes, CFA/II does not. CFA/II mediates mannose-resistant hemagglutination of bovine erythrocytes, and mannose-resistant hemagglutination is rapid only at reduced temperature (4°C). Because CFA/II, like CFA/I, is spontaneously lost by many ETEC isolates in the laboratory, it was possible to produce specific anti-CFA/II serum by preparing antiserum against living cells of a prototype strain (PB-176) and adsorbing this serum with living and heat-treated cells of its CFA/II-negative derivative strain PB-176-P. This serum, which neutralized the colonization factor activity of CFA/II-positive strains in infant rabbits, was employed to confirm the presence of CFA/II on ETEC which exhibited mannose-resistant hemagglutination of bovine but not human erythrocytes. CFA/II, like CFA/I, mediates adherence of the bacteria to the mucosal surface of the small intestine, as demonstrated by indirect immunofluorescence. CFA/II appears to be an important virulence factor for humans since CFA/II-positive ETEC are frequently isolated from diarrhea cases, particularly travelers' diarrhea, in Mexico; these ETEC were not uncommon in a collection of isolates from Bangladesh. The O6:H16 strain of ETEC responsible for an outbreak of diarrhea in the United States was also shown to be CFA/II positive. CFA/I and CFA/II were never found on the same serotypes of ETEC, but 98% of the heat-stable and heat-labile enterotoxin-producing ETEC belonging to the frequently isolated serogroups O6, O8, O15, O25, O63, and O78 were positive for either CFA/I or CFA/II. Images PMID:80383

  19. The A3 adenosine receptor agonist CF502 inhibits the PI3K, PKB/Akt and NF-kappaB signaling pathway in synoviocytes from rheumatoid arthritis patients and in adjuvant-induced arthritis rats.

    PubMed

    Ochaion, A; Bar-Yehuda, S; Cohen, S; Amital, H; Jacobson, K A; Joshi, B V; Gao, Z G; Barer, F; Patoka, R; Del Valle, L; Perez-Liz, G; Fishman, P

    2008-08-15

    The A(3) adenosine receptor (A(3)AR) is over-expressed in inflammatory cells and was defined as a target to combat inflammation. Synthetic agonists to this receptor, such as IB-MECA and Cl-IB-MECA, exert an anti-inflammatory effect in experimental animal models of adjuvant- and collagen-induced arthritis. In this study we present a novel A(3)AR agonist, CF502, with high affinity and selectivity at the human A(3)AR. CF502 induced a dose dependent inhibitory effect on the proliferation of fibroblast-like synoviocytes (FLS) via de-regulation of the nuclear factor-kappa B (NF-kappaB) signaling pathway. Furthermore, CF502 markedly suppressed the clinical and pathological manifestations of adjuvant-induced arthritis (AIA) in a rat experimental model when given orally at a low dose (100 microg/kg). As is typical of other G-protein coupled receptors, the A(3)AR expression level was down-regulated shortly after treatment with agonist CF502 in paw and in peripheral blood mononuclear cells (PBMCs) derived from treated AIA animals. Subsequently, a decrease in the expression levels of protein kinase B/Akt (PKB/Akt), IkappaB kinase (IKK), I kappa B (IkappaB), NF-kappaB and tumor necrosis factor-alpha (TNF-alpha) took place. In addition, the expression levels of glycogen synthase kinase-3 beta (GSK-3beta), beta-catenin, and poly(ADP-ribose)polymerase (PARP), known to control the level and activity of NF-kappaB, were down-regulated upon treatment with CF502. Taken together, CF502 inhibits FLS growth and the inflammatory manifestations of arthritis, supporting the development of A(3)AR agonists for the treatment of rheumatoid arthritis. PMID:18602896

  20. The A3 Adenosine Receptor Agonist CF502 Inhibits the PI3K, PKB/Akt and NF-κB Signaling Pathway in Synoviocytes from Rheumatoid Arthritis Patients and in Adjuvant Induced Arthritis Rats

    PubMed Central

    Ochaion, A.; Bar-Yehuda, S.; Cohen, S.; Amital, H.; Jacobson, K.A.; Joshi, B.V.; Gao, Z.G.; Barer, F.; Patoka, R.; Del Valle, L.; Perez-Liz, G.; Fishman, P.

    2009-01-01

    The A3 adenosine receptor (A3AR) is over-expressed in inflammatory cells and was defined as a target to combat inflammation. Synthetic agonists to this receptor, such as IB-MECA and Cl-IB-MECA, exert an anti-inflammatory effect in experimental animal models of adjuvant and collagen induced arthritis. In this study we present a novel A3AR agonist, CF502, with high affinity and selectivity at the human A3AR. CF502 induced a dose dependent inhibitory effect on the proliferation of fibroblast-like synoviocytes (FLS) via de-regulation of the nuclear factor-kappa B (NF-κB) signaling pathway. Furthermore, CF502 markedly suppressed the clinical and pathological manifestations of Adjuvant Induced Arthritis (AIA) in a rat experimental model when given orally at a low dose (100 μg/kg). As is typical of other G-protein coupled receptors, the A3AR expression level was down-regulated shortly after treatment with agonist CF502 in paw and in peripheral blood mononuclear cells (PBMCs) derived from treated AIA animals. Subsequently, a decrease in the expression levels of Protein Kinase B/Akt (PKB/Akt), IκB kinase (IKK), (I kappa B) IκB, NF-κB and tumor necrosis factor-alpha (TNF-α) took place. In addition, the expression levels of Glycogen synthase kinase-3 beta (GSK-3β), β-catenin, and Poly (ADP-ribose) polymerase (PARP), known to control the level and activity of NF-κB, were down-regulated upon treatment with CF502. Taken together, CF502 inhibits FLS growth and the inflammatory manifestations of arthritis, supporting the development of A3AR agonists for the treatment of rheumatoid arthritis. PMID:18602896

  1. Computer Modeling of Sand Transport on Mars Using a Compart-Mentalized Fluids Algorithm (CFA)

    NASA Technical Reports Server (NTRS)

    Marshall, J.; Stratton, D.

    1999-01-01

    It has been postulated that aeolian transport on Mars may be significantly different from that on Earth. From laboratory experiments simulating martian grain transport [2], it has been observed that (saltating) grains striking the bed can cause hundreds of secondary reptation trajectories when impact occurs at speeds postulated for Mars. Some of the ballistically induced trajectories "die ouf' and effectively join the ranks on the creep population that is merely nudged along by impact. Many of the induced reptation trajectories, however, are sufficiently high for the grains to become part of the saltation load (it is irrelevant to the boundary layer how a grain attained its initial lift force). When these grains, in turn, strike the surface, they too are capable of inducing more reptating grains. This cascading effect has been discussed in connection with terrestrial aeolian transport in an attempt to dispel the notion that sand motion is divisible only into creep and saltation loads. On Earth, only a few grains are splashed by impact. On Mars, it may be hundreds. We developed a computer model to address this phenomenon because there are some important ramifications: First, this ratio may mean that martian aeolian transport is dominated by reptation flux rather than saltation. On Earth, the flux would be a roughly balanced mixture between reptation/creep and saltation. On Venus, there would be no transport other than by saltation. In other words, an understanding of planetary aeolian processes may not be necessarily understood by extrapolating from the "Earth case", with only gravity and atmospheric density/viscosity being considered as variables. Second, the reptation flux on Mars may be self sustaining, so that little input is required by the wind once transport has been initiated. The number of grains saturating the boundary layer near the bed may mean that average grain speed on Mars might conceivably be less than that on Earth. This would say much for models

  2. Adjuvant Therapy Trials.

    PubMed

    Ursem, Carling; Van Loon, Katherine; Venook, Alan

    2016-01-01

    In 2015, ramucirumab and TAS-102 became the 10th and 11th drugs approved by the Food and Drug administration for the treatment of patients with colorectal cancer, not counting leucovorin, and yet only 3 agents, 5-fluorouracil, capecitabine, and oxaliplatin, have proven benefit in adjuvant treatment. In fact, there have been no additions (and 1 subtraction levamisole) to our arsenal of therapies for patients with stages II and III colon cancer for more than a decade. How did we get here? Are we stuck? And how do we move forward? PMID:27341598

  3. Carbohydrate-based immune adjuvants

    PubMed Central

    Petrovsky, Nikolai; Cooper, Peter D

    2011-01-01

    The role for adjuvants in human vaccines has been a matter of vigorous scientific debate, with the field hindered by the fact that for over 80 years, aluminum salts were the only adjuvants approved for human use. To this day, alum-based adjuvants, alone or combined with additional immune activators, remain the only adjuvants approved for use in the USA. This situation has not been helped by the fact that the mechanism of action of most adjuvants has been poorly understood. A relative lack of resources and funding for adjuvant development has only helped to maintain alum’s relative monopoly. To seriously challenge alum’s supremacy a new adjuvant has many major hurdles to overcome, not least being alum’s simplicity, tolerability, safety record and minimal cost. Carbohydrate structures play critical roles in immune system function and carbohydrates also have the virtue of a strong safety and tolerability record. A number of carbohydrate compounds from plant, bacterial, yeast and synthetic sources have emerged as promising vaccine adjuvant candidates. Carbohydrates are readily biodegradable and therefore unlikely to cause problems of long-term tissue deposits seen with alum adjuvants. Above all, the Holy Grail of human adjuvant development is to identify a compound that combines potent vaccine enhancement with maximum tolerability and safety. This has proved to be a tough challenge for many adjuvant contenders. Nevertheless, carbohydrate-based compounds have many favorable properties that could place them in a unique position to challenge alum’s monopoly over human vaccine usage. PMID:21506649

  4. Adjuvant Therapy: Melanoma

    PubMed Central

    Davar, Diwakar; Tarhini, Ahmad; Kirkwood, John M.

    2011-01-01

    With an incidence that is increasing at 2–5% per year, cutaneous melanoma is an international scourge that disproportionately targets young individuals. Despite much research, the treatment of advanced disease is still quite challenging. Immunotherapy with high-dose interferon-α2b or interleukin-2 benefits a select group of patients in the adjuvant and metastatic settings, respectively, with significant attendant toxicity. Advances in the biology of malignant melanoma and the role of immunomodulatory therapy have produced advances that have stunned the field. In this paper, we review the data for the use of interferon-α2b in various dosing ranges, vaccine therapy, and the role of radiotherapy in the adjuvant setting for malignant melanoma. Recent trials in the metastatic setting using anticytoxic T-lymphocyte antigen-4 (anti-CTLA-4) monoclonal antibody therapy and BRAF inhibitor therapy have demonstrated clear benefit with prolongation of survival. Trials investigating combinations of these novel agents with existing immunomodulators are at present underway. PMID:22220281

  5. Cytotoxic T cell adjuvant effects of three Salmonella enterica flagellins

    PubMed Central

    Braga, Catarina J.M.; Massis, Liliana M.; Alencar, Bruna C.G.; Rodrigues, Maurício M.; Sbrogio-Almeida, M.E.; Ferreira, Luís C.S.

    2008-01-01

    Bacterial flagellins are important virulence-associated factors and strong inducers of inflammatory responses in mammalian hosts. Flagellins have also been investigated as potential vaccine adjuvants, either for induction of humoral or cellular immune responses, to different target antigens. In this study we investigated the adjuvant properties of three Salmonella enterica flagellins types (FliCd, FliCi and FljB) to an ovalbumin-derived CD8+ T cell-restricted epitope (OVA257–264). Although mice immunized with the three tested flagellins elicited antigen-specific activated CD8+ T cells, only animals immunized with FliCi and FliCd flagellins admixed with ovalbumin mounted specific in vivo cytotoxic responses to peptide-pulsed target cells. The present results indicate that Salmonella flagellins are endowed with type-specific adjuvant effects toward murine CD8+ T cells, a feature that may impact their use as adjuvants for prophylatic or therapeutic vaccines. PMID:24031176

  6. Alzheimer’s disease AdvaxCpG- adjuvanted MultiTEP-based dual and single vaccines induce high-titer antibodies against various forms of tau and Aβ pathological molecules

    PubMed Central

    Davtyan, Hayk; Zagorski, Karen; Rajapaksha, Harinda; Hovakimyan, Armine; Davtyan, Arpine; Petrushina, Irina; Kazarian, Konstantin; Cribbs, David H.; Petrovsky, Nikolai; Agadjanyan, Michael G.; Ghochikyan, Anahit

    2016-01-01

    Although β-amyloid (Aβ) may be the primary driver of Alzheimer’s disease (AD) pathology, accumulation of pathological tau correlates with dementia in AD patients. Thus, the prevention/inhibition of AD may require vaccine/s targeting Aβ and tau simultaneously or sequentially. Since high antibody titers are required for AD vaccine efficacy, we have decided to generate vaccines, targeting Aβ (AV-1959R), Tau (AV-1980R) or Aβ/tau (AV-1953R) B cell epitopes, based on immunogenic MultiTEP platform and evaluate the immunogenicity of these vaccines formulated with AdvaxCpG, delta inulin, Alhydrogel®, Montanide-ISA51, Montanide-ISA720, MPLA-SM pharmaceutical grade adjuvants. Formulation of AV-1959R in AdvaxCpG induced the highest cellular and humoral immune responses in mice. The dual-epitope vaccine, AV-1953R, or the combination of AV-1959R and AV-1980R vaccines formulated with AdvaxCpG induced robust antibody responses against various forms of both, Aβ and tau pathological molecules. While anti-Aβ antibody titers after AV-1953R immunization were similar to that in mice vaccinated with AV-1959R or AV-1959R/AV-1980R combination, anti-tau titers were significantly lower after AV-1953R injection when compared to the AV-1980R or AV-1959R/AV-1980R. In silico 3D-modeling provided insight into the differences in immunogenicity of these vaccine constructs. In sum, AV-1959R and AV-1980R formulated with AdvaxCpG adjuvant were identified as promising immunogenic vaccines for ongoing pre-clinical assessment and future human clinical trials. PMID:27363809

  7. Triphala herbal extract suppresses inflammatory responses in LPS-stimulated RAW 264.7 macrophages and adjuvant-induced arthritic rats via inhibition of NF-κB pathway.

    PubMed

    Kalaiselvan, Sowmiya; Rasool, Mahaboob Khan

    2016-07-01

    This study sought to explore the mechanism of anti-inflammatory effect of triphala in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and in adjuvant-induced arthritic rats. In stimulated RAW 264.7 cells, triphala (100-300 μg/ml) significantly suppressed production of inflammatory mediators (e.g. TNFα, IL-1β, IL-6, MCP-1, VEGF, NO, PGE2), intracellular free radicals and release of lysosomal enzymes (e.g. acid phosphatase, β-galactosidase, N-acetyl glucosamindase and cathepsin D) in a dose-related manner. With triphala, mRNA levels of genes for pro-inflammatory TNFα, IL-1β, IL-6 and MCP-1, inflammatory iNOS and COX-2 enzymes and NF-κBp65 were down-regulated in the stimulated cells; in contrast, there was up-regulation of heme oxygenase-1 (HO-1) expression. Western blot analyses revealed that triphala suppressed the protein expression of NF-κB p65 and p-NF-κB p65 in the stimulated cells, which subsequently reduced over-expression of TNFα, IL-17, iNOS and COX-2 in a manner similar to that observed with BAY 11-7082, an IκB kinase inhibitor. Immunofluorescence analysis revealed inhibition of p-NF-κB p65 nuclear translocation and COX-2 protein expression caused by triphala. Consistent with these findings, the animal studies presented confirmed that triphala exhibited anti-inflammatory effects in a rat adjuvant-induced arthritis model by reducing of inflammatory mediator (e.g. IL-17, COX-2 and RANKL) expression via inhibition of NF-κB activation. Taken together, the results here demonstrated that triphala has potential anti-inflammatory applications that could be used for the treatment of inflammatory disorders, including rheumatoid arthritis. PMID:27438966

  8. Alzheimer's disease Advax(CpG)- adjuvanted MultiTEP-based dual and single vaccines induce high-titer antibodies against various forms of tau and Aβ pathological molecules.

    PubMed

    Davtyan, Hayk; Zagorski, Karen; Rajapaksha, Harinda; Hovakimyan, Armine; Davtyan, Arpine; Petrushina, Irina; Kazarian, Konstantin; Cribbs, David H; Petrovsky, Nikolai; Agadjanyan, Michael G; Ghochikyan, Anahit

    2016-01-01

    Although β-amyloid (Aβ) may be the primary driver of Alzheimer's disease (AD) pathology, accumulation of pathological tau correlates with dementia in AD patients. Thus, the prevention/inhibition of AD may require vaccine/s targeting Aβ and tau simultaneously or sequentially. Since high antibody titers are required for AD vaccine efficacy, we have decided to generate vaccines, targeting Aβ (AV-1959R), Tau (AV-1980R) or Aβ/tau (AV-1953R) B cell epitopes, based on immunogenic MultiTEP platform and evaluate the immunogenicity of these vaccines formulated with Advax(CpG), delta inulin, Alhydrogel(®), Montanide-ISA51, Montanide-ISA720, MPLA-SM pharmaceutical grade adjuvants. Formulation of AV-1959R in Advax(CpG) induced the highest cellular and humoral immune responses in mice. The dual-epitope vaccine, AV-1953R, or the combination of AV-1959R and AV-1980R vaccines formulated with Advax(CpG) induced robust antibody responses against various forms of both, Aβ and tau pathological molecules. While anti-Aβ antibody titers after AV-1953R immunization were similar to that in mice vaccinated with AV-1959R or AV-1959R/AV-1980R combination, anti-tau titers were significantly lower after AV-1953R injection when compared to the AV-1980R or AV-1959R/AV-1980R. In silico 3D-modeling provided insight into the differences in immunogenicity of these vaccine constructs. In sum, AV-1959R and AV-1980R formulated with Advax(CpG) adjuvant were identified as promising immunogenic vaccines for ongoing pre-clinical assessment and future human clinical trials. PMID:27363809

  9. Cancer Familial Aggregation (CFA) and G446A polymorphism in ARLTS1 gene.

    PubMed

    Masojć, Bartłomiej; Mierzejewski, Marek; Cybulski, Cezary; van de Wetering, Thierry; Debniak, Tadeusz; Górski, Bohdan; Jaworowska, Ewa; Tarnowska, Czesława; Lenner, Marcin; Scott, Rodney J; Lubiński, Jan

    2006-09-01

    ARLTS1--a member of ADP-ribosylation factor family, is a newly described candidate tumour suppressor gene. Recent studies show that a nonsense polymorphism, G446A (Trp149Stop), in ARLTS1 gene is significantly more frequent in familial cancer cases than in sporadic cancer cases. This study presents analysis of the germ-line G446A polymorphism in the ARLTS1 gene among 1686 consecutively collected patients with breast cancer, prostate cancer, malignant melanoma, thyroid papillary cancer or laryngeal cancer in Poland. The G446A allele was present in 1.81% (9/497) breast cancer patients, 1.46% (5/343) prostate cancer patients, 1.76% (7/397) melanoma patients, 1.65% (3/182) thyroid papillary carcinoma patients and 2.68% (8/299) of laryngeal cancer patients. The frequency of this polymorphism in the control group was 1.45% (8/552). Differences in the frequency of the G446A polymorphism between case and control groups were not statistically significant. In addition, there was no significant difference in the number of Cancer Familial Aggregations (CFA) among breast, prostate, thyroid or laryngeal cancer cases harbouring the G446A polymorphism, when compared to the G446A negative cases. Interestingly out of the CFA melanoma cases, 4/6 (66.6%) were found to harbour the change compared to only 20.2% (69/341) sporadic melanoma cases. This difference was statistically significant (p = 0.02, OR = 7.8). The results of this study suggest that the G446A in ARLTS1 gene is probably not associated with an increased risk of sporadic breast cancer, prostate cancer, melanoma, thyroid papillary cancer or laryngeal cancer. Moreover, the G446A polymorphism is not significantly more frequent in CFA cases except for families in which the proband had melanoma. To confirm this result more cases of melanoma should be analysed. PMID:16570116

  10. Chitosan as an adjuvant for a Helicobacter pylori therapeutic vaccine.

    PubMed

    Gong, Yanfeng; Tao, Liming; Wang, Fucai; Liu, Wei; Jing, Lei; Liu, Dongsheng; Hu, Sijun; Xie, Yong; Zhou, Nanjin

    2015-09-01

    The aim of the present study was to delineate the therapeutic effect of a Helicobacter pylori vaccine with chitosan as an adjuvant, as well as to identify the potential mechanism against H. pylori infection when compared with an H. pylori vaccine, with cholera toxin (CT) as an adjuvant. Mice were first infected with H. pylori and, following the establishment of an effective infection model, were vaccinated using an H. pylori protein vaccine with chitosan as an adjuvant. Levels of H. pylori colonization, H. pylori‑specific antibodies and cytokines were determined by enzyme‑linked immunosorbent assay. The TLR4 and Foxp3 mRNA and protein levels were determined by reverse transcription polymerase chain reaction and immunohistochemistry, respectively. It was identified that the H. pylori elimination rate of the therapeutic vaccine with chitosan as an adjuvant (58.33%) was greater than the therapeutic vaccine with CT as an adjuvant (45.45%). The therapeutic H. pylori vaccine with chitosan as an adjuvant induced significantly greater antibody and cytokine levels when compared with the control groups. Notably, the IL‑10 and IL‑4 levels in the groups with chitosan as an adjuvant to the H. pylori vaccine were significantly greater than those in the groups with CT as an adjuvant. The mRNA expression levels of TLR4 and Foxp3 were significantly elevated in the mice that were vaccinated with chitosan as an adjuvant to the H. pylori vaccine, particularly in mice where the H. pylori infection had been eradicated. The H. pylori vaccine with chitosan as an adjuvant effectively increased the H. pylori elimination rate, the humoral immune response and the Th1/Th2 cell immune reaction; in addition, the therapeutic H. pylori vaccine regulated the Th1 and Th2 response. The significantly increased TLR4 expression and decreased CD4+CD25+Foxp3+Treg cell number contributed to the immune clearance of the H. pylori infection. Thus, the present findings demonstrate that in mice the H

  11. Decontamination and dismantlement of the old hot laundry, CFA-669. Final report

    SciTech Connect

    Smith, D.L.; Perry, E.F.

    1995-01-01

    This final report describes the decontamination and dismantlement (D&D) of the old hot laundry, located at the Idaho National Engineering Laboratory (INEL) Central Facilities Area (CFA). The report describes the site before and after D&D, processes used, cost and duration, and waste volume generated. In addition, lessons learned are presented. Pre-D&D characterization indicated gross alpha concentrations in the building ranged from 6 to 310 pCi/g and gross beta measurements from 6 to 15,000 pCi/g. Gamma spectrum analysis identified cobalt-60, cesium-137, antimony-125, europium-152, europium-154, and niobium-94.

  12. Improved Dark Energy Constraints From ~ 100 New CfA Supernova Type Ia Light Curves

    SciTech Connect

    Hicken, Malcolm; Wood-Vasey, W.Michael; Blondin, Stephane; Challis, Peter; Jha, Saurabh; Kelly, Patrick L.; Rest, Armin; Kirshner, Robert P.; /Harvard-Smithsonian Ctr. Astrophys.

    2012-04-06

    We combine the CfA3 supernovae Type Ia (SN Ia) sample with samples from the literature to calculate improved constraints on the dark energy equation of state parameter, w. The CfA3 sample is added to the Union set of Kowalski et al. to form the Constitution set and, combined with a BAO prior, produces 1 + w = 0.013{sub -0.068}{sup +0.066} (0.11 syst), consistent with the cosmological constant. The CfA3 addition makes the cosmologically useful sample of nearby SN Ia between 2.6 and 2.9 times larger than before, reducing the statistical uncertainty to the point where systematics play the largest role. We use four light-curve fitters to test for systematic differences: SALT, SALT2, MLCS2k2 (R{sub V} = 3.1), and MLCS2k2 (R{sub V} = 1.7). SALT produces high-redshift Hubble residuals with systematic trends versus color and larger scatter than MLCS2k2. MLCS2k2 overestimates the intrinsic luminosity of SN Ia with 0.7 < {Delta} < 1.2. MLCS2k2 with R{sub V} = 3.1 overestimates host-galaxy extinction while R{sub V} {approx} 1.7 does not. Our investigation is consistent with no Hubble bubble. We also find that, after light-curve correction, SN Ia in Scd/Sd/Irr hosts are intrinsically fainter than those in E/S0 hosts by 2{sigma}, suggesting that they may come from different populations. We also find that SN Ia in Scd/Sd/Irr hosts have low scatter (0.1 mag) and reddening. Current systematic errors can be reduced by improving SN Ia photometric accuracy, by including the CfA3 sample to retrain light-curve fitters, by combining optical SN Ia photometry with near-infrared photometry to understand host-galaxy extinction, and by determining if different environments give rise to different intrinsic SN Ia luminosity after correction for light-curve shape and color.

  13. IMPROVED DARK ENERGY CONSTRAINTS FROM {approx}100 NEW CfA SUPERNOVA TYPE Ia LIGHT CURVES

    SciTech Connect

    Hicken, Malcolm; Challis, Peter; Kirshner, Robert P.; Wood-Vasey, W. Michael; Blondin, Stephane; Jha, Saurabh; Kelly, Patrick L.; Rest, Armin E-mail: kirshner@cfa.harvard.edu

    2009-08-01

    We combine the CfA3 supernovae Type Ia (SN Ia) sample with samples from the literature to calculate improved constraints on the dark energy equation of state parameter, w. The CfA3 sample is added to the Union set of Kowalski et al. to form the Constitution set and, combined with a BAO prior, produces 1 + w = 0.013{sup +0.066} {sub -0.068} (0.11 syst), consistent with the cosmological constant. The CfA3 addition makes the cosmologically useful sample of nearby SN Ia between 2.6 and 2.9 times larger than before, reducing the statistical uncertainty to the point where systematics play the largest role. We use four light-curve fitters to test for systematic differences: SALT, SALT2, MLCS2k2 (R{sub V} = 3.1), and MLCS2k2 (R{sub V} = 1.7). SALT produces high-redshift Hubble residuals with systematic trends versus color and larger scatter than MLCS2k2. MLCS2k2 overestimates the intrinsic luminosity of SN Ia with 0.7 < {delta} < 1.2. MLCS2k2 with R{sub V} = 3.1 overestimates host-galaxy extinction while R{sub V} {approx} 1.7 does not. Our investigation is consistent with no Hubble bubble. We also find that, after light-curve correction, SN Ia in Scd/Sd/Irr hosts are intrinsically fainter than those in E/S0 hosts by 2{sigma}, suggesting that they may come from different populations. We also find that SN Ia in Scd/Sd/Irr hosts have low scatter (0.1 mag) and reddening. Current systematic errors can be reduced by improving SN Ia photometric accuracy, by including the CfA3 sample to retrain light-curve fitters, by combining optical SN Ia photometry with near-infrared photometry to understand host-galaxy extinction, and by determining if different environments give rise to different intrinsic SN Ia luminosity after correction for light-curve shape and color.

  14. The luminosity function for the CfA redshift survey slices

    NASA Technical Reports Server (NTRS)

    De Lapparent, Valerie; Geller, Margaret J.; Huchra, John P.

    1989-01-01

    The luminosity function for two complete slices of the extension of the CfA redshift survey is calculated. The nonparametric technique of Lynden-Bell (1971) and Turner (1979) is used to determine the shape for the luminosity function of the 12 deg slice of the redshift survey. The amplitude of the luminosity function is determined, taking large-scale inhomogeneities into account. The effects of the Malmquist bias on a magnitude-limited redshift survey are examined, showing that the random errors in the magnitudes for the 12 deg slice affect both the determination of the luminosity function and the spatial density constrast of large scale structures.

  15. Comparative Model Tests of SDP and CFA Pile Groups in Non-Cohesive Soil

    NASA Astrophysics Data System (ADS)

    Krasiński, Adam; Kusio, Tomasz

    2015-02-01

    The research topic relates to the subject of deep foundations supported on continuous flight auger (CFA) piles and screw displacement piles (SDP). The authors have decided to conduct model tests of foundations supported on the group of piles mentioned above and also the tests of the same piles working as a single. The tests are ongoing in Geotechnical Laboratory of Gdaňsk University of Technology. The description of test procedure, interpretation and analysis of the preliminary testing series results are presented in the paper.

  16. The adjuvanted influenza vaccines with novel adjuvants: experience with the MF59-adjuvanted vaccine.

    PubMed

    Podda, A

    2001-03-21

    Elderly people and subjects with underlying chronic diseases are at increased risk for influenza and related complications. Conventional influenza vaccines provide only limited protection in the elderly population. In order to enhance the immune response to influenza vaccines, several adjuvants have been evaluated. Among these, an oil in water adjuvant emulsion containing squalene, MF59, has been combined with subunit influenza antigens and tested in clinical trials in comparison with non-adjuvanted conventional vaccines. Data from a clinical database of over 10000 elderly subjects immunised with this adjuvanted vaccine (Fluad, Chiron Vaccines, Siena, Italy) demonstrate that, although common postimmunisation reactions are more frequent in recipients of the adjuvanted vaccine, this vaccine is well tolerated, also after re-immunisation in subsequent influenza seasons. Immunogenicity analyses demonstrate a consistently higher immune response with statistically significant increases of postimmunisation geometric mean titres, and of seroconversion and seroprotection rates compared to non-adjuvanted subunit and split influenza vaccines, particularly for the A/H3N2 and the B strains. The higher immunogenicity profile of the MF59-adjuvanted vaccine is maintained also after subsequent immunisations. An even higher adjuvant effect was shown in subjects with low pre-immunisation titre and in those affected by chronic underlying diseases. In conclusion, the addition of MF59 to subunit influenza vaccines enhances significantly the immune response in elderly subjects without causing clinically important changes in the safety profile of the influenza vaccine. PMID:11257408

  17. An innovative approach to induce cross-protective immunity against porcine reproductive and respiratory syndrome virus in the lungs of pigs through adjuvanted nanotechnology-based vaccination

    PubMed Central

    Binjawadagi, Basavaraj; Dwivedi, Varun; Manickam, Cordelia; Ouyang, Kang; Torrelles, Jordi B; Renukaradhya, Gourapura J

    2014-01-01

    Porcine reproductive and respiratory syndrome (PRRS) is an economically devastating respiratory disease of pigs. The disease is caused by the PRRS virus (PRRSV), an Arterivirus which is a highly mutating RNA virus. Widely used modified live PRRSV vaccines have failed to prevent PRRS outbreaks and reinfections; moreover, safety of the live virus vaccines is questionable. Though poorly immunogenic, inactivated PRRSV vaccine is safe. The PRRSV infects primarily the lung macrophages. Therefore, we attempted to strengthen the immunogenicity of inactivated/killed PRRSV vaccine antigens (KAg), especially in the pig respiratory system, through: 1) entrapping the KAg in biodegradable poly(lactic-co-glycolic acid) nanoparticles (NP-KAg); 2) coupling the NP-KAg with a potent mucosal adjuvant, whole cell lysate of Mycobacterium tuberculosis (M. tb WCL); and 3) delivering the vaccine formulation twice intranasally to growing pigs. We have previously shown that a single dose of NP-KAg partially cleared the challenged heterologous PRRSV. Recently, we reported that NP-KAg coupled with unentrapped M. tb WCL significantly cleared the viremia of challenged heterologous PRRSV. Since PRRSV is primarily a lung disease, our goal in this study was to investigate lung viral load and various immune correlates of protection at the lung mucosal surfaces and its parenchyma in vaccinated heterologous PRRSV-challenged pigs. Our results indicated that out of five different vaccine-adjuvant formulations, the combination of NP-KAg and unentrapped M. tb WCL significantly cleared detectable replicating infective PRRSV with a tenfold reduction in viral RNA load in the lungs, associated with substantially reduced gross and microscopic lung pathology. Immunologically, strong humoral (enhanced virus neutralization titers by high avidity antibodies) and cell-mediated immune responses (augmented population of interferon-γ secreting CD4+ and CD8+ lymphocytes and reduced secretion of immunosuppressive

  18. Choice and Design of Adjuvants for Parenteral and Mucosal Vaccines

    PubMed Central

    Savelkoul, Huub F. J.; Ferro, Valerie A.; Strioga, Marius M.; Schijns, Virgil E. J. C.

    2015-01-01

    The existence of pathogens that escape recognition by specific vaccines, the need to improve existing vaccines and the increased availability of therapeutic (non-infectious disease) vaccines necessitate the rational development of novel vaccine concepts based on the induction of protective cell-mediated immune responses. For naive T-cell activation, several signals resulting from innate and adaptive interactions need to be integrated, and adjuvants may interfere with some or all of these signals. Adjuvants, for example, are used to promote the immunogenicity of antigens in vaccines, by inducing a pro-inflammatory environment that enables the recruitment and promotion of the infiltration of phagocytic cells, particularly antigen-presenting cells (APC), to the injection site. Adjuvants can enhance antigen presentation, induce cytokine expression, activate APC and modulate more downstream adaptive immune reactions (vaccine delivery systems, facilitating immune Signal 1). In addition, adjuvants can act as immunopotentiators (facilitating Signals 2 and 3) exhibiting immune stimulatory effects during antigen presentation by inducing the expression of co-stimulatory molecules on APC. Together, these signals determine the strength of activation of specific T-cells, thereby also influencing the quality of the downstream T helper cytokine profiles and the differentiation of antigen-specific T helper populations (Signal 3). New adjuvants should also target specific (innate) immune cells in order to facilitate proper activation of downstream adaptive immune responses and homing (Signal 4). It is desirable that these adjuvants should be able to exert such responses in the context of mucosal administered vaccines. This review focuses on the understanding of the potential working mechanisms of the most well-known classes of adjuvants to be used effectively in vaccines. PMID:26344951

  19. Choice and Design of Adjuvants for Parenteral and Mucosal Vaccines.

    PubMed

    Savelkoul, Huub F J; Ferro, Valerie A; Strioga, Marius M; Schijns, Virgil E J C

    2015-01-01

    The existence of pathogens that escape recognition by specific vaccines, the need to improve existing vaccines and the increased availability of therapeutic (non-infectious disease) vaccines necessitate the rational development of novel vaccine concepts based on the induction of protective cell-mediated immune responses. For naive T-cell activation, several signals resulting from innate and adaptive interactions need to be integrated, and adjuvants may interfere with some or all of these signals. Adjuvants, for example, are used to promote the immunogenicity of antigens in vaccines, by inducing a pro-inflammatory environment that enables the recruitment and promotion of the infiltration of phagocytic cells, particularly antigen-presenting cells (APC), to the injection site. Adjuvants can enhance antigen presentation, induce cytokine expression, activate APC and modulate more downstream adaptive immune reactions (vaccine delivery systems, facilitating immune Signal 1). In addition, adjuvants can act as immunopotentiators (facilitating Signals 2 and 3) exhibiting immune stimulatory effects during antigen presentation by inducing the expression of co-stimulatory molecules on APC. Together, these signals determine the strength of activation of specific T-cells, thereby also influencing the quality of the downstream T helper cytokine profiles and the differentiation of antigen-specific T helper populations (Signal 3). New adjuvants should also target specific (innate) immune cells in order to facilitate proper activation of downstream adaptive immune responses and homing (Signal 4). It is desirable that these adjuvants should be able to exert such responses in the context of mucosal administered vaccines. This review focuses on the understanding of the potential working mechanisms of the most well-known classes of adjuvants to be used effectively in vaccines. PMID:26344951

  20. Safety and persistence of the humoral and cellular immune responses induced by 2 doses of an AS03-adjuvanted A(H1N1)pdm09 pandemic influenza vaccine administered to infants, children and adolescents: Two open, uncontrolled studies

    PubMed Central

    Garcia-Sicilia, José; Arístegui, Javier; Omeñaca, Félix; Carmona, Alfonso; Tejedor, Juan C; Merino, José M; García-Corbeira, Pilar; Walravens, Karl; Bambure, Vinod; Moris, Philippe; Caplanusi, Adrian; Gillard, Paul; Dieussaert, Ilse

    2015-01-01

    In children, 2 AS03-adjuvanted A(H1N1)pdm09 vaccine doses given 21 days apart were previously shown to induce a high humoral immune response and to have an acceptable safety profile up to 42 days following the first vaccination. Here, we analyzed the persistence data from 2 open-label studies, which assessed the safety, and humoral and cell-mediated immune responses induced by 2 doses of this vaccine. The first study was a phase II, randomized trial conducted in 104 children aged 6–35 months vaccinated with the A(H1N1)pdm09 vaccine containing 1.9 µg haemagglutinin antigen (HA) and AS03B (5.93 mg tocopherol) and the second study, a phase III, non-randomized trial conducted in 210 children and adolescents aged 3–17 years vaccinated with the A(H1N1)pdm09 vaccine containing 3.75 µg HA and AS03A (11.86 mg tocopherol). Approximately one year after the first dose, all children with available data were seropositive for haemagglutinin inhibition and neutralising antibody titres, but a decline in geometric mean antibody titres was noted. The vaccine induced a cell-mediated immune response in terms of antigen-specific CD4+ T-cells, which persisted up to one year post-vaccination. The vaccine did not raise any safety concern, though these trials were not designed to detect rare events. In conclusion, 2 doses of the AS03-adjuvanted A(H1N1)pdm09 vaccine at 2 different dosages had a clinically acceptable safety profile, and induced high and persistent humoral and cell-mediated immune responses in children aged 6–35 months and 3–17 years. These studies have been registered at www.clinicaltrials.gov NCT00971321 and NCT00964158. PMID:26176592

  1. Report on the Best Available Technology (BAT) for the treatment of the INEL Central Laundry and Respirator Facility (CFA-617)

    SciTech Connect

    Miyasaki, D.H.; Heiser, D.L.

    1991-01-01

    The Central Laundry and Respirator Facility (CLRF) designated by the building number of CFA-617 has been addressed as a potential source of contamination to the Central Facilities Area (CFA) subsurface drainage field which also receives waste water from the current CFA Sewage Treatment Plant (STP). Currently, discharges from the CLRF have been below set guidelines, DCG. A new STP has been proposed for the CFA. Since the CLRF has been designated as a potential source of contamination, a Best Available Technology (BAT) assessment was requested to determine what action should be taken in respect to the aqueous discharges from the CLRF. The BAT assessment involved source definition, technology evaluation, BAT matrix development, BAT selection, and BAT documentation. The BAT for the Central laundry and Respirator Facility selected the treatment which would impact the CLRF and the new STP the least in all aspects considered and was the system of filtration and a lined pond for natural evaporation of the water. The system will provide an isolation of this waste stream from all other CFA waste water which will be treated at the new STP. Waste minimization possibilities exist within the laundry process and are considered. These minimization actions will reduce the amount of waste water being released, but will result in raising the contaminate's concentrations (the total mass will remain the same). The second option was the use of ion exchange to remove the contaminates and recycle the water back to the wash and rinse cycles in the laundry. 3 refs., 9 figs., 11 tabs.

  2. On the generation of a bubbly universe - A quantitative assessment of the CfA slice

    NASA Technical Reports Server (NTRS)

    Ostriker, J. P.; Strassler, M. J.

    1989-01-01

    A first attempt is made to calculate the properties of the matter distribution in a universe filled with overlapping bubbles produced by multiple explosions. Each spherical shell follows the cosmological Sedov-Taylor solution until it encounters another shell. Thereafter, mergers are allowed to occur in pairs on the basis of N-body results. At the final epoch, the matrix of overlapping shells is populated with 'galaxies' and the properties of slices through the numerically constructed cube compare well with CfA survey results for specified initial conditions. A statistic is found which measures the distance distribution from uniformly distributed points to the nearest galaxies on the projected plane which appears to provide a good measure of the bubbly character of the galaxy distribution. In a quantitative analysis of the CfA 'slice of the universe', a very good match is found between simulation and the real data for final average bubble radii of (13.5 + or - 1.5)/h Mpc with formal filling factor 1.0-1.5 or actual filling factor of 65-80 percent.

  3. N-point correlation functions in the CfA and SSRS redshift distribution of galaxies

    NASA Technical Reports Server (NTRS)

    Gaztanaga, Enrique

    1992-01-01

    Using counts in cells, we estimate the volume-average N-point galaxy correlation functions for N = 2, 3, and 4, in redshift samples of the CfA and SSRS catalogs. Volume-limited samples of different sizes are used to study the uncertainties at different scales, the shot noise, and the problem with the boundaries. The hierarchical constants S3 and S4 agree well in all samples in CfA and SSRS, with average S3 = 194 +/- 0.07 and S4 = 4.56 +/- 0.53. We compare these results with estimates obtained from angular catalogs and recent analysis over IRAS samples. The amplitudes SJ seem larger in real space than in redshift space, although the values from the angular analysis correspond to smaller scales, where we might expect larger nonperturbative effects. It is also found that S3 and S4 are smaller for IRAS than for optical galaxies. This, together with the fact that IRAS galaxies have smaller amplitude for the above correlation functions, indicates that the density fluctuations of IRAS galaxies cannot be simply proportional to the density fluctuations of optical galaxies, i.e., biasing has to be nonlinear between them.

  4. Post-decontamination and dismantlement (D&D) characterization report for CFA-669 site

    SciTech Connect

    Smith, D.L.

    1995-01-01

    This report presents results of post-decontamination and dismantling (D&D) characterization surveys performed by EG&G Idaho, Inc. (EG&G Idaho), at Central Facilities Area (CFA)-669, which was the Hot Laundry Facility. The site was characterized to determine and document the radiological and chemical conditions of the site following D&D and to determine if the site satisfies the release criteria. Constructed in 1950, CFA-669 served as the ``hot`` and ``cold`` laundry for Idaho National Engineering Laboratory site contractors until the boiler exploded in 1981. The building was shut down at that time. Before D&D activities began in 1992, the facility was characterized and the results documented. D&D activities were completed in July 1994. The post-D&D radiological characterization consisted of radiation measurements and analyses of soil samples to identify man-made radionuclides and determine the specific activity of each sample. The chemical characterization consisted of toxicity characterization leaching procedure (TCLP) analysis for metals and for volatile and semivolatile organic contamination.

  5. Learning Impairment in Honey Bees Caused by Agricultural Spray Adjuvants

    PubMed Central

    Ciarlo, Timothy J.; Mullin, Christopher A.; Frazier, James L.; Schmehl, Daniel R.

    2012-01-01

    Background Spray adjuvants are often applied to crops in conjunction with agricultural pesticides in order to boost the efficacy of the active ingredient(s). The adjuvants themselves are largely assumed to be biologically inert and are therefore subject to minimal scrutiny and toxicological testing by regulatory agencies. Honey bees are exposed to a wide array of pesticides as they conduct normal foraging operations, meaning that they are likely exposed to spray adjuvants as well. It was previously unknown whether these agrochemicals have any deleterious effects on honey bee behavior. Methodology/Principal Findings An improved, automated version of the proboscis extension reflex (PER) assay with a high degree of trial-to-trial reproducibility was used to measure the olfactory learning ability of honey bees treated orally with sublethal doses of the most widely used spray adjuvants on almonds in the Central Valley of California. Three different adjuvant classes (nonionic surfactants, crop oil concentrates, and organosilicone surfactants) were investigated in this study. Learning was impaired after ingestion of 20 µg organosilicone surfactant, indicating harmful effects on honey bees caused by agrochemicals previously believed to be innocuous. Organosilicones were more active than the nonionic adjuvants, while the crop oil concentrates were inactive. Ingestion was required for the tested adjuvant to have an effect on learning, as exposure via antennal contact only induced no level of impairment. Conclusions/Significance A decrease in percent conditioned response after ingestion of organosilicone surfactants has been demonstrated here for the first time. Olfactory learning is important for foraging honey bees because it allows them to exploit the most productive floral resources in an area at any given time. Impairment of this learning ability may have serious implications for foraging efficiency at the colony level, as well as potentially many social interactions

  6. The adjuvancy of silicones: dependency on compartmentalization.

    PubMed

    Klykken, P C; White, K L

    1996-01-01

    Studies have been conducted in mice (B6C3F1) and rats (Sprague Dawley, Fischer 344) to investigate the adjuvancy potential of silicone mammary gel and the low molecular weight silicone fluid, octamethylcyclotetrasiloxane (D4). Dependent on the experimental conditions employed, a divergent data profile emerges. If the antigen (bovine serum albumin, BSA) is emulsified with either the gel or the D4 prior to intramuscular immunization, an amplified anti-BSA IgG antibody response, as measured by multipoint ELISA methodology, is noted over the 8 week measurement period. In parallel studies, a variety of non-silicone personal care ingredients (lanolin, white mineral oil, isopropyl palmitate) were also capable of amplifying this humoral response relative to the non-adjuvant phosphate buffered saline control. These observations are consistent with the empirical knowledge that hydrophobic substances tend to augment immune responses. However, under conditions in which the antigen is not blended with the silicone prior to immunization, normal immune responses are noted. In short (10 day) and long (180 day) term gel implant studies, the optimal IgM and IgG antibody responses, as determined in the antibody forming cell assay, were equivalent between the gel implanted and control animals. Moreover, under similar exposure conditions, no adjuvancy was noted in the three Host Resistance models (B16F10 Melanoma, Listeria monocytogenes, and Streptococcus pneumoniae) tested. Antibody forming cell studies conducted after 28 days of oral or inhalation exposure to D4 have also yielded responses similar to the non-silicone exposed vehicle controls. Collectively, these data suggest that in the absence of premixing the antigen with the silicone test material, there does not appear to be any silicone induced adjuvant response. PMID:8565549

  7. A new modified animal model of myosin-induced experimental autoimmune myositis enhanced by defibrase

    PubMed Central

    Wen-Jing, Luo; Hong-Hua, Li; Xiang-Hui, Lu; Jie-Xiao, Liu

    2015-01-01

    Introduction We investigated the effect of defibrase (a proteolytic enzyme extraction of Agkistrodon halys venom) on experimental autoimmune myositis (EAM) in guinea pigs and explored the option of using a modified pig model of EAM to enhance the study of this disease. Material and methods Guinea pigs were divided into 3 groups: group A (control group) was immunized with complete Freund adjuvant (CFA), then received 6 injections of saline weekly; group B (EAM group) was immunized with partially purified rabbit myosin emulsified with CFA, then received an injection of saline; group C (EAM + defibrase group) was immunized with purified rabbit myosin emulsified with CFA, then received an injection of defibrase. The animals were observed for their general health condition and the body weight was measured daily. Plasma levels of fibrinogen and creatine kinase (CK) were determined. Muscle tissues were examined histologically. Results After immunizations for 6 weeks, incidence of EAM in groups A, B and C was 0 (0/7), 83.3% (10/12) and 100% (15/15), respectively. Guinea pigs with EAM presented angeitis symptoms of muscle weakness. Histological analysis revealed a significant difference. Muscles with EAM had scattered or diffuse inflammatory manifestations, which are also common pathological features of human idiopathic polymyositis (IPM). Defibrase-treated animals displayed extensive inflammation and fiber necrosis compared with the EAM group (histological score: 2.80 ±1.15 vs. 1.88 ±1.32, p < 0.05). Severity of inflammation of group B was mainly mild to moderate; 16.7% (2/12) of animals developed severe inflammation. Incidence of severe inflammation with a score up to 4 in group C was 40% (6/15). Conclusions Defibrase can exacerbate myosin-induced EAM; thus a new modified model was generated. PMID:26788090

  8. Different human vaccine adjuvants promote distinct antigen-independent immunological signatures tailored to different pathogens.

    PubMed

    Knudsen, Niels Peter H; Olsen, Anja; Buonsanti, Cecilia; Follmann, Frank; Zhang, Yuan; Coler, Rhea N; Fox, Christopher B; Meinke, Andreas; D'Oro, Ugo; Casini, Daniele; Bonci, Alessandra; Billeskov, Rolf; De Gregorio, Ennio; Rappuoli, Rino; Harandi, Ali M; Andersen, Peter; Agger, Else Marie

    2016-01-01

    The majority of vaccine candidates in clinical development are highly purified proteins and peptides relying on adjuvants to enhance and/or direct immune responses. Despite the acknowledged need for novel adjuvants, there are still very few adjuvants in licensed human vaccines. A vast number of adjuvants have been tested pre-clinically using different experimental conditions, rendering it impossible to directly compare their activity. We performed a head-to-head comparison of five different adjuvants Alum, MF59®, GLA-SE, IC31® and CAF01 in mice and combined these with antigens from M. tuberculosis, influenza, and chlamydia to test immune-profiles and efficacy in infection models using standardized protocols. Regardless of antigen, each adjuvant had a unique immunological signature suggesting that the adjuvants have potential for different disease targets. Alum increased antibody titers; MF59® induced strong antibody and IL-5 responses; GLA-SE induced antibodies and Th1; CAF01 showed a mixed Th1/Th17 profile and IC31® induced strong Th1 responses. MF59® and GLA-SE were strong inducers of influenza HI titers while CAF01, GLA-SE and IC31® enhanced protection to TB and chlamydia. Importantly, this is the first extensive attempt to categorize clinical-grade adjuvants based on their immune profiles and protective efficacy to inform a rational development of next generation vaccines for human use. PMID:26791076

  9. Different human vaccine adjuvants promote distinct antigen-independent immunological signatures tailored to different pathogens

    PubMed Central

    Knudsen, Niels Peter H.; Olsen, Anja; Buonsanti, Cecilia; Follmann, Frank; Zhang, Yuan; Coler, Rhea N.; Fox, Christopher B.; Meinke, Andreas; D´Oro, Ugo; Casini, Daniele; Bonci, Alessandra; Billeskov, Rolf; De Gregorio, Ennio; Rappuoli, Rino; Harandi, Ali M.; Andersen, Peter; Agger, Else Marie

    2016-01-01

    The majority of vaccine candidates in clinical development are highly purified proteins and peptides relying on adjuvants to enhance and/or direct immune responses. Despite the acknowledged need for novel adjuvants, there are still very few adjuvants in licensed human vaccines. A vast number of adjuvants have been tested pre-clinically using different experimental conditions, rendering it impossible to directly compare their activity. We performed a head-to-head comparison of five different adjuvants Alum, MF59®, GLA-SE, IC31® and CAF01 in mice and combined these with antigens from M. tuberculosis, influenza, and chlamydia to test immune-profiles and efficacy in infection models using standardized protocols. Regardless of antigen, each adjuvant had a unique immunological signature suggesting that the adjuvants have potential for different disease targets. Alum increased antibody titers; MF59® induced strong antibody and IL-5 responses; GLA-SE induced antibodies and Th1; CAF01 showed a mixed Th1/Th17 profile and IC31® induced strong Th1 responses. MF59® and GLA-SE were strong inducers of influenza HI titers while CAF01, GLA-SE and IC31® enhanced protection to TB and chlamydia. Importantly, this is the first extensive attempt to categorize clinical-grade adjuvants based on their immune profiles and protective efficacy to inform a rational development of next generation vaccines for human use. PMID:26791076

  10. Physiochemical Properties of Aluminum Adjuvants Elicit Differing Reorganization of Phospholipid Domains in Model Membranes.

    PubMed

    Antúnez, Lorena R; Livingston, Andrea; Berkland, Cory; Dhar, Prajnaparamita

    2016-05-01

    Most vaccines contain aluminum adjuvants; however, their exact mechanism of action remains unclear. A novel mechanism by Shi and colleagues proposes aluminum adjuvants may enhance immune activation by binding and reorganizing lipids that are key components of lipid rafts. To better understand the specificity of interaction between aluminum adjuvants and the cell membrane lipids, we present a biophysical study of lipid domain clustering in simple model phospholipid monolayers containing dipalmitoyl-phosphatidylcholine (DPPC) and dioleoyl-phosphatidylcholine (DOPC) exposed to two aluminum adjuvants, Alhydrogel and Adju-Phos. Surface pressure measurements and fluorescence microscopy images verified aluminum adjuvant-induced increase in lipid domain size, even in the key lipid raft components. Additionally, adjuvant induced lipid clustering differed based on the physicochemical properties of the adjuvants. Alhydrogel appeared to reduce monolayer compressibility and insert into the monolayer, while Adju-Phos induced more significant changes in domain size, without compromising the integrity of the monolayer. The Alhydrogel and Adju-Phos-mediated reorganization of phospholipid domains reported here supports the new mechanistic paradigm proposed by Shi and co-workers, and further suggests that lipid clustering is induced even in simple phospholipid membranes. The results present the basis for future exploration into lipid-mediated mechanisms of action for adjuvants. PMID:26998680

  11. Development of CpG ODN Based Vaccine Adjuvant Formulations.

    PubMed

    Gursel, Mayda; Gursel, Ihsan

    2016-01-01

    Development of effective vaccine mediated immune responses relies on the use of vaccine adjuvants capable of enhancing and directing the adaptive immune response to the antigen. When used as vaccine adjuvants, type I interferon inducing agents can elicit potent effector/memory T cell responses and humoral immunity. Distinct sequences of single stranded synthetic oligodeoxynucleotides containing unmethylated cytosine-phosphate-guanine oligodeoxynucleotide motifs (CpG ODN) can generate type I interferon production via a TLR9-MyD88-IRF7-mediated signaling pathway. Here, we describe two different methods of preparing CpG ODN-based vaccine adjuvant formulations that can induce a robust IFNα response from human peripheral blood mononuclear cells. PMID:27076306

  12. Anti-inflammation effect of methyl salicylate 2-O-β-D-lactoside on adjuvant induced-arthritis rats and lipopolysaccharide (LPS)-treated murine macrophages RAW264.7 cells.

    PubMed

    Zhang, Xue; Sun, Jialin; Xin, Wenyu; Li, Yongjie; Ni, Lin; Ma, Xiaowei; Zhang, Dan; Zhang, Dongming; Zhang, Tiantai; Du, Guanhua

    2015-03-01

    Methyl salicylate 2-O-β-D-lactoside (MSL) is a derivative of natural salicylate isolated from Gaultheria yunnanensis (Franch.) Rehder, which is widely used for treating rheumatoid arthritis (RA), swelling and pain. The aim of the present study was to investigate the effect of MSL on the progression of adjuvant-induced arthritis (AIA) in rat in vivo and explore the anti-inflammatory effects and mechanism of MSL in lipopolysaccharide (LPS)-treated murine macrophages RAW264.7 cells in vitro. Our results showed that MSL significantly inhibited the arthritis progression in AIA rats, decreasing the right hind paw swelling and ankle diameter, attenuating histopathological changes and suppressing the plasma levels of TNF-α and IL-1β in AIA rats. Besides, MSL had potent anti-inflammatory effects on the LPS-activated RAW264.7. MSL dose-dependently inhibited the activity of COX-1, and COX-2. Moreover, MSL prominently inhibited LPS-induced activation of MAPK in RAW264.7 cells by blocking phosphorylation of p38 and ERK. Our study suggests that MSL may be effective in the treatment of inflammatory diseases by inhibiting the pro-inflammatory cytokine production and regulating the MAPK signal pathway. PMID:25637446

  13. Innate immunity and adjuvants.

    PubMed

    Akira, Shizuo

    2011-10-12

    Innate immunity was for a long time considered to be non-specific because the major function of this system is to digest pathogens and present antigens to the cells involved in acquired immunity. However, recent studies have shown that innate immunity is not non-specific, but is instead sufficiently specific to discriminate self from pathogens through evolutionarily conserved receptors, designated Toll-like receptors (TLRs). Indeed, innate immunity has a crucial role in early host defence against invading pathogens. Furthermore, TLRs were found to act as adjuvant receptors that create a bridge between innate and adaptive immunity, and to have important roles in the induction of adaptive immunity. This paradigm shift is now changing our thinking on the pathogenesis and treatment of infectious, immune and allergic diseases, as well as cancers. Besides TLRs, recent findings have revealed the presence of a cytosolic detector system for invading pathogens. I will review the mechanisms of pathogen recognition by TLRs and cytoplasmic receptors, and then discuss the roles of these receptors in the development of adaptive immunity in response to viral infection. PMID:21893536

  14. Innate immunity and adjuvants

    PubMed Central

    Akira, Shizuo

    2011-01-01

    Innate immunity was for a long time considered to be non-specific because the major function of this system is to digest pathogens and present antigens to the cells involved in acquired immunity. However, recent studies have shown that innate immunity is not non-specific, but is instead sufficiently specific to discriminate self from pathogens through evolutionarily conserved receptors, designated Toll-like receptors (TLRs). Indeed, innate immunity has a crucial role in early host defence against invading pathogens. Furthermore, TLRs were found to act as adjuvant receptors that create a bridge between innate and adaptive immunity, and to have important roles in the induction of adaptive immunity. This paradigm shift is now changing our thinking on the pathogenesis and treatment of infectious, immune and allergic diseases, as well as cancers. Besides TLRs, recent findings have revealed the presence of a cytosolic detector system for invading pathogens. I will review the mechanisms of pathogen recognition by TLRs and cytoplasmic receptors, and then discuss the roles of these receptors in the development of adaptive immunity in response to viral infection. PMID:21893536

  15. Persistent Suppression of Type 1 Diabetes by a Multicomponent Vaccine Containing a Cholera Toxin B Subunit-Autoantigen Fusion Protein and Complete Freund's Adjuvant

    PubMed Central

    Dénes, Béla; Fodor, István; Langridge, William H. R.

    2013-01-01

    Data presented here demonstrate multifunctional vaccination strategies that harness vaccinia virus mediated delivery of a gene encoding an immunoenhanced diabetes autoantigen in combination with complete Freund's adjuvant (CFA) that can maintain safe and durable immunologic homeostasis in NOD mice. Systemic coinoculation of prediabetic mice with recombinant vaccinia virus rVV-CTB::GAD and undiluted or 10-fold diluted CFA demonstrated a significant decrease in hyperglycemia and pancreatic islet inflammation in comparison with control animals during 17–61 and 17–105 weeks of age, respectively. Synergy in these beneficial effects was observed during 43–61 and 61–105 wks of age, respectively. Inflammatory cytokine and chemokine levels in GAD-stimulated splenocytes isolated from vaccinated mice were generally lower than those detected in unvaccinated mice. The overall health and humoral immune responses of the vaccinated animals remained normal throughout the duration of the experiments. PMID:24319466

  16. The spatial distribution of dwarf galaxies in the CfA slice of the universe

    NASA Technical Reports Server (NTRS)

    Thuan, Trinh X.; Gott, J. Richard, III; Schneider, Stephen E.

    1987-01-01

    A complete (with the the exception of one) redshift sample of 58 galaxies in the Nilson catalog classified as dwarf, irregular, or Magellanic irregular is used to investigate the large-scale clustering properties of these low-surface brightness galaxies in the CfA slice of the universe (alpha in the range of 8-17 h, delta in the range of 26.5-32.5 deg). It is found that the low-surface brightness dwarf galaxies also lie on the structures delineated by the high-surface brightness normal galaxies and that they do not fill in the voids. This is inconsistent with a class of biased galaxy formation theories which predict that dwarf galaxies should be present everywhere, including the voids.

  17. The CFA BATSE IMAGE SEARCH (CBIS) as used for a Galactic plane survey

    SciTech Connect

    Barret, D.; Grindlay, J. E.; Bloser, P. F.; Monnelly, G. P.; Harmon, B. A.; Robinson, C. R.; Zhang, S. N.

    1997-05-10

    The CFA BATSE IMAGE SEARCH (CBIS) system allows automated analysis of large sets of BATSE images. CBIS is being used to conduct a deep survey of the Galactic plane to search for faint transients ({approx}100 mCrab) in the archival data [2]. Furthermore, together with the earth occultation technique [3], CBIS is now applied to a real time imaging survey of the plane to discover new transients and monitor known sources. The CBIS processing is made of two sequential steps: First, the images are scanned to search for excesses. Second, the positions of all these excesses are cross-correlated to produce a list of candidate sources. In this paper, we will detail the algorithms of the scanner and the cross-correlator.

  18. Broad-band properties of the CfA Seyfert galaxies. III - Ultraviolet variability

    NASA Technical Reports Server (NTRS)

    Edelson, R. A.; Pike, G. F.; Krolik, J. H.

    1990-01-01

    A total of 657 archived IUE spectra are used to study the UV variability properties of six members of the CfA Seyfert I galaxy sample. All show strong evidence for continuum and line variations and a tendency for less luminous objects to be more strongly variable. Most objects show a clear correlation at zero lag between UV spectral index and luminosity, evidence that the variable component is an accretion disk around a black hole which is systematically smaller in less luminous sources. No correlation is seen between the continuum luminosity and equivalent width of the C IV, Mg II, and semiforbidden C III emission lines when the entire sample is examined, but a clear anticorrelation is present when only repeated observations of individual objects are considered. This is due to a combination of light-travel time effects in the broad-line region and the nonlinear responses of lines to continuum fluctuations.

  19. Evaluation of adjuvants for a candidate conjugate vaccine against benzo[a]pyrene.

    PubMed

    Schellenberger, Mario T; Farinelle, Sophie; Willième, Stéphanie; Muller, Claude P

    2011-01-01

    We have recently developed an experimental vaccine based on benzo[a]pyrene (B[a]P) conjugated to tetanus toxoid as a carrier protein. In combination with Freund adjuvant, this vaccine induces high levels of B[a]P-specific antibodies to protect against detrimental effects of this carcinogen. Here we evaluate this conjugate vaccine by replacing Freund adjuvant by adjuvants that are potentially compatible with their use in humans. We showed that all adjuvants tested induced specific antibodies against B[a]P and 7,8-diol-B[a]P, its carcinogenic metabolite. The best antibody levels were obtained with Quil A, MF-59 and Alum. Biological activity in terms of enhanced retention of B[a]P was confirmed in mice immunised with Quil A, Montanide, Alum and MF-59. Our findings demonstrate that a vaccination against B[a]P is feasible in combination with adjuvants licensed in humans. PMID:21245662

  20. Classification of Laser Vaccine Adjuvants

    PubMed Central

    Kashiwagi, Satoshi; Brauns, Timothy; Poznansky, Mark C

    2016-01-01

    An immunologic adjuvant, which enhances the magnitude and quality of immune responses to vaccine antigens, has become an essential part of modern vaccine practice. Chemicals and biologicals have been typically used for this purpose, but there are an increasing number of studies that are being conducted on the vaccine adjuvant effect of laser light on the skin. Currently, four different types or classes of laser devices have been shown to systemically enhance immune responses to intradermal vaccination: ultra-short pulsed lasers, non-pulsed lasers, non-ablative fractional lasers and ablative fractional lasers. Aside from involving the application of laser light to the skin in a manner that minimizes discomfort and damage, each type of laser vaccine adjuvant involves emission parameters, modes of action and immunologic adjuvant effects that are quite distinct from each other. This review provides a summary of the four major classes of “laser vaccine adjuvant” and clarifies and resolves their characteristics as immunologic adjuvants. These aspects of each adjuvant’s properties will ultimately help define which laser would be most efficacious in delivering a specific clinical benefit with a specific vaccine. PMID:27104047

  1. Structure of CfaA Suggests a New Family of Chaperones Essential for Assembly of Class 5 Fimbriae

    PubMed Central

    Bao, Rui; Fordyce, April; Chen, Yu-Xing; McVeigh, Annette; Savarino, Stephen J.; Xia, Di

    2014-01-01

    Adhesive pili on the surface of pathogenic bacteria comprise polymerized pilin subunits and are essential for initiation of infections. Pili assembled by the chaperone-usher pathway (CUP) require periplasmic chaperones that assist subunit folding, maintain their stability, and escort them to the site of bioassembly. Until now, CUP chaperones have been classified into two families, FGS and FGL, based on the short and long length of the subunit-interacting loops between its F1 and G1 β-strands, respectively. CfaA is the chaperone for assembly of colonization factor antigen I (CFA/I) pili of enterotoxigenic E. coli (ETEC), a cause of diarrhea in travelers and young children. Here, the crystal structure of CfaA along with sequence analyses reveals some unique structural and functional features, leading us to propose a separate family for CfaA and closely related chaperones. Phenotypic changes resulting from mutations in regions unique to this chaperone family provide insight into their function, consistent with involvement of these regions in interactions with cognate subunits and usher proteins during pilus assembly. PMID:25122114

  2. Structure of CfaA suggests a new family of chaperones essential for assembly of class 5 fimbriae.

    PubMed

    Bao, Rui; Fordyce, April; Chen, Yu-Xing; McVeigh, Annette; Savarino, Stephen J; Xia, Di

    2014-08-01

    Adhesive pili on the surface of pathogenic bacteria comprise polymerized pilin subunits and are essential for initiation of infections. Pili assembled by the chaperone-usher pathway (CUP) require periplasmic chaperones that assist subunit folding, maintain their stability, and escort them to the site of bioassembly. Until now, CUP chaperones have been classified into two families, FGS and FGL, based on the short and long length of the subunit-interacting loops between its F1 and G1 β-strands, respectively. CfaA is the chaperone for assembly of colonization factor antigen I (CFA/I) pili of enterotoxigenic E. coli (ETEC), a cause of diarrhea in travelers and young children. Here, the crystal structure of CfaA along with sequence analyses reveals some unique structural and functional features, leading us to propose a separate family for CfaA and closely related chaperones. Phenotypic changes resulting from mutations in regions unique to this chaperone family provide insight into their function, consistent with involvement of these regions in interactions with cognate subunits and usher proteins during pilus assembly. PMID:25122114

  3. Understanding the Depth and Richness of the Cultural Context in Career Counseling through the Cultural Formulation Approach (CFA)

    ERIC Educational Resources Information Center

    Heppner, Mary J.; Fu, Chu-Chun

    2010-01-01

    In this article, the authors discuss the Cultural Formulation Approach (CFA) proposed by Leong and his colleagues, and the strong and insightful applications of the approach offered by Leong, Arthur, Juntunen, Byars-Winston, and Flores. They think this model has phenomenal possibilities in providing a methodology for counselors to be able to…

  4. Immunization with the Chlamydia trachomatis mouse pneumonitis major outer membrane protein by use of CpG oligodeoxynucleotides as an adjuvant induces a protective immune response against an intranasal chlamydial challenge.

    PubMed

    Pal, Sukumar; Davis, Heather L; Peterson, Ellena M; de la Maza, Luis M

    2002-09-01

    Recently, we have shown that a vaccine consisting of a purified preparation of the Chlamydia trachomatis mouse pneumonitis (MoPn) major outer membrane protein (MOMP) and Freund's adjuvant can protect mice against a genital challenge. Here, we wanted to determine if CpG motifs could be used as an immune modulator to the MOMP to induce protection in mice against an intranasal (i.n.) challenge. One-week-old BALB/c mice were immunized intramuscularly and subcutaneously either once or three times at 2-week intervals with MOMP and CpG suspended in aluminum hydroxide (alum). Negative controls received ovalbumin, CpG, and alum. Positive controls were immunized i.n. with C. trachomatis MoPn elementary bodies (EB). Six weeks after the last immunization, mice were challenged i.n. with 10(4) inclusion-forming units (IFU) of the C. trachomatis MoPn serovar. Mice that received MOMP, CpG, and alum had a strong immune response, as shown by a high titer of serum antibodies to Chlamydia and significant lymphoproliferation of T-cells following stimulation with C. trachomatis EB. After the i.n. challenge mice immunized with MOMP, CpG, and alum showed significantly less body weight loss than the corresponding control mice immunized with ovalbumin, CpG, and alum. Ten days after the challenge the animals were euthanized, their lungs were weighed, and the numbers of IFU in the lungs were determined. The average weight of the lungs of the mice immunized with MOMP, CpG, and alum was significantly less than average weight of the lungs of the mice immunized with ovalbumin, CpG, and alum. Also, the average number of IFU recovered per mouse immunized with MOMP, CpG, and alum was significantly less than the average number of IFU per mouse detected in the mice inoculated with ovalbumin, CpG, and alum. In conclusion, our data show that CpG sequences can be used as an effective adjuvant with the C. trachomatis MoPn MOMP to elicit a protective immune response in mice against a chlamydial respiratory

  5. DNA-Protein Immunization Using Leishmania Peroxidoxin-1 Induces a Strong CD4+ T Cell Response and Partially Protects Mice from Cutaneous Leishmaniasis: Role of Fusion Murine Granulocyte-Macrophage Colony-Stimulating Factor DNA Adjuvant

    PubMed Central

    Bayih, Abebe Genetu; Daifalla, Nada S.; Gedamu, Lashitew

    2014-01-01

    Background To date, no universally effective and safe vaccine has been developed for general human use. Leishmania donovani Peroxidoxin-1 (LdPxn-1) is a member of the antioxidant family of proteins and is predominantly expressed in the amastigote stage of the parasite. The aim of this study was to evaluate the immunogenicity and protective efficacy of LdPxn-1 in BALB/c mice in heterologous DNA-Protein immunization regimen in the presence of fusion murine granulocyte-macrophage colony-stimulating factor (mGMCSF) DNA adjuvant. Methodology and Principal Findings A fusion DNA of LdPxn1 and mGMCSF was cloned into a modified pcDNA vector. To confirm the expression in mammalian system, Chinese hamster ovary cells were transfected with the plasmid vector containing LdPxn1 gene. BALB/c mice were immunized twice with pcDNA-mGMCSF-LdPxn-1 or pcDNA-LdPxn1 DNA and boosted once with recombinant LdPxn-1 protein. Three weeks after the last immunization, mice were infected with Leishmania major promastigotes. The result showed that immunization with pcDNA-mGMCSF-LdPxn1 elicited a mixed Th-1/Th-2 immune response with significantly higher production of IFN-γ than controls. Intracellular cytokine staining of antigen-stimulated spleen cells showed that immunization with this antigen elicited significantly higher proportion of CD4+ T cells that express IFN-γ, TNF-α, or IL-2. The antigen also induced significantly higher proportion of multipotent CD4+ cells that simultaneously express the three Th-1 cytokines. Moreover, a significant reduction in the footpad swelling was seen in mice immunized with pcDNA-mGMCSF-LdPxn1 antigen. Expression study in CHO cells demonstrated that pcDNA-mGMCSF-LdPxn-1 was expressed in mammalian system. Conclusion The result demonstrates that immunization of BALB/c mice with a plasmid expressing LdPxn1 in the presence of mGMCSF adjuvant elicits a strong specific immune response with high level induction of multipotent CD4+ cells that mediate protection of the

  6. Old and new adjuvants for hepatitis B vaccines.

    PubMed

    Leroux-Roels, Geert

    2015-02-01

    The safety and immunogenicity profiles of currently available recombinant hepatitis B vaccines are excellent. However, it remains a real challenge to induce protective immunity in the target groups that respond poorly or not at all to conventional vaccines. Ideally, a hepatitis B vaccine can be developed that conveys lifelong protection against infection rapidly after the injection of a single dose. Although this goal is far from being reached, important improvements have been made. Novel vaccine adjuvants have been developed that enhance the immunogenicity of recombinant hepatitis B vaccines while maintaining a good safety profile. The different adjuvants and adjuvant systems that are discussed herein have all been thoroughly evaluated in clinical trials and some have reached or are close to reach the market. PMID:25523196

  7. Adjuvant treatment for pancreatic cancer.

    PubMed

    Daoud, Vladimir; Saif, Muhammad Wasif; Goodman, Martin

    2014-07-01

    Pancreatic cancer is the fourth leading cause of cancer deaths in both men and women. Surgical resection has been shown to be the only curable treatment available. Unfortunately only 20% of all patients diagnosed with pancreatic cancer are surgical candidates due to the aggressive biology of this disease. There is no clear consensus on what type of adjuvant therapy should be used for patients with pancreatic cancer. Chemoradiation is the favored treatment modality by many in the United States while gemcitabine based chemotherapy is favored in Europe. Both of these approaches have been shown by large prospective, randomized trials to improve disease free intervals and in some studies overall survival. The survival of these patients, even status post resection and adjuvant therapy, remains poor and therefore the need for alternative adjuvant therapies is needed. We will therefore discuss Abstracts #4124, #TPS4162, #4120 and #E15191 in this paper which are relevant to the issues described above. PMID:25076340

  8. Dynamics of antigen delivery and the functional roles of L121-adjuvant.

    PubMed

    Shen, Shan-Shan; Yang, Ya-Wun

    2015-08-20

    This study investigates the intracellular transport of protein antigens facilitated by L121-adjuvants and examines the associated cytotoxic T lymphocyte (CTL) effect. EL4 mouse thymoma cells were treated with L121-adjuvant and stained with AnnexinV-propidium iodide (PI) followed by flow cytometric analysis. The intracellular trafficking dynamics of bovine serum albumin (BSA)-FITC in the J774.A.1 macrophages, influenced by the L121-adjuvant, was visualized by confocal microscopy. The antigen-specific cytotoxic T lymphocyte (CTL) effect induced by the L121-adjuvant was determined by the cleavage-specific fluorogenic caspase substrate. The trafficking of BSA-FITC in the J774A.1 cells by confocal microscopy illustrated that the L121-adjuvant facilitated the intracellular transport of proteins to the subcellular compartments, including the lysosome, endoplasmic reticulum (ER), and the cis-Golgi apparatus. The L121-adjuvant also facilitated antigen delivery to the dendritic cells in the lymph nodes. Immunization of mice with the L121-adjuvant resulted in cell-mediated cytotoxic responses in the target cells, as detected by PhiPhiLux, a fluorogenic caspase substrate. Taken together, the L121-adjuvant improved the dynamics of protein delivery to antigen presenting cells, and also induced caspase activation, thereby illustrating the mechanism of antigen-specific CTL effects. PMID:25917678

  9. An Enhanced Synthetic Multiclade DNA Prime Induces Improved Cross-Clade-Reactive Functional Antibodies when Combined with an Adjuvanted Protein Boost in Nonhuman Primates

    PubMed Central

    Wise, Megan C.; Hutnick, Natalie A.; Pollara, Justin; Myles, Devin J. F.; Williams, Constance; Yan, Jian; LaBranche, Celia C.; Khan, Amir S.; Sardesai, Niranjan Y.; Montefiori, David; Barnett, Susan W.; Zolla-Pazner, Susan; Ferrari, Guido

    2015-01-01

    ABSTRACT The search for an efficacious human immunodeficiency virus type 1 (HIV-1) vaccine remains a pressing need. The moderate success of the RV144 Thai clinical vaccine trial suggested that vaccine-induced HIV-1-specific antibodies can reduce the risk of HIV-1 infection. We have made several improvements to the DNA platform and have previously shown that improved DNA vaccines alone are capable of inducing both binding and neutralizing antibodies in small-animal models. In this study, we explored how an improved DNA prime and recombinant protein boost would impact HIV-specific vaccine immunogenicity in rhesus macaques (RhM). After DNA immunization with either a single HIV Env consensus sequence or multiple constructs expressing HIV subtype-specific Env consensus sequences, we detected both CD4+ and CD8+ T-cell responses to all vaccine immunogens. These T-cell responses were further increased after protein boosting to levels exceeding those of DNA-only or protein-only immunization. In addition, we observed antibodies that exhibited robust cross-clade binding and neutralizing and antibody-dependent cellular cytotoxicity (ADCC) activity after immunization with the DNA prime-protein boost regimen, with the multiple-Env formulation inducing a more robust and broader response than the single-Env formulation. The magnitude and functionality of these responses emphasize the strong priming effect improved DNA immunogens can induce, which are further expanded upon protein boost. These results support further study of an improved synthetic DNA prime together with a protein boost for enhancing anti-HIV immune responses. IMPORTANCE Even with effective antiretroviral drugs, HIV remains an enormous global health burden. Vaccine development has been problematic in part due to the high degree of diversity and poor immunogenicity of the HIV Env protein. Studies suggest that a relevant HIV vaccine will likely need to induce broad cellular and humoral responses from a simple vaccine

  10. Perpendicular magnetization of Co2FeAl full-Heusler alloy films induced by MgO interface

    NASA Astrophysics Data System (ADS)

    Wen, Zhenchao; Sukegawa, Hiroaki; Mitani, Seiji; Inomata, Koichiro

    2011-06-01

    The perpendicular magnetization of Co2FeAl (CFA) full-Heusler alloy films was achieved in the structures of CFA/MgO and MgO/CFA with the perpendicular magnetic anisotropy energy density (KU) of 2-3×106 erg/cm3, which can be used as the perpendicular ferromagnetic electrodes of MgO-based magnetic tunnel junctions (MTJs) with high thermal stability at sub-50-nm dimension. The CFA thickness dependence of KU was investigated at different annealing temperatures, indicating that the perpendicular anisotropy of CFA is contributed by the interfacial anisotropy between CFA and MgO. This letter will open up a way for obtaining perpendicular magnetization of Co-based full-Heusler alloys, which is promising for further reduction in the critical current of current induced magnetization switching in MgO-based MTJ nanopillars with perpendicular full-Heusler alloy electrodes.

  11. Chemokines as Cancer Vaccine Adjuvants

    PubMed Central

    Bobanga, Iuliana D.; Petrosiute, Agne; Huang, Alex Y.

    2013-01-01

    We are witnessing a new era of immune-mediated cancer therapies and vaccine development. As the field of cancer vaccines advances into clinical trials, overcoming low immunogenicity is a limiting step in achieving full success of this therapeutic approach. Recent discoveries in the many biological roles of chemokines in tumor immunology allow their exploitation in enhancing recruitment of antigen presenting cells (APCs) and effector cells to appropriate anatomical sites. This knowledge, combined with advances in gene therapy and virology, allows researchers to employ chemokines as potential vaccine adjuvants. This review will focus on recent murine and human studies that use chemokines as therapeutic anti-cancer vaccine adjuvants. PMID:24967094

  12. Characterization of the Antigen-Specific CD4+ T Cell Response Induced by Prime-Boost Strategies with CAF01 and CpG Adjuvants Administered by the Intranasal and Subcutaneous Routes

    PubMed Central

    Ciabattini, Annalisa; Prota, Gennaro; Christensen, Dennis; Andersen, Peter; Pozzi, Gianni; Medaglini, Donata

    2015-01-01

    The design of heterologous prime-boost vaccine combinations that optimally shape the immune response is of critical importance for the development of next generation vaccines. Here, we tested different prime-boost combinations using the tuberculosis vaccine antigen H56 with CAF01 or CpG ODN 1826 adjuvants, administered by the parenteral and nasal routes. Using peptide-MHC class II tetramers, antigen-specific CD4+ T cells were tracked following primary and booster immunizations. Both parenteral priming with H56 plus CAF01 and nasal priming with H56 plus CpG elicited significant expansion of CD4+ tetramer-positive T cells in the spleen; however, only parenterally primed cells responded to booster immunization. Subcutaneous (SC) priming with H56 and CAF01 followed by nasal boosting with H56 and CpG showed the greater expansion of CD4+ tetramer-positive T cells in the spleen and lungs compared to all the other homologous and heterologous prime-boost combinations. Nasal boosting exerted a recruitment of primed CD4+ T cells into lungs that was stronger in subcutaneously than nasally primed mice, in accordance with different chemokine receptor expression induced by primary immunization. These data demonstrate that SC priming is fundamental for eliciting CD4+ T cells that can be efficiently boosted by the nasal route and results in the recruitment of antigen-experienced cells into the lungs. Combination of different vaccine formulations and routes of delivery for priming and boosting is a strategic approach for improving and directing vaccine-induced immune responses. PMID:26379666

  13. Cellular Adjuvant Properties, Direct Cytotoxicity of Re-differentiated Vα24 Invariant NKT-like Cells from Human Induced Pluripotent Stem Cells

    PubMed Central

    Kitayama, Shuichi; Zhang, Rong; Liu, Tian-Yi; Ueda, Norihiro; Iriguchi, Shoichi; Yasui, Yutaka; Kawai, Yohei; Tatsumi, Minako; Hirai, Norihito; Mizoro, Yasutaka; Iwama, Tatsuaki; Watanabe, Akira; Nakanishi, Mahito; Kuzushima, Kiyotaka; Uemura, Yasushi; Kaneko, Shin

    2016-01-01

    Summary Vα24 invariant natural killer T (iNKT) cells are a subset of T lymphocytes implicated in the regulation of broad immune responses. They recognize lipid antigens presented by CD1d on antigen-presenting cells and induce both innate and adaptive immune responses, which enhance effective immunity against cancer. Conversely, reduced iNKT cell numbers and function have been observed in many patients with cancer. To recover these numbers, we reprogrammed human iNKT cells to pluripotency and then re-differentiated them into regenerated iNKT cells in vitro through an IL-7/IL-15-based optimized cytokine combination. The re-differentiated iNKT cells showed proliferation and IFN-γ production in response to α-galactosylceramide, induced dendritic cell maturation and downstream activation of both cytotoxic T lymphocytes and NK cells, and exhibited NKG2D- and DNAM-1-mediated NK cell-like cytotoxicity against cancer cell lines. The immunological features of re-differentiated iNKT cells and their unlimited availability from induced pluripotent stem cells offer a potentially effective immunotherapy against cancer. PMID:26862702

  14. Drift reduction with drift control adjuvants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Numerous drift reduction adjuvants and spray deposition aids are available to applicators of crop production and protection chemicals. Performance of many of the newly introduced drift control adjuvants has not been well documented for aerial application. Five new drift control adjuvants were sele...

  15. Spray drift mitigation with spray mix adjuvants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Numerous drift reduction adjuvants and spray deposition aids are available to applicators of crop production and protection chemicals. Performance of many of the newly introduced drift control adjuvants has not been well documented for aerial application. Four new drift control adjuvants were sele...

  16. Drift reduction with drift control adjuvants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Numerous drift reduction adjuvants and spray deposition aids are available to applicators of crop production and protection chemicals. Performance of many of the newly introduced drift control adjuvants has not been well documented for aerial application. Four new drift control adjuvants were sele...

  17. QS-21: a potent vaccine adjuvant

    Technology Transfer Automated Retrieval System (TEKTRAN)

    QS-21 is an potent adjuvant derived from the bark of a Chilean tree, Quillaja saponaria. One of the advantages of this adjuvant is that it promotes a balanced humoral and cell-mediaed immune response and can be widely applicable to a variety of vaccines. This adjuvant has used for some veterinary va...

  18. Cell Recruitment and Cytokines in Skin Mice Sensitized with the Vaccine Adjuvants: Saponin, Incomplete Freund’s Adjuvant, and Monophosphoryl Lipid A

    PubMed Central

    Vitoriano-Souza, Juliana; Moreira, Nádia das Dores; Teixeira-Carvalho, Andréa; Carneiro, Cláudia Martins; Siqueira, Fernando Augusto Mathias; Vieira, Paula Melo de Abreu; Giunchetti, Rodolfo Cordeiro; Moura, Sandra Aparecida de Lima; Fujiwara, Ricardo Toshio; Melo, Maria Norma; Reis, Alexandre Barbosa

    2012-01-01

    Vaccine adjuvants are substances associated with antigens that are fundamental to the formation of an intense, durable, and fast immune response. In this context, the use of vaccine adjuvants to generate an effective cellular immune response is crucial for the design and development of vaccines against visceral leishmaniasis. The objective of this study was to evaluate innate inflammatory response induced by the vaccine adjuvants saponin (SAP), incomplete Freund’s adjuvant (IFA), and monophosphoryl lipid A (MPL). After a single dose of adjuvant was injected into the skin of mice, we analyzed inflammatory reaction, selective cell migration, and cytokine production at the injection site, and inflammatory cell influx in the peripheral blood. We found that all vaccine adjuvants were able to promote cell recruitment to the site without tissue damage. In addition, they induced selective migration of neutrophils, macrophages, and lymphocytes. The influx of neutrophils was notable at 12 h in all groups, but at other time points it was most evident after inoculation with SAP. With regard to cytokines, the SAP led to production of interleukin (IL)-2, IL-6, and IL-4. IFA promoted production of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-6, IL-17, IL-4, and IL-10. We also observed that MPL induced high production of IL-2, TNF-α, and IFN-γ, in addition to IL-6, IL-17, and IL-10. In peripheral blood, values of certain cell populations in the local response changed after stimulation. Our data demonstrate that the three vaccine adjuvants stimulate the early events of innate immune response at the injection site, suggesting their ability to increase the immunogenicity of co-administered antigens. Moreover, this work provides relevant information about elements of innate and acquired immune response induced by vaccine adjuvants administered alone. PMID:22829882

  19. Adjuvant Cationic Liposomes Presenting MPL and IL-12 Induce Cell Death, Suppress Tumor Growth, and Alter the Cellular Phenotype of Tumors in a Murine Model of Breast Cancer

    PubMed Central

    2015-01-01

    Dendritic cells (DC) process and present antigens to T lymphocytes, inducing potent immune responses when encountered in association with activating signals, such as pathogen-associated molecular patterns. Using the 4T1 murine model of breast cancer, cationic liposomes containing monophosphoryl lipid A (MPL) and interleukin (IL)-12 were administered by intratumoral injection. Combination multivalent presentation of the Toll-like receptor-4 ligand MPL and cytotoxic 1,2-dioleoyl-3-trmethylammonium-propane lipids induced cell death, decreased cellular proliferation, and increased serum levels of IL-1β and tumor necrosis factor (TNF)-α. The addition of recombinant IL-12 further suppressed tumor growth and increased expression of IL-1β, TNF-α, and interferon-γ. IL-12 also increased the percentage of cytolytic T cells, DC, and F4/80+ macrophages in the tumor. While single agent therapy elevated levels of nitric oxide synthase 3-fold above basal levels in the tumor, combination therapy with MPL cationic liposomes and IL-12 stimulated a 7-fold increase, supporting the observed cell cycle arrest (loss of Ki-67 expression) and apoptosis (TUNEL positive). In mice bearing dual tumors, the growth of distal, untreated tumors mirrored that of liposome-treated tumors, supporting the presence of a systemic immune response. PMID:25179345

  20. Intranasal hydroxypropyl-β-cyclodextrin-adjuvanted influenza vaccine protects against sub-heterologous virus infection.

    PubMed

    Kusakabe, Takato; Ozasa, Koji; Kobari, Shingo; Momota, Masatoshi; Kishishita, Natsuko; Kobiyama, Kouji; Kuroda, Etsushi; Ishii, Ken J

    2016-06-01

    Intranasal vaccination with inactivated influenza viral antigens is an attractive and valid alternative to currently available influenza (flu) vaccines; many of which seem to need efficient and safe adjuvant, however. In this study, we examined whether hydroxypropyl-β-cyclodextrin (HP-β-CD), a widely used pharmaceutical excipient to improve solubility and drug delivery, can act as a mucosal adjuvant for intranasal flu vaccines. We found that intranasal immunization of mice with hemagglutinin split- as well as inactivated whole-virion influenza vaccine with HP-β-CD resulted in secretion of antigen-specific IgA and IgGs in the airway mucosa and the serum as well. As a result, both HP-β-CD adjuvanted-flu intranasal vaccine protected mice against lethal challenge with influenza virus, equivalent to those induced by experimental cholera toxin-adjuvanted ones. Of note, intranasal use of HP-β-CD as an adjuvant induced significantly lower antigen-specific IgE responses than that induced by aluminum salt adjuvant. These results suggest that HP-β-CD may be a potent mucosal adjuvant for seasonal and pandemic influenza vaccine. PMID:27160037

  1. Broad-band properties of the CfA Seyfert Galaxies. II - Infrared to millimeter properties

    NASA Technical Reports Server (NTRS)

    Edelson, R. A.; Malkan, M. A.; Rieke, G. H.

    1987-01-01

    IR and mm observations of the 48 Seyfert 1 and 2 galaxies (SG1s and SG2s) of the CfA sample (Huchra and Berg, 1987) are reported. Data obtained (1) in the NIR using the 1.55-m reflector at Stewart Observatory and the 3-m IRTF during 1984-1986, (2) in the FIR with IRAS, and (3) at 1.3 mm using the 12-m NRAO telescope at KPNO in June 1984 are presented in extensive tables and graphs and characterized in detail. None of the objects was detected at 1.3 mm, and the IR spectra of the SG2s are found to be significantly steeper (indicating thermal emission) than those of SG1s and QSOs (nonthermal emission). Turnover in the IR emission below 100 microns (in half of the objects detected at three or more IRAS wavelengths) is shown to be consistent with an accretion disk in dust-free SG1s and with unusually warm (35-65 K) dust in SG2s. It is inferred that a 60-100-micron cool excess is masking turnover in the other SGs, so that a general association of SG nuclei with strong star formation can be confirmed.

  2. CMOS CFA database under varying illumination for benchmarking of face detection algorithms

    NASA Astrophysics Data System (ADS)

    Bocchio, Sara; Beverina, Fabrizio; Rosti, Alberto; Castelli, L.; Dominelli, S.

    2003-12-01

    In this paper we present a database containing human faces images, for benchmarking face detection algorithms. Face detection is one of the most critical steps for applications such as recognition, identification, and surveillance. We developed the database systematically, choosing a set of twenty subjects of different gender, performing more acquisitions for each one of them. All faces have different poses and expressions and various characteristics of haircut, beard and accessories. Complex backgrounds and noise conditions reflect the variability of a typical image capture in practical office applications. We performed also experiments of multi-face acquisition. All the subjects are acquired under different illuminants, such as incandescent and halogen lamps, to reproduce realistic indoor environments. The database is a color one, because most face location algorithms are based on skin location, which depends on color identification. For every picture the database contains the full color images in bitmap format and the Color Filter Array (CFA) images with the classic Bayer pattern. We also use this database as a test for our Coupled Metal Oxide Semiconductor (CMOS) sensor, to introduce low cost devices for digital color imaging acquisition and elaboration.

  3. Adjuvants and myeloid-derived suppressor cells: Enemies or allies in therapeutic cancer vaccination

    PubMed Central

    Fernández, Audry; Oliver, Liliana; Alvarez, Rydell; Fernández, Luis E; Lee, Kelvin P; Mesa, Circe

    2014-01-01

    Adjuvants are a critical but largely overlooked and poorly understood component included in vaccine formulations to stimulate and modulate the desired immune responses to an antigen. However, unlike in the protective infectious disease vaccines, adjuvants for cancer vaccines also need to overcome the effect of tumor-induced suppressive immune populations circulating in tumor-bearing individuals. Myeloid-derived suppressor cells (MDSC) are considered to be one of the key immunosuppressive populations that inhibit tumor-specific T cell responses in cancer patients. This review focuses on the different signals for the activation of the immune system induced by adjuvants, and the close relationship to the mechanisms of recruitment and activation of MDSC. This work explores the possibility that a cancer vaccine adjuvant may either strengthen or weaken the effect of tumor-induced MDSC, and the crucial need to address this in present and future cancer vaccines. PMID:25483674

  4. Antibody response in silver catfish (Rhamdia quelen) immunized with a model antigen associated with different adjuvants.

    PubMed

    Pavan, T R; Di Domenico, J; Kirsten, K S; Nied, C O; Frandoloso, R; Kreutz, L C

    2016-07-25

    Adjuvants are essential to boost the immune response to inoculated antigen and play a central role in vaccine development. In this study, we investigated the efficacy of several adjuvants in the production of anti-bovine serum albumin (BSA) antibodies in silver catfish. Two hundred and seventy juvenile silver catfish (60-80 g) of both sexes were intraperitoneally vaccinated with BSA (200 µg/fish) alone or mixed to the following adjuvants: Freund's complete adjuvant (FCA), Freund's incomplete adjuvant (FIA), aluminum hydroxide (AlOH), Montanide, four types of cytosine-phosphate-guanine (CpG) oligodeoxynucleotides (ODNs) and three concentrations of β-glucan, and the immune enhancing property was evaluated by measuring anti-BSA antibodies in blood samples at biweekly intervals. Our results demonstrated that CpGs ODNs and β-glucan were as effective as classical adjuvants (FCA, FIA, AlOH and Montanide) in promoting anti-BSA antibodies and that the kinetics of antibody production induced by all adjuvants used in our study had a similar trend to that observed in other fish species, with a peak at 28 days post-vaccination. These results may be useful for the selection of adjuvants for vaccine formulation intended for silver catfish and for the development of vaccine and vaccination strategies to other fish species. PMID:27464022

  5. Antibody response in silver catfish (Rhamdia quelen) immunized with a model antigen associated with different adjuvants

    PubMed Central

    Pavan, T.R.; Di Domenico, J.; Kirsten, K.S.; Nied, C.O.; Frandoloso, R.; Kreutz, L.C.

    2016-01-01

    Adjuvants are essential to boost the immune response to inoculated antigen and play a central role in vaccine development. In this study, we investigated the efficacy of several adjuvants in the production of anti-bovine serum albumin (BSA) antibodies in silver catfish. Two hundred and seventy juvenile silver catfish (60–80 g) of both sexes were intraperitoneally vaccinated with BSA (200 µg/fish) alone or mixed to the following adjuvants: Freund’s complete adjuvant (FCA), Freund’s incomplete adjuvant (FIA), aluminum hydroxide (AlOH), Montanide, four types of cytosine-phosphate-guanine (CpG) oligodeoxynucleotides (ODNs) and three concentrations of β-glucan, and the immune enhancing property was evaluated by measuring anti-BSA antibodies in blood samples at biweekly intervals. Our results demonstrated that CpGs ODNs and β-glucan were as effective as classical adjuvants (FCA, FIA, AlOH and Montanide) in promoting anti-BSA antibodies and that the kinetics of antibody production induced by all adjuvants used in our study had a similar trend to that observed in other fish species, with a peak at 28 days post-vaccination. These results may be useful for the selection of adjuvants for vaccine formulation intended for silver catfish and for the development of vaccine and vaccination strategies to other fish species. PMID:27464022

  6. The protein moiety of Brucella abortus outer membrane protein 16 is a new bacterial pathogen-associated molecular pattern that activates dendritic cells in vivo, induces a Th1 immune response, and is a promising self-adjuvanting vaccine against systemic and oral acquired brucellosis.

    PubMed

    Pasquevich, Karina A; García Samartino, Clara; Coria, Lorena M; Estein, Silvia M; Zwerdling, Astrid; Ibañez, Andrés E; Barrionuevo, Paula; Oliveira, Fernanda Souza de; Carvalho, Natalia Barbosa; Borkowski, Julia; Oliveira, Sergio Costa; Warzecha, Heribert; Giambartolomei, Guillermo H; Cassataro, Juliana

    2010-05-01

    Knowing the inherent stimulatory properties of the lipid moiety of bacterial lipoproteins, we first hypothesized that Brucella abortus outer membrane protein (Omp)16 lipoprotein would be able to elicit a protective immune response without the need of external adjuvants. In this study, we demonstrate that Omp16 administered by the i.p. route confers significant protection against B. abortus infection and that the protective response evoked is independent of the protein lipidation. To date, Omp16 is the first Brucella protein that without the requirement of external adjuvants is able to induce similar protection levels to the control live vaccine S19. Moreover, the protein portion of Omp16 (unlipidated Omp16 [U-Omp16]) elicits a protective response when administered by the oral route. Either systemic or oral immunization with U-Omp16 elicits a Th1-specific response. These abilities of U-Omp16 indicate that it is endowed with self-adjuvanting properties. The adjuvanticity of U-Omp16 could be explained, at least in part, by its capacity to activate dendritic cells in vivo. U-Omp16 is also able to stimulate dendritic cells and macrophages in vitro. The latter property and its ability to induce a protective Th1 immune response against B. abortus infection have been found to be TLR4 dependent. The facts that U-Omp16 is an oral protective Ag and possesses a mucosal self-adjuvanting property led us to develop a plant-made vaccine expressing U-Omp16. Our results indicate that plant-expressed recombinant U-Omp16 is able to confer protective immunity, when given orally, indicating that a plant-based oral vaccine expressing U-Omp16 could be a valuable approach to controlling this disease. PMID:20351187

  7. Mucosal SIV Vaccines Comprising Inactivated Virus Particles and Bacterial Adjuvants Induce CD8+ T-Regulatory Cells that Suppress SIV-Positive CD4+ T-Cell Activation and Prevent SIV Infection in the Macaque Model

    PubMed Central

    Andrieu, Jean-Marie; Chen, Song; Lai, Chunhui; Guo, Weizhong; Lu, Wei

    2014-01-01

    A new paradigm of mucosal vaccination against human immunodeficiency virus (HIV) infection has been investigated in the macaque model. A vaccine consisting of inactivated simian immunodeficiency virus (SIV)mac239 particles together with a living bacterial adjuvant (either the Calmette and Guerin bacillus, Lactobacillus plantarum or Lactobacillus rhamnosus) was administered to macaques via the vaginal or oral/intragastric route. In contrast to all established human and veterinary vaccines, these three vaccine regimens did not elicit SIV-specific antibodies nor cytotoxic T-lymphocytes but induced a previously unrecognized population of non-cytolytic MHCIb/E-restricted CD8+ T-regulatory cells that suppressed the activation of SIV-positive CD4+ T-lymphocytes. SIV reverse transcription was thereby blocked in inactivated CD4+ T-cells; the initial burst of virus replication was prevented and the vaccinated macaques were protected from a challenge infection. For 3–14 months after intragastric immunization, 24 macaques were challenged intrarectally with a high dose of SIVmac239 or with the heterologous strain SIV B670 (both strains grown on macaques PBMC). Twenty-three of these animals were found to be protected for up to 48 months while all 24 control macaques became infected. This protective effect against SIV challenge together with the concomitant identification of a robust ex vivo correlate of protection suggests a new approach for developing an HIV vaccine in humans. The induction of this new class of CD8+ T-regulatory cells could also possibly be used therapeutically for suppressing HIV replication in infected patients and this novel tolerogenic vaccine paradigm may have potential applications for treating a wide range of immune disorders and is likely to may have profound implications across immunology generally. PMID:25071760

  8. Majoon ushba, a polyherbal compound, suppresses pro-inflammatory mediators and RANKL expression via modulating NFкB and MAPKs signaling pathways in fibroblast-like synoviocytes from adjuvant-induced arthritic rats.

    PubMed

    Ganesan, Ramamoorthi; Doss, Hari Madhuri; Rasool, Mahaboobkhan

    2016-08-01

    Fibroblast-like synoviocytes (FLS) are inhabitant mesenchymal cells of synovial joints and have been recognized to play an imperative role in the immunopathogenesis of rheumatoid arthritis (RA). Blocking these pathological roles of FLS provides a potentially important therapeutic strategy for the treatment for RA. A recent study had confirmed that majoon ushba (MU), a polyherbal unani compound, possesses anti-arthritic effects in in vivo. Toward this direction, an effort has been made to understand the effect of MU on FLS derived from adjuvant-induced arthritis (AIA) rats. Here, we observed that MU administration (100-300 µg/ml) significantly inhibited the expression and phosphorylation of NFкB-p65 protein similar to that of the Bay 11-7082 (NFкB inhibitor) in NFкB signaling pathway and suppressed the protein expression of ERK1/2 and JNK1/2 in MAPKs signaling pathway in AIA-FLS. In addition, the protein expression of TNF-α, IL-17, RANKL, and iNOS was also found reduced. MU treatment significantly inhibited the mRNA expression of pro-inflammatory mediators (TNF-α, IL-1β, IL-6, MCP-1, IL-17, iNOS, and COX-2), transcription factors (NFкB-p65 and AP-1), and RANKL and attenuated the overproduction of TNF-α, IL-1β, IL-6, and MCP-1 (ELISA) in AIA-FLS. Furthermore, MU treatment significantly inhibited the level of lipid peroxidation, lysosomal enzymes release, and glycoproteins and increased antioxidant status (superoxide dismutase and catalase) in AIA-FLS. In conclusion, the results of this study provide evidence that MU possesses anti-inflammatory effect against AIA-FLS through the decrease in pro-inflammatory mediators expression by suppressing NFкB and MAPKs signaling pathways. PMID:27067226

  9. Antiarthritic effect of aqueous and ethanolic leaf extracts of Pistia stratiotes in adjuvant-induced arthritis in Sprague-Dawley rats

    PubMed Central

    Kyei, Samuel; Koffuor, George A; Boampong, Johnson N

    2012-01-01

    Background Pistia stratiotes has been used effectively to treat a number of inflammatory conditions. This study aims to determine the antiarthritic effect of aqueous and ethanolic leaf extracts of P. stratiotes. Methods Arthritis was induced in Sprague-Dawley rats, paw swelling was measured, and arthritis indices were estimated in rats treated with aqueous and ethanolic leaf extracts of P. stratiotes (AQ PSE and ET PSE, respectively), methotrexate, diclofenac, dexamethasone, and normal saline-treated rats. Radiologic imaging, hematological assessment of red and white blood cells, C-reactive protein and erythrocyte sedimentation rate, as well as histopathological studies were also done. The data were analyzed using GraphPad Prism 5. Results The 30, 100, and 300 mg/kg doses of AQ PSE and the 30 and 100 mg/kg doses of ET PSE caused a significant (P ≤ 0.05–0.001) reduction in ipsilateral paw swelling, similar to the effects of methotrexate, dexamethasone, and diclofenac. Only the 30 mg/kg dose of AQ PSE caused a significant (P ≤ 0.01) reduction in contralateral paw swelling. Arthritic indices reduced significantly (P ≤ 0.05–0.001) at all drug doses, except for the 100 and 300 mg/kg doses of ET PSE. White blood cell levels decreased significantly (P ≤ 0.05–0.01) in arthritic rats treated with the 30 mg/kg dose of AQ PSE and those treated with methotrexate. Erythrocyte sedimentation rate and C-reactive protein levels were significantly (P ≤ 0.01–0.001) lower in all the treatment groups except for the rats treated with AQ PSE 300 mg/kg and ET PSE 100 and 300 mg/kg doses. The arthritic animals treated with 30 mg/kg of the aqueous extract showed no inflammatory changes in the ipsilateral paw, while the contralateral paw showed only foci of mild chronic inflammatory changes, as seen with the reference drug treatment in histopathological studies. Conclusion This study establishes that aqueous and ethanolic extracts of P. stratiotes have antiarthritic

  10. Monoclonal antibodies against enterotoxigenic Escherichia coli colonization factor antigen I (CFA/I) that cross-react immunologically with heterologous CFAs.

    PubMed Central

    Rudin, A; McConnell, M M; Svennerholm, A M

    1994-01-01

    Enterotoxigenic Escherichia coli binds to enterocytes in the small intestine by means of antigenically distinct colonization factors (CFs), usually termed colonization factor antigens (CFAs), coli surface antigens (CS), or putative colonization factor antigens (PCFs). To explore the immunological relationship between different CFs, we dissociated CFA/I fimbriae into subunits and produced monoclonal antibodies (MAbs) against these subunits. We selected three MAbs that cross-reacted immunologically with a number of different, whole purified CFs in a dot blot test and with the corresponding subunits in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. One of the MAbs, i.e., subunit CFA/I 17:8 (S-CFA/I 17:8), reacted more strongly with subunits of CFA/I than with whole purified fimbriae. This MAb cross-reacted with whole purified fimbriae and subunits of CS4, PCFO166, CS1, and CS2. Moreover, it bound strongly to a peptide of 25 amino acids corresponding to the N-terminal end of CFA/I. The other two MAbs, i.e., S-CFA/I 5:6 and S-CFA/I 8:11, cross-reacted with CS1, CS2, CS4, PCFO166, and CS17 fimbriae but reacted only slightly or not at all with the CFA/I peptide. MAbs S-CFA/I 17:8 and S-CFA/I 5:6 were shown to inhibit hemagglutination by bacterial strains that express either CFA/I, CS1, or CS4. In addition, the binding of enterotoxigenic E. coli strains expressing CFA/I, CS2, CS4, and PCFO166 to enterocyte-like cell-line Caco-2 was inhibited by both MAbs. These results show that several antigenically different CFs have common epitopes and that among these at least one is located in the N-terminal end of the subunit protein. Moreover, antibodies against the common epitopes seem to block binding of the bacterial strains that express different CFs to both erythrocytes and Caco-2 cells. Images PMID:7927693

  11. Improving vaccine delivery using novel adjuvant systems.

    PubMed

    Pichichero, Michael E

    2008-01-01

    Adjuvants have been common additions to vaccines to help facilitate vaccine delivery. With advancements in vaccine technology, several adjuvants which activate immune specific responses have emerged. Available data show these adjuvants elicit important immune responses in both healthy and immunocompromised populations, as well as the elderly. Guidelines for the use and licensure of vaccine adjuvants remain under discussion. However, there is a greater understanding of the innate and adaptive immune response, and the realization of the need for immune specific adjuvants appears to be growing. This is a focused review of four adjuvants currently in clinical trial development: ASO4, ASO2A, CPG 7907, and GM-CSF. The vaccines including these adjuvants are highly relevant today, and are expected to reduce the disease burden of cervical cancer, hepatitis B and malaria. PMID:18398303

  12. The mean density and two-point correlation function for the CfA redshift survey slices

    NASA Technical Reports Server (NTRS)

    De Lapparent, Valerie; Geller, Margaret J.; Huchra, John P.

    1988-01-01

    The effect of large-scale inhomogeneities on the determination of the mean number density and the two-point spatial correlation function were investigated for two complete slices of the extension of the Center for Astrophysics (CfA) redshift survey (de Lapparent et al., 1986). It was found that the mean galaxy number density for the two strips is uncertain by 25 percent, more so than previously estimated. The large uncertainty in the mean density introduces substantial uncertainty in the determination of the two-point correlation function, particularly at large scale; thus, for the 12-deg slice of the CfA redshift survey, the amplitude of the correlation function at intermediate scales is uncertain by a factor of 2. The large uncertainties in the correlation functions might reflect the lack of a fair sample.

  13. Biosafe Nanoscale Pharmaceutical Adjuvant Materials

    PubMed Central

    Jin, Shubin; Li, Shengliang; Wang, Chongxi; Liu, Juan; Yang, Xiaolong; Wang, Paul C.; Zhang, Xin; Liang, Xing-Jie

    2014-01-01

    Thanks to developments in the field of nanotechnology over the past decades, more and more biosafe nanoscale materials have become available for use as pharmaceutical adjuvants in medical research. Nanomaterials possess unique properties which could be employed to develop drug carriers with longer circulation time, higher loading capacity, better stability in physiological conditions, controlled drug release, and targeted drug delivery. In this review article, we will review recent progress in the application of representative organic, inorganic and hybrid biosafe nanoscale materials in pharmaceutical research, especially focusing on nanomaterial-based novel drug delivery systems. In addition, we briefly discuss the advantages and notable functions that make these nanomaterials suitable for the design of new medicines; the biosafety of each material discussed in this article is also highlighted to provide a comprehensive understanding of their adjuvant attributes. PMID:25429253

  14. Adjuvant therapy for endometrial cancer

    PubMed Central

    DeLeon, Maria C.; Ammakkanavar, Natraj R.

    2014-01-01

    Endometrial cancer is a common gynecologic malignancy typically diagnosed at early stage and cured with surgery alone. Adjuvant therapy is tailored according to the risk of recurrence, estimated based on the International Federation of Gynecology and Obstetrics (FIGO) stage and other histological factors. The objective of this manuscript is to review the evidence guiding adjuvant therapy for early stage and locally advanced uterine cancer. For patients with early stage disease, minimizing toxicity, while preserving outstanding cure rates remains the major goal. For patients with locally advanced endometrial cancer optimal combined regimens are being defined. Risk stratification based on molecular traits is under development and may aid refine the current risk prediction model and permit personalized approaches for women with endometrial cancer. PMID:24761218

  15. Impact of smoking on the quantity and quality of antibodies induced by human papillomavirus type 16 and 18 AS04-adjuvanted virus-like-particle vaccine – a pilot study

    PubMed Central

    2014-01-01

    Background The AS04-adjuvanted bivalent L1 virus-like-particle (VLP) vaccine (Cervarix™) against infection with human papillomavirus (HPV) types 16/18 holds great promise to prevent HPV16/18 infections and associated neoplasias, but it is important to rule out significant co-factors of the neoplasias like smoking. Methods We conducted a pilot study to compare the quantity and quality of HPV16/18 antibody response at baseline and 7 months post vaccination in 104 non-smoking and 112 smoking female participants vaccinated at 0, 1 and 6 months with Cervarix™ (55 and 48 study participants) or with Hepatitis A vaccine (HAVRIX™) (48 and 64 participants, respectively). These 216 women were a sub-sample of 4808 baseline 16- to 17-year old Finnish women initially enrolled in the double-blind, randomized controlled phase III PATRICIA trial. Following end-of-study unblinding in 2009 they were randomly chosen out of all the participants of the three major Finnish PATRICIA study sites in the Helsinki metropolitan area (University of Helsinki, N = 535, and Family Federation Finland, N = 432) and Tampere (University of Tampere, N = 428). Following enrolment, serum samples were collected at month 0 and month 7 post 1st vaccination shot, and were analysed for levels and avidity of IgG antibodies to HPV16 and HPV18 using standard and modified (4 M urea elution) VLP ELISAs. Results We found that at month 7 post vaccination women who smoked (cotinine level > 20 ng/ml) had levels of anti-HPV16/18 antibodies comparable to those of non-smoking women. Low-avidity HPV16/18 IgG antibodies were observed in 16% of the vaccinated women, and active smoking conferred a three-fold increased risk (95% CI 1.0-9.3) of having the low-avidity antibodies. Conclusion Our data suggest that while smoking does not interfere with the quantity of vaccine-induced peak IgG levels, it may affect the avidity of IgG induced by HPV16/18 vaccination. PMID:25011477

  16. Attenuation of antigenic immunogenicity by kynurenine, a novel suppressive adjuvant.

    PubMed

    Duan, Zhiqing; Duan, Yunqing; Lei, Huangui; Hu, Ningzhu; Shi, Jiandong; Shen, Dong; Wang, Xi; Hu, Yunzhang

    2014-01-01

    A novel therapeutic strategy is required for autoimmune diseases characterized by the production of autoantibody, because current clinical strategies have limitations. Vaccination against autoimmune diseases is a feasible strategy because vaccines induce immune response memory and the antigen specificity. However, no suitable adjuvant is available to direct the immune response toward tolerance or suppression. In the current study, we evaluated whether kynurenine (Kyn) could serve as a novel suppressive adjuvant to decrease the humoral immune responses against hepatitis A virus (HAV) in the ICR mouse model in vivo and lipopolysaccharide (LPS) in B cells in vitro. The underlying mechanisms of Kyn-mediated suppression of LPS-induced IgM responses were explored. The results showed that Kyn significantly decreased HAV immunogenicity when co-administered with HAV, and that Kyn (100 μM/1000 μM) impaired IgM generation compared with that induced by LPS alone. We also demonstrated that microRNA30b (miR30b) played a critical role in the process of Kyn-mediated suppression of IgM responses induced by LPS, and that Bach2, a transcriptional repressor of B cell terminal differentiation, was a novel target of miR30b. These findings suggest that Kyn can serve as a novel and effective suppressive adjuvant for vaccines. PMID:24583631

  17. Attenuation of antigenic immunogenicity by kynurenine, a novel suppressive adjuvant

    PubMed Central

    Duan, Zhiqing; Duan, Yunqing; Lei, Huangui; Hu, Ningzhu; Shi, Jiandong; Shen, Dong; Wang, Xi; Hu, Yunzhang

    2014-01-01

    A novel therapeutic strategy is required for autoimmune diseases characterized by the production of autoantibody, because current clinical strategies have limitations. Vaccination against autoimmune diseases is a feasible strategy because vaccines induce immune response memory and the antigen specificity. However, no suitable adjuvant is available to direct the immune response toward tolerance or suppression. In the current study, we evaluated whether kynurenine (Kyn) could serve as a novel suppressive adjuvant to decrease the humoral immune responses against hepatitis A virus (HAV) in the ICR mouse model in vivo and lipopolysaccharide (LPS) in B cells in vitro. The underlying mechanisms of Kyn-mediated suppression of LPS-induced IgM responses were explored. The results showed that Kyn significantly decreased HAV immunogenicity when co-administered with HAV, and that Kyn (100 μM/1000 μM) impaired IgM generation compared with that induced by LPS alone. We also demonstrated that microRNA30b (miR30b) played a critical role in the process of Kyn-mediated suppression of IgM responses induced by LPS, and that Bach2, a transcriptional repressor of B cell terminal differentiation, was a novel target of miR30b. These findings suggest that Kyn can serve as a novel and effective suppressive adjuvant for vaccines. PMID:24583631

  18. Peripheral therapeutic ultrasound stimulation alters the distribution of spinal C-fos immunoreactivity induced by early or late phase of inflammation.

    PubMed

    Hsieh, Yueh-Ling

    2008-03-01

    The purpose of this investigation was to examine the central modulated effects of therapeutic ultrasound (US) on neuronal activity in the spinal cord on early and late phases of inflammation. In this study, induction of c-Fos protein, which reflects neuronal activation (particularly inflammatory nociception), was investigated in the lumbar spinal cord with immunohistochemistry. Inflammatory monoarthritis was induced in 20 male Wistar rats (weighing 250-300 g) via intra-articular injection of complete Freund's adjuvant (CFA) into the tibiotarsal joint. Two phases of arthritis, early phase (18 h after adjuvant injection) and late phase (7 d after adjuvant injection), were studied in the rats. Pulsed-mode US (1 MHz, the spatial average temporal average intensity [I(SATA)] = 0.5 W/cm(2), 50% duty cycle) was applied for 5 min. The effects of US and sham treatments against these phases of arthritis were demonstrated by spinal c-Fos-like immunoreactivity (c-Fos-LI). All data were evaluated statistically with the paired t-test or analysis of variance with Bonferroni corrections. c-Fos-LI neurons were abundant (average 264.2 +/- 11.9) in the L3 and L4 neurons of the spinal cord in areas ipsilateral to the CFA-induced arthritic leg in the early phase, but few were present (average 40.4 +/- 4.5) in the late phase in sham-treated animals. Bonferroni corrections to the alpha level were used to check the group differences in spinal c-Fos expression, and significance was reached when p < 0.025. In the early inflammatory phase, US treatment significantly suppressed the increased number of c-Fos-LI neurons associated with CFA-induced arthritis in superficial laminae, nucleus proprius, deep laminae and ventral horn of the spinal cord. However, during the late inflammatory phase, US significantly triggered c-Fos expression in most laminae, particularly in the nucleus proprius, deep laminae and ventral horn of the spinal cord. The results of our study suggest that administration of US

  19. Molecular adjuvants and immunomodulators: new approaches to immunization.

    PubMed Central

    Johnson, A G

    1994-01-01

    Epitopes on microbial antigens responsible for protective immunity have begun to be identified and isolated, and their chemical structures have been determined. Ensuing knowledge of their weak immunizing capacity per se has led to an appreciation of the need for adjuvants to increase the immunogenicity of these low-molecular-weight synthetic structures. As such, a recent surge in adjuvant research has emerged. Accordingly, this review will highlight a number of those adjuvant substances whose activity in animals indicates a potential use in human vaccines. In addition, the potential of several well-defined substances, termed immunomodulators, which nonspecifically stimulate resistance of animals to multiple 50% lethal doses of microbial challenge is described. Among the most extensively characterized adjuvants of microbial origin discussed in detail are (i) the lipopolysaccharides isolated from gram-negative bacteria and their nontoxic analogs, (ii) the synthetic muramyl dipeptides and their multiple analogs, and (iii) the synthetic polyribonucleotide complexes, mimicking the interferon-inducing capacity of viruses. Discussed also are the heat-labile enterotoxin of Escherichia coli, the nonionic block copolymers, the saponins, a quinolamine derivative, and the hormone dihydroepiandrosterone. PMID:7923049

  20. Molecular adjuvants and immunomodulators: new approaches to immunization.

    PubMed

    Johnson, A G

    1994-07-01

    Epitopes on microbial antigens responsible for protective immunity have begun to be identified and isolated, and their chemical structures have been determined. Ensuing knowledge of their weak immunizing capacity per se has led to an appreciation of the need for adjuvants to increase the immunogenicity of these low-molecular-weight synthetic structures. As such, a recent surge in adjuvant research has emerged. Accordingly, this review will highlight a number of those adjuvant substances whose activity in animals indicates a potential use in human vaccines. In addition, the potential of several well-defined substances, termed immunomodulators, which nonspecifically stimulate resistance of animals to multiple 50% lethal doses of microbial challenge is described. Among the most extensively characterized adjuvants of microbial origin discussed in detail are (i) the lipopolysaccharides isolated from gram-negative bacteria and their nontoxic analogs, (ii) the synthetic muramyl dipeptides and their multiple analogs, and (iii) the synthetic polyribonucleotide complexes, mimicking the interferon-inducing capacity of viruses. Discussed also are the heat-labile enterotoxin of Escherichia coli, the nonionic block copolymers, the saponins, a quinolamine derivative, and the hormone dihydroepiandrosterone. PMID:7923049

  1. [Expression and adjuvant effects of the fusion peptide TBP5].

    PubMed

    Wang, Chen; Guo, Xiangling; Li, Xiaokang; Wu, Tingcai; Li, Deyuan; Chen, Puyan

    2015-05-01

    Thymopentin (TP5) and bursopentin (BP5) are both immunopotentiators. To explore whether the TP5-BP5 fusion peptide (TBP5) has adjuvant activity or not, we cloned the TBP5 gene and confirmed that the TBP5 gene in a recombinant prokaryotic expression plasmid was successfully expressed in Escherichia coli BL21. TBP5 significantly promoted the proliferation of thymic and splenic lymphocytes of mice. The potential adjuvant activity of the TBP5 was examined in mice by coinjecting TBP5 and H9N2 avian influenza virus (AIV) inactivated vaccine. HI antibody titers, HA antibodies and cytokines levels (IL-4 and IFN-γ) were determined. We found that TBP5 markedly elevated serum HI titers and HA antibody levels, induced the secretion of both IL-4 and IFN-γ cytokines. Furthermore, virus challenge experiments confirmed that TBP5 contributed to inhibition replication of the virus [H9N2 AIV (A/chicken/Jiangsu/NJ07/05)] from mouse lungs. Altogether, these findings suggest that TBP5 may be an effective adjuvant for avian vaccine and that this study provides a reference for further research on new vaccine adjuvants. PMID:26571686

  2. Vaccine Adjuvants Alter TCR-Based Selection Thresholds

    PubMed Central

    Malherbe, Laurent; Mark, Linda; Fazilleau, Nicolas; McHeyzer-Williams, Louise J.; McHeyzer-Williams, Michael G.

    2009-01-01

    SUMMARY How TCR specificity evolves in vivo following protein vaccination is central to the development of T helper cell function. Most models of clonal selection in the T helper cell compartment favor TCR affinity-based thresholds. Here, we demonstrate that depot-forming vaccine adjuvants do not require TLR agonists to induce clonal dominance in antigen-specific T helper cell responses. However, readily dispersible adjuvants using TLR-9 and TLR-4 agonists skew TCR repertoire usage by increasing TCR selection thresholds and enhancing antigen-specific clonal expansion. In this manner, vaccine adjuvants control the local accumulation of T helper cells expressing TCR with the highest peptide MHC class II binding. Clonal composition was altered by mechanisms that blocked the local propagation of clonotypes independent of antigen dose and not as a consequence of inter-clonal competition. This capacity of adjuvants to modify antigen-specific Th cell clonal composition has fundamental implications for the design of future protein sub-unit vaccines. PMID:18450485

  3. Regulation of Coronafacoyl Phytotoxin Production by the PAS-LuxR Family Regulator CfaR in the Common Scab Pathogen Streptomyces scabies

    PubMed Central

    Cheng, Zhenlong; Bown, Luke; Tahlan, Kapil; Bignell, Dawn R. D.

    2015-01-01

    Potato common scab is an economically important crop disease that is characterized by the formation of superficial, raised or pitted lesions on the potato tuber surface. The most widely distributed causative agent of the disease is Streptomyces scabies, which produces the phytotoxic secondary metabolite thaxtomin A that serves as a key virulence factor for the organism. Recently, it was demonstrated that S. scabies can also produce the phytotoxic secondary metabolite coronafacoyl-L-isoleucine (CFA-L-Ile) as well as other related metabolites in minor amounts. The expression of the biosynthetic genes for CFA-L-Ile production is dependent on a PAS-LuxR family transcriptional regulator, CfaR, which is encoded within the phytotoxin biosynthetic gene cluster in S. scabies. In this study, we show that CfaR activates coronafacoyl phytotoxin production by binding to a single site located immediately upstream of the putative -35 hexanucleotide box within the promoter region for the biosynthetic genes. The binding activity of CfaR was shown to require both the LuxR and PAS domains, the latter of which is involved in protein homodimer formation. We also show that CFA-L-Ile production is greatly enhanced in S. scabies by overexpression of both cfaR and a downstream co-transcribed gene, orf1. Our results provide important insight into the regulation of coronafacoyl phytotoxin production, which is thought to contribute to the virulence phenotype of S. scabies. Furthermore, we provide evidence that CfaR is a novel member of the PAS-LuxR family of regulators, members of which are widely distributed among actinomycete bacteria. PMID:25826255

  4. Regulation of coronafacoyl phytotoxin production by the PAS-LuxR family regulator CfaR in the common scab pathogen Streptomyces scabies.

    PubMed

    Cheng, Zhenlong; Bown, Luke; Tahlan, Kapil; Bignell, Dawn R D

    2015-01-01

    Potato common scab is an economically important crop disease that is characterized by the formation of superficial, raised or pitted lesions on the potato tuber surface. The most widely distributed causative agent of the disease is Streptomyces scabies, which produces the phytotoxic secondary metabolite thaxtomin A that serves as a key virulence factor for the organism. Recently, it was demonstrated that S. scabies can also produce the phytotoxic secondary metabolite coronafacoyl-L-isoleucine (CFA-L-Ile) as well as other related metabolites in minor amounts. The expression of the biosynthetic genes for CFA-L-Ile production is dependent on a PAS-LuxR family transcriptional regulator, CfaR, which is encoded within the phytotoxin biosynthetic gene cluster in S. scabies. In this study, we show that CfaR activates coronafacoyl phytotoxin production by binding to a single site located immediately upstream of the putative -35 hexanucleotide box within the promoter region for the biosynthetic genes. The binding activity of CfaR was shown to require both the LuxR and PAS domains, the latter of which is involved in protein homodimer formation. We also show that CFA-L-Ile production is greatly enhanced in S. scabies by overexpression of both cfaR and a downstream co-transcribed gene, orf1. Our results provide important insight into the regulation of coronafacoyl phytotoxin production, which is thought to contribute to the virulence phenotype of S. scabies. Furthermore, we provide evidence that CfaR is a novel member of the PAS-LuxR family of regulators, members of which are widely distributed among actinomycete bacteria. PMID:25826255

  5. Why item parcels are (almost) never appropriate: two wrongs do not make a right--camouflaging misspecification with item parcels in CFA models.

    PubMed

    Marsh, Herbert W; Lüdtke, Oliver; Nagengast, Benjamin; Morin, Alexandre J S; Von Davier, Matthias

    2013-09-01

    The present investigation has a dual focus: to evaluate problematic practice in the use of item parcels and to suggest exploratory structural equation models (ESEMs) as a viable alternative to the traditional independent clusters confirmatory factor analysis (ICM-CFA) model (with no cross-loadings, subsidiary factors, or correlated uniquenesses). Typically, it is ill-advised to (a) use item parcels when ICM-CFA models do not fit the data, and (b) retain ICM-CFA models when items cross-load on multiple factors. However, the combined use of (a) and (b) is widespread and often provides such misleadingly good fit indexes that applied researchers might believe that misspecification problems are resolved--that 2 wrongs really do make a right. Taking a pragmatist perspective, in 4 studies we demonstrate with responses to the Rosenberg Self-Esteem Inventory (Rosenberg, 1965), Big Five personality factors, and simulated data that even small cross-loadings seriously distort relations among ICM-CFA constructs or even decisions on the number of factors; although obvious in item-level analyses, this is camouflaged by the use of parcels. ESEMs provide a viable alternative to ICM-CFAs and a test for the appropriateness of parcels. The use of parcels with an ICM-CFA model is most justifiable when the fit of both ICM-CFA and ESEM models is acceptable and equally good, and when substantively important interpretations are similar. However, if the ESEM model fits the data better than the ICM-CFA model, then the use of parcels with an ICM-CFA model typically is ill-advised--particularly in studies that are also interested in scale development, latent means, and measurement invariance. PMID:23834417

  6. Adjuvant progestagens for endometrial cancer

    PubMed Central

    Martin-Hirsch, Pierre PL; Bryant, Andrew; Keep, Sarah L; Kitchener, Henry C; Lilford, Richard

    2014-01-01

    Background Endometrial cancer is the most common genital tract carcinoma among women in developed countries, with most women presenting with stage 1 disease. Adjuvant progestagen therapy has been advocated following primary surgery to reduce the risk of recurrence of disease. Objectives To evaluate the effectiveness and safety of adjuvant progestagen therapy for the treatment of endometrial cancer. Search methods We searched the Cochrane Gynaecological Cancer Group Trials Specilaised Register, Cochrane Central Register of Controlled Trials (CENTRAL) Issue 2, 2009. MEDLINE and EMBASE up to April 2009. Selection criteria Randomised controlled trials (RCTs) of progestagen therapy in women who have had surgery for endometrial cancer. Data collection and analysis Two review authors independently abstracted data and assessed risk of bias. Risk ratios (RRs) comparing survival in women who did and did not receive progestagen were pooled in random effects meta-analyses.. Main results Seven trials assessing 4556 women were identified. Three trials included women with stage one disease only, whereas four included women with more advanced disease. Meta-analysis of four trials showed that there was no significant difference in the risk of death at five years between adjuvant progestagen therapy and no further treatment (RR = 1.00, 95% CI 0.85 to 1.18). This conclusion is also robust to single trial analyses at 4 and 7 years and in one trial across all points in time using a hazard ratio (HR). There was also no significant difference between progestagen therapy and control in terms of the risk of death from endometrial cancer, cardiovascular disease and intercurrent disease. Relapse of disease appeared to be reduced by progestagen therapy in one trial (HR = 0.71, 95% CI 0.52 to 0.97 and 5 year RR = 0.74, 95% CI 0.58 to 0.96), but there was no evidence of a difference in disease recurrence in another trial at 7 years (RR = 1.34, 95% CI 0.79 to 2.27). Authors’ conclusions There

  7. Plant Derived Aporphinic Alkaloid S-(+)-Dicentrine Induces Antinociceptive Effect in Both Acute and Chronic Inflammatory Pain Models: Evidence for a Role of TRPA1 Channels

    PubMed Central

    Montrucchio, Deise Prehs; Córdova, Marina Machado; Soares Santos, Adair Roberto

    2013-01-01

    S-(+)-Dicentrine is an aporphinic alkaloid found in several plant species, mainly from Lauraceae family, which showed significant antinociceptive activity in an acute model of visceral pain in mice. In this work, we extended the knowledge on the antinociceptive properties of S-(+)-dicentrine and showed that this alkaloid also attenuates mechanical and cold hypersensitivity associated with cutaneous inflammation induced by Complete Freund’s Adjuvant in mice. Given orally, S-(+)-dicentrine (100 mg/kg) reversed CFA-induced mechanical hypersensitivity, evaluated as the paw withdrawal threshold to von Frey hairs, and this effect lasted up to 2 hours. S-(+)-Dicentrine also reversed CFA-induced cold hypersensitivity, assessed as the responses to a drop of acetone in the injured paw, but did not reverse the heat hypersensitivity, evaluated as the latency time to paw withdrawal in the hot plate (50°C). Moreover, S-(+)-dicentrine (100 mg/kg, p.o.) was effective in inhibit nociceptive responses to intraplantar injections of cinnamaldehyde, a TRPA1 activator, but not the responses induced by capsaicin, a TRPV1 activator. When administered either by oral or intraplantar routes, S-(+)-dicentrine reduced the licking time (spontaneous nociception) and increased the latency time to paw withdrawal in the cold plate (cold hypersensitivity), both induced by the intraplantar injection of cinnamaldehyde. Taken together, our data adds information about antinociceptive properties of S-(+)-dicentrine in inflammatory conditions, reducing spontaneous nociception and attenuating mechanical and cold hypersensitivity, probably via a TRPA1-dependent mechanism. It also indicates that S-(+)-dicentrine might be potentially interesting in the development of new clinically relevant drugs for the management of persistent pain, especially under inflammatory conditions. PMID:23861794

  8. The requirement for potent adjuvants to enhance the immunogenicity and protective efficacy of protein vaccines can be overcome by prior immunization with a recombinant adenovirus

    PubMed Central

    de Cassan, Simone C.; Forbes, Emily K.; Douglas, Alexander D.; Milicic, Anita; Singh, Bijender; Gupta, Puneet; Chauhan, Virander S.; Chitnis, Chetan E.; Gilbert, Sarah C.; Hill, Adrian V. S.; Draper, Simon J.

    2011-01-01

    A central goal in vaccinology is the induction of high and sustained antibody responses. Protein-in-adjuvant formulations are commonly used to achieve such responses. However, their clinical development can be limited by the reactogenicity of some of the most potent pre-clinical adjuvants and the cost and complexity of licensing new adjuvants for human use. Also, few adjuvants induce strong cellular immunity which is important for protection against many diseases, such as malaria. We compared classical adjuvants such as alum to new pre-clinical adjuvants and adjuvants in clinical development such as Abisco®100, CoVaccine HT™, Montanide®ISA720 and SE-GLA, for their ability to induce high and sustained antibody responses and T cell responses. These adjuvants induced a broad range of antibody responses when used in a three-shot protein-in-adjuvant regime using the model antigen ovalbumin and leading blood-stage malaria vaccine candidate antigens. Surprisingly, this range of antibody immunogenicity was greatly reduced when a protein-in-adjuvant vaccine was used to boost antibody responses primed by a human adenovirus serotype 5 (AdHu5) vaccine recombinant for the same antigen. This AdHu5-protein regime also induced a more cytophilic antibody response and demonstrated improved efficacy of merozoite surface protein-1 (MSP-1) protein vaccines against a Plasmodium yoelii blood-stage challenge. This indicates that the differential immunogenicity of protein vaccine adjuvants may be largely overcome by prior immunization with recombinant adenovirus, especially for adjuvants that are traditionally considered poorly immunogenic in the context of subunit vaccination, and may circumvent the need for more potent chemical adjuvants. PMID:21813775

  9. Acidosis Mediates the Switching of Gs-PKA and Gi-PKCε Dependence in Prolonged Hyperalgesia Induced by Inflammation

    PubMed Central

    Huang, Wei-Yu; Dai, Shih-Ping; Chang, Yan-Ching; Sun, Wei-Hsin

    2015-01-01

    Chronic inflammatory pain, when not effectively treated, is a costly health problem and has a harmful effect on all aspects of health-related quality of life. Previous studies suggested that in male Sprague Dawley rats, prostaglandin E2 (PGE2)-induced short-term hyperalgesia depends on protein kinase A (PKA) activity, whereas long-lasting hyperalgesia induced by PGE2 with carrageenan pre-injection, requires protein kinase Cε (PKCε). However, the mechanism underlying the kinase switch with short- to long-term hyperalgesia remains unclear. In this study, we used the inflammatory agents carrageenan or complete Freund’s adjuvant (CFA) to induce long-term hyperalgesia, and examined PKA and PKCε dependence and switching time. Hyperalgesia induced by both agents depended on PKA/PKCε and Gs/Gi-proteins, and the switching time from PKA to PKCε and from Gs to Gi was about 3 to 4 h after inflammation induction. Among the single inflammatory mediators tested, PGE2 and 5-HT induced transient hyperalgesia, which depended on PKA and PKCε, respectively. Only acidic solution-induced hyperalgesia required Gs-PKA and Gi-PKCε, and the switch time for kinase dependency matched inflammatory hyperalgesia, in approximately 2 to 4 h. Thus, acidosis in inflamed tissues may be a decisive factor to regulate switching of PKA and PKCε dependence via proton-sensing G-protein–coupled receptors. PMID:25933021

  10. GLA-AF, an emulsion-free vaccine adjuvant for pandemic influenza.

    PubMed

    Clegg, Christopher H; Roque, Richard; Perrone, Lucy A; Rininger, Joseph A; Bowen, Richard; Reed, Steven G

    2014-01-01

    The ongoing threat from Influenza necessitates the development of new vaccine and adjuvant technologies that can maximize vaccine immunogenicity, shorten production cycles, and increase global vaccine supply. Currently, the most successful adjuvants for Influenza vaccines are squalene-based oil-in-water emulsions. These adjuvants enhance seroprotective antibody titers to homologous and heterologous strains of virus, and augment a significant dose sparing activity that could improve vaccine manufacturing capacity. As an alternative to an emulsion, we tested a simple lipid-based aqueous formulation containing a synthetic TLR4 ligand (GLA-AF) for its ability to enhance protection against H5N1 infection. GLA-AF was very effective in adjuvanting recombinant H5 hemagglutinin antigen (rH5) in mice and was as potent as the stable emulsion, SE. Both adjuvants induced similar antibody titers using a sub-microgram dose of rH5, and both conferred complete protection against a highly pathogenic H5N1 challenge. However, GLA-AF was the superior adjuvant in ferrets. GLA-AF stimulated a broader antibody response than SE after both the prime and boost immunization with rH5, and ferrets were better protected against homologous and heterologous strains of H5N1 virus. Thus, GLA-AF is a potent emulsion-free adjuvant that warrants consideration for pandemic influenza vaccine development. PMID:24551202

  11. Transcutaneous Immunization with Bacterial ADP-Ribosylating Exotoxins, Subunits, and Unrelated Adjuvants

    PubMed Central

    Scharton-Kersten, Tanya; Yu, Jian-mei; Vassell, Russell; O'Hagan, Derek; Alving, Carl R.; Glenn, Gregory M.

    2000-01-01

    We have recently described a needle-free method of vaccination, transcutaneous immunization, consisting of the topical application of vaccine antigens to intact skin. While most proteins themselves are poor immunogens on the skin, we have shown that the addition of cholera toxin (CT), a mucosal adjuvant, results in cellular and humoral immune responses to the adjuvant and coadministered antigens. The present study explores the breadth of adjuvants that have activity on the skin, using diphtheria toxoid (DTx) and tetanus toxoid as model antigens. Heat-labile enterotoxin (LT) displayed adjuvant properties similar to those of CT when used on the skin and induced protective immune responses against tetanus toxin challenge when applied topically at doses as low as 1 μg. Interestingly, enterotoxin derivatives LTR192G, LTK63, and LTR72 and the recombinant CT B subunit also exhibited adjuvant properties on the skin. Consistent with the latter finding, non-ADP-ribosylating exotoxins, including an oligonucleotide DNA sequence, as well as several cytokines (interleukin-1β [IL-1β] fragment, IL-2, IL-12, and tumor necrosis factor alpha) and lipopolysaccharide also elicited detectable anti-DTx immunoglobulin G titers in the immunized mice. These results indicate that enhancement of the immune response to topical immunization is not restricted to CT or the ADP-ribosylating exotoxins as adjuvants. This study also reinforces earlier findings that addition of an adjuvant is important for the induction of robust immune responses to vaccine antigens delivered by topical application. PMID:10948159

  12. Power spectrum, correlation function, and tests for luminosity bias in the CfA redshift survey

    NASA Technical Reports Server (NTRS)

    Park, Changbom; Vogeley, Michael S.; Geller, Margaret J.; Huchra, John P.

    1994-01-01

    We describe and apply a method for directly computing the power spectrum for the galaxy distribution in the extension of the Center for Astrophysics Redshift Survey. Tests show that our technique accurately reproduces the true power spectrum for k greater than 0.03 h Mpc(exp -1). The dense sampling and large spatial coverage of this survey allow accurate measurement of the redshift-space power spectrum on scales from 5 to approximately 200 h(exp -1) Mpc. The power spectrum has slope n approximately equal -2.1 on small scales (lambda less than or equal 25 h(exp -1) Mpc) and n approximately -1.1 on scales 30 less than lambda less than 120 h(exp -1) Mpc. On larger scales the power spectrum flattens somewhat, but we do not detect a turnover. Comparison with N-body simulations of cosmological models shows that an unbiased, open universe CDM model (OMEGA h = 0.2) and a nonzero cosmological constant (CDM) model (OMEGA h = 0.24, lambda(sub zero) = 0.6, b = 1.3) match the CfA power spectrum over the wavelength range we explore. The standard biased CDM model (OMEGA h = 0.5, b = 1.5) fails (99% significance level) because it has insufficient power on scales lambda greater than 30 h(exp -1) Mpc. Biased CDM with a normalization that matches the Cosmic Microwave Background (CMB) anisotropy (OMEGA h = 0.5, b = 1.4, sigma(sub 8) (mass) = 1) has too much power on small scales to match the observed galaxy power spectrum. This model with b = 1 matches both Cosmic Background Explorer Satellite (COBE) and the small-scale power spect rum but has insufficient power on scales lambda approximately 100 h(exp -1) Mpc. We derive a formula for the effect of small-scale peculiar velocities on the power spectrum and combine this formula with the linear-regime amplification described by Kaiser to compute an estimate of the real-space power spectrum. Two tests reveal luminosity bias in the galaxy distribution: First, the amplitude of the pwer spectrum is approximately 40% larger for the brightest

  13. Acute inflammation induces immunomodulatory effects on myeloid cells associated with anti-tumor responses in a tumor mouse model.

    PubMed

    Salem, Mohamed L; Attia, Zeinab I; Galal, Sohaila M

    2016-03-01

    Given the self nature of cancer, anti-tumor immune response is weak. As such, acute inflammation induced by microbial products can induce signals that result in initiation of an inflammatory cascade that helps activation of immune cells. We aimed to compare the nature and magnitude of acute inflammation induced by toll-like receptor ligands (TLRLs) on the tumor growth and the associated inflammatory immune responses. To induce acute inflammation in tumor-bearing host, CD1 mice were inoculated with intraperitoneal (i.p.) injection of Ehrlich ascites carcinoma (EAC) (5 × 10(5) cells/mouse), and then treated with i.p. injection on day 1, day 7 or days 1 + 7 with: (1) polyinosinic:polycytidylic (poly(I:C)) (TLR3L); (2) Poly-ICLC (clinical grade of TLR3L); (3) Bacillus Calmette Guerin (BCG) (coding for TLR9L); (4) Complete Freund's adjuvant (CFA) (coding for TLR9L); and (5) Incomplete Freund's Adjuvant (IFA). Treatment with poly(I:C), Poly-ICLC, BCG, CFA, or IFA induced anti-tumor activities as measured by 79.1%, 75.94%, 73.94%, 71.88% and 47.75% decreases, respectively in the total number of tumor cells collected 7 days after tumor challenge. Among the tested TLRLs, both poly(I:C) (TLR3L) and BCG (contain TLR9L) showed the highest anti-tumor effects as reflected by the decrease in the number of EAc cells. These effects were associated with a 2-fold increase in the numbers of inflammatory cells expressing the myeloid markers CD11b(+)Ly6G(+), CD11b(+)Ly6G(-), and CD11b(+)Ly6G(-). We concluded that Provision of the proper inflammatory signal with optimally defined magnitude and duration during tumor growth can induce inflammatory immune cells with potent anti-tumor responses without vaccination. PMID:26966565

  14. Acute inflammation induces immunomodulatory effects on myeloid cells associated with anti-tumor responses in a tumor mouse model

    PubMed Central

    Salem, Mohamed L.; Attia, Zeinab I.; Galal, Sohaila M.

    2015-01-01

    Given the self nature of cancer, anti-tumor immune response is weak. As such, acute inflammation induced by microbial products can induce signals that result in initiation of an inflammatory cascade that helps activation of immune cells. We aimed to compare the nature and magnitude of acute inflammation induced by toll-like receptor ligands (TLRLs) on the tumor growth and the associated inflammatory immune responses. To induce acute inflammation in tumor-bearing host, CD1 mice were inoculated with intraperitoneal (i.p.) injection of Ehrlich ascites carcinoma (EAC) (5 × 105 cells/mouse), and then treated with i.p. injection on day 1, day 7 or days 1 + 7 with: (1) polyinosinic:polycytidylic (poly(I:C)) (TLR3L); (2) Poly-ICLC (clinical grade of TLR3L); (3) Bacillus Calmette Guerin (BCG) (coding for TLR9L); (4) Complete Freund’s adjuvant (CFA) (coding for TLR9L); and (5) Incomplete Freund’s Adjuvant (IFA). Treatment with poly(I:C), Poly-ICLC, BCG, CFA, or IFA induced anti-tumor activities as measured by 79.1%, 75.94%, 73.94%, 71.88% and 47.75% decreases, respectively in the total number of tumor cells collected 7 days after tumor challenge. Among the tested TLRLs, both poly(I:C) (TLR3L) and BCG (contain TLR9L) showed the highest anti-tumor effects as reflected by the decrease in the number of EAc cells. These effects were associated with a 2-fold increase in the numbers of inflammatory cells expressing the myeloid markers CD11b+Ly6G+, CD11b+Ly6G−, and CD11b+Ly6G−. We concluded that Provision of the proper inflammatory signal with optimally defined magnitude and duration during tumor growth can induce inflammatory immune cells with potent anti-tumor responses without vaccination. PMID:26966565

  15. In vitro cytokine induction by TLR-activating vaccine adjuvants in human blood varies by age and adjuvant.

    PubMed

    van Haren, Simon D; Ganapathi, Lakshmi; Bergelson, Ilana; Dowling, David J; Banks, Michaela; Samuels, Ronald C; Reed, Steven G; Marshall, Jason D; Levy, Ofer

    2016-07-01

    Most infections occur in early life, prompting development of novel adjuvanted vaccines to protect newborns and infants. Several Toll-like receptor (TLR) agonists (TLRAs) are components of licensed vaccine formulations or are in development as candidate adjuvants. However, the type and magnitude of immune responses to TLRAs may vary with the TLR activated as well as age and geographic location. Most notably, in newborns, as compared to adults, the immune response to TLRAs is polarized with lower Th1 cytokine production and robust Th2 and anti-inflammatory cytokine production. The ontogeny of TLR-mediated cytokine responses in international cohorts has been reported, but no study has compared cytokine responses to TLRAs between U.S. neonates and infants at the age of 6months. Both are critical age groups for the currently pediatric vaccine schedule. In this study, we report quantitative differences in the production of a panel of 14 cytokines and chemokines after in vitro stimulation of newborn cord blood and infant and adult peripheral blood with agonists of TLR4, including monophosphoryl lipid A (MPLA) and glucopyranosyl lipid Adjuvant aqueous formulation (GLA-AF), as well as agonists of TLR7/8 (R848) and TLR9 (CpG). Both TLR4 agonists, MPLA and GLA-AF, induced greater concentrations of Th1 cytokines CXCL10, TNF and Interleukin (IL)-12p70 in infant and adult blood compared to newborn blood. All the tested TLRAs induced greater infant IFN-α2 production compared to newborn and adult blood. In contrast, CpG induced greater IFN-γ, IL-1β, IL-4, IL-12p40, IL-10 and CXCL8 in newborn than in infant and adult blood. Overall, to the extent that these in vitro studies mirror responses in vivo, our study demonstrates distinct age-specific effects of TLRAs that may inform their development as candidate adjuvants for early life vaccines. PMID:27081760

  16. Novel adjuvant formulations for delivery of anti-tuberculosis vaccine candidates.

    PubMed

    Agger, Else Marie

    2016-07-01

    There is an urgent need for a new and improved vaccine against tuberculosis for controlling this disease that continues to pose a global health threat. The current research strategy is to replace the present BCG vaccine or boost BCG-immunity with subunit vaccines such as viral vectored- or protein-based vaccines. The use of recombinant proteins holds a number of production advantages including ease of scalability, but requires an adjuvant inducing cell-mediated immune responses. A number of promising novel adjuvant formulations have recently been designed and show evidence of induction of cellular immune responses in humans. A common trait of effective TB adjuvants including those already in current clinical testing is a two-component approach combining a delivery system with an appropriate immunomodulator. This review summarizes the status of current TB adjuvant research with a focus on the division of labor between delivery systems and immunomodulators. PMID:26596558

  17. The effect of immunological adjuvants on the relative affinity of anti-protein antibodies.

    PubMed Central

    Petty, R E; Steward, M W

    1977-01-01

    Inbred mice of a strain (B1OD2 new) known to produce either no detectable antibody or antibody of low affinity to two protein antigens administered in saline, were immunized with human serum transferrin (HST) in one of nine adjuvants. Such immunization increases the level and relative affinity of anti-HST antibody. The adjuvants used varied in the degree to which they augmented these parameters of the antibody response--that is, FCA and FIA were capable of inducing high levels of high affinity antibody, whereas other adjuvants elicited lower levels of high affinity antibody. The possibility is discussed that substances with adjuvant activity may effect antibody production at two stages: (1) at the stage of antigen selection of cells for proliferation and (2) at the stage or proliferation of antibody producing cell precursors. PMID:844888

  18. Adjuvants: Classification, Modus Operandi, and Licensing

    PubMed Central

    Apostólico, Juliana de Souza

    2016-01-01

    Vaccination is one of the most efficient strategies for the prevention of infectious diseases. Although safer, subunit vaccines are poorly immunogenic and for this reason the use of adjuvants is strongly recommended. Since their discovery in the beginning of the 20th century, adjuvants have been used to improve immune responses that ultimately lead to protection against disease. The choice of the adjuvant is of utmost importance as it can stimulate protective immunity. Their mechanisms of action have now been revealed. Our increasing understanding of the immune system, and of correlates of protection, is helping in the development of new vaccine formulations for global infections. Nevertheless, few adjuvants are licensed for human vaccines and several formulations are now being evaluated in clinical trials. In this review, we briefly describe the most well known adjuvants used in experimental and clinical settings based on their main mechanisms of action and also highlight the requirements for licensing new vaccine formulations. PMID:27274998

  19. Self-adjuvanting vaccine against group A streptococcus: application of fibrillized peptide and immunostimulatory lipid as adjuvant.

    PubMed

    Azmi, Fazren; Ahmad Fuaad, Abdullah Al Hadi; Giddam, Ashwini Kumar; Batzloff, Michael R; Good, Michael F; Skwarczynski, Mariusz; Toth, Istvan

    2014-11-15

    Peptides are of great interest to be used as vaccine antigens due to their safety, ease of manufacturing and specificity in generating immune response. There have been massive discoveries of peptide antigens over the past decade. However, peptides alone are poorly immunogenic, which demand co-administration with strong adjuvant to enhance their immunogenicity. Recently, fibril-forming peptides such as Q11 and lipoamino acid-based carrier have been identified to induce substantial immune responses when covalently linked to peptide epitope. In this study, we have incorporated either Q11 or lipoamino acids to a peptide epitope (J14) derived from M protein of group A streptococcus to develop self-adjuvanting vaccines. J14, Q11 and lipoamino acids were also conjugated together in a single vaccine construct in an attempt to evaluate the synergy effect of combining multiple adjuvants. Physicochemical characterization demonstrated that the vaccine constructs folded differently and self-assembled into nanoparticles. Significantly, only vaccine constructs containing double copies of lipoamino acids (regardless in conjugation with Q11 or not) were capable to induce significant dendritic cells uptake and subsequent J14-specific antibody responses in non-sizes dependent manners. Q11 had minimal impact in enhancing the immunogenicity of J14 even when it was used in combination with lipoamino acids. These findings highlight the impact of lipoamino acids moiety as a promising immunostimulant carrier and its number of attachment to peptide epitope was found to have a profound effect on the vaccine immunogenicity. PMID:25438764

  20. Potent response of QS-21 as a vaccine adjuvant in the skin when delivered with the Nanopatch, resulted in adjuvant dose sparing

    PubMed Central

    Ng, Hwee-Ing; Fernando, Germain J. P.; Depelsenaire, Alexandra C. I.; Kendall, Mark A. F.

    2016-01-01

    Adjuvants play a key role in boosting immunogenicity of vaccines, particularly for subunit protein vaccines. In this study we investigated the induction of antibody response against trivalent influenza subunit protein antigen and a saponin adjuvant, QS-21. Clinical trials of QS-21 have demonstrated the safety but, also a need of high dose for optimal immunity, which could possibly reduce patient acceptability. Here, we proposed the use of a skin delivery technology – the Nanopatch – to reduce both adjuvant and antigen dose but also retain its immune stimulating effects when compared to the conventional needle and syringe intramuscular (IM) delivery. We have demonstrated that Nanopatch delivery to skin requires only 1/100th of the IM antigen dose to induce equivalent humoral response. QS-21 enhanced humoral response in both skin and muscle route. Additionally, Nanopatch has demonstrated 30-fold adjuvant QS-21 dose sparing while retaining immune stimulating effects compared to IM. QS-21 induced localised, controlled cell death in the skin, suggesting that the danger signals released from dead cells contributed to the enhanced immunogenicity. Taken together, these findings demonstrated the suitability of reduced dose of QS-21 and the antigen using the Nanopatch to enhance humoral responses, and the potential to increase patient acceptability of QS-21 adjuvant. PMID:27404789

  1. Potent response of QS-21 as a vaccine adjuvant in the skin when delivered with the Nanopatch, resulted in adjuvant dose sparing.

    PubMed

    Ng, Hwee-Ing; Fernando, Germain J P; Depelsenaire, Alexandra C I; Kendall, Mark A F

    2016-01-01

    Adjuvants play a key role in boosting immunogenicity of vaccines, particularly for subunit protein vaccines. In this study we investigated the induction of antibody response against trivalent influenza subunit protein antigen and a saponin adjuvant, QS-21. Clinical trials of QS-21 have demonstrated the safety but, also a need of high dose for optimal immunity, which could possibly reduce patient acceptability. Here, we proposed the use of a skin delivery technology - the Nanopatch - to reduce both adjuvant and antigen dose but also retain its immune stimulating effects when compared to the conventional needle and syringe intramuscular (IM) delivery. We have demonstrated that Nanopatch delivery to skin requires only 1/100(th) of the IM antigen dose to induce equivalent humoral response. QS-21 enhanced humoral response in both skin and muscle route. Additionally, Nanopatch has demonstrated 30-fold adjuvant QS-21 dose sparing while retaining immune stimulating effects compared to IM. QS-21 induced localised, controlled cell death in the skin, suggesting that the danger signals released from dead cells contributed to the enhanced immunogenicity. Taken together, these findings demonstrated the suitability of reduced dose of QS-21 and the antigen using the Nanopatch to enhance humoral responses, and the potential to increase patient acceptability of QS-21 adjuvant. PMID:27404789

  2. Isatis indigotica root polysaccharides as adjuvants for an inactivated rabies virus vaccine.

    PubMed

    Zhang, Weijiao; Zheng, Xuexing; Cheng, Nan; Gai, Weiwei; Xue, Xianghong; Wang, Yuxia; Gao, Yuwei; Shan, Junjie; Yang, Songtao; Xia, Xianzhu

    2016-06-01

    Adjuvants can enhance vaccine immunogenicity and induce long-term enhancement of immune responses. Thus, adjuvants are important for vaccine research. Polysaccharides isolated from select Chinese herbs have been demonstrated to possess various beneficial functions and excellent adjuvant abilities. In the present study, the polysaccharides IIP-A-1 and IIP-2 were isolated from Isatis indigotica root and compared with the common vaccine adjuvant aluminum hydroxide via intramuscular co-administration of inactivated rabies virus rCVS-11-G into mice. Blood was collected to determine virus neutralizing antibody (VNA) titers and B and T lymphocyte activation status. Inguinal lymph node samples were collected and used to measure B lymphocyte proliferation. Splenocytes were isolated, from which antigen-specific cellular immune responses were detected via ELISpot, ELISA and intracellular cytokine staining. The results revealed that both types of polysaccharides induce more rapid changes and higher VNA titers than aluminum hydroxide. Flow cytometry assays revealed that the polysaccharides activated more B lymphocytes in the lymph nodes and more B and T lymphocytes in the blood than aluminum hydroxide. Antigen-specific cellular immune responses showed that IIP-2 strongly induced T lymphocyte proliferation in the spleen and high levels of cytokine secretion from splenocytes, whereas aluminum hydroxide induced proliferation in only a small number of lymphocytes and the secretion of only small quantities of cytokines. Collectively, these data suggest that the polysaccharide IIP-2 exhibits excellent adjuvant activity and can enhance both cellular and humoral immunity. PMID:26875535

  3. Lagoon Seepage Testing Report for Central Facilities Area (CFA) Sewage Lagoons at Idaho National Laboratory, Butte County, Idaho

    SciTech Connect

    Bridger Morrison

    2014-09-01

    J-U-B ENGINEERS, Inc. (J-U-B) performed seepage tests on the CFA Wastewater Lagoons 1, 2, and 3 between August 26th and September 22nd, 2014. The lagoons were tested to satisfy the Idaho Department of Environmental Quality (DEQ) Rules (IDAPA 58.01.16) that require all lagoons be tested at a frequency of every 10 years and the Compliance Activity CA-141-03 in the DEQ Wastewater Reuse Permit for the CFA Sewage Treatment Plant (LA-000141-03). The lagoons were tested to determine if the average seepage rates are less than 0.25 in/day, the maximum seepage rate allowed for lagoons built prior to April 15, 2007. The average seepage rates were estimated for each lagoon and are given in Table-ES1. The average seepage rates for Lagoons 1 and 2 are less than the allowable seepage rate of 0.25 in/day. Lagoon 1 and 2 passed the seepage test and will not have to be tested again until the year 20241. However, the average seepage rate for Lagoon 3 appears to exceed the allowable seepage rate of 0.25 in/day which means the potential source for the excessive leakage should be investigated further.

  4. Salidroside ameliorates arthritis-induced brain cognition deficits by regulating Rho/ROCK/NF-κB pathway.

    PubMed

    Zhu, Lingpeng; Chen, Tong; Chang, Xiayun; Zhou, Rui; Luo, Fen; Liu, Jingyan; Zhang, Kai; Wang, Yue; Yang, Ying; Long, Hongyan; Liu, Yu; Yan, Tianhua; Ma, Chunhua

    2016-04-01

    The prevalence of cognitive impairment in rheumatoid arthritis (RA) patients was increasingly serious nowadays. The purpose of the current study was to explore whether salidroside (Sal) could alleviate arthritis-induced cognition deficits and examine the relationship between the impairment and Rho/ROCK/NF-κB pathway. Collagen-induced arthritis (CIA) was established by the injection of chicken type II collagen (CII), complete Freund's adjuvant (CFA) and incomplete Freund's adjuvant (IFA). Arthritic lesions of CIA rats were assessed by arthritis index score, swelling of paws and histological analysis. Cognitive deficits symptoms of CIA rats were monitored through Morris water maze test. The contents of pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) in hippocampus and serum were significantly reduced with salidroside (20 mg/kg, 40 mg/kg) treatment compared with those in the CIA group. In parallel, we demonstrated that the expressions of RhoA, ROCK1, ROCK2, p-NF-κBp65, p-IκBα, p-IKKα and p-IKKβ were enhanced accompanying the investigation arthritis-induced cognition deficits, which were remarkably down-regulated by salidroside and confirmed by the results obtained from western blot and immunohistochemistry. LC-MS/MS results ascertained that Sal could enter into the blood and brain tissues to exhibit the protective effect on arthritis-induced cognitive dysfunction. Therefore, it was assumed that Sal might be a potential therapeutic candidate to treat arthritis-induced brain cognition deficits through the regulation of Rho/ROCK/NF-κB signaling. PMID:26690894

  5. Immunostimulatory Oligodeoxynucleotides Containing the CpG Motif are Effective as Immune Adjuvants in Tumor Antigen Immunization

    NASA Astrophysics Data System (ADS)

    Weiner, George J.; Liu, Hsin-Ming; Wooldridge, James E.; Dahle, Christopher E.; Krieg, Arthur M.

    1997-09-01

    Recent advances in our understanding of the immune response are allowing for the logical design of new approaches to cancer immunization. One area of interest is the development of new immune adjuvants. Immunostimulatory oligodeoxynucleotides containing the CpG motif (CpG ODN) can induce production of a wide variety of cytokines and activate B cells, monocytes, dendritic cells, and NK cells. Using the 38C13 B cell lymphoma model, we assessed whether CpG ODN can function as immune adjuvants in tumor antigen immunization. The idiotype served as the tumor antigen. Select CpG ODN were as effective as complete Freund's adjuvant at inducing an antigen-specific antibody response but were associated with less toxicity. These CpG ODN induced a higher titer of antigen-specific IgG2a than did complete Freund's adjuvant, suggesting an enhanced TH1 response. Mice immunized with CpG ODN as an adjuvant were protected from tumor challenge to a degree similar to that seen in mice immunized with complete Freund's adjuvant. We conclude that CpG ODN are effective as immune adjuvants and are attractive as part of a tumor immunization strategy.

  6. Evaluation of Widely Consumed Botanicals as Immunological Adjuvants

    PubMed Central

    Ragupathi, Govind; Hood, Chandra; Yeung, K. Simon; Vickers, Andrew; Hood, Chandra; Deng, Gary; Cheung, Nai-Kong; Vickers, Andrew; Cassileth, Barrie; Livingston, Philip

    2008-01-01

    ), a 95% ethanol extract of astragalus and yeast β-glucan, and (to a lesser extent) Maitake. Antibodies against KLH in all cases and against globo H in most cases were induced by these botanicals. Little or no adjuvant activity was demonstrated with H48 or Echinacea extracts or the astragalus water extract. Experiments with GD3-KLH as immunogen confirmed the adjuvant activity of the Coriolus, yeast β-glucan and Astragalus extracts. While extraction with ethanol concentrated the active ingredients in astragalus, it had no impact on coriolus where the 90% ethanol precipitate and solute were equally active. Conclusions Some, but not all, botanicals purported to be immune stimulants had adjuvant activity in our model. PSK and astragalus were surprisingly active and are being further fractionated to identify the most active adjuvant components. PMID:18640165

  7. Inhibition of endogenous NGF degradation induces mechanical allodynia and thermal hyperalgesia in rats

    PubMed Central

    2013-01-01

    Background We have previously shown a sprouting of sympathetic fibers into the upper dermis of the skin following subcutaneous injection of complete Freund’s adjuvant (CFA) into the hindpaw. This sprouting correlated with an increase in pain-related sensitivity. We hypothesized that this sprouting and pain-related behavior were caused by an increase in nerve growth factor (NGF) levels. In this study, we investigated whether the inhibition of mature NGF degradation, using a matrix metalloproteinase 2 and 9 (MMP-2/9) inhibitor, was sufficient to reproduce a similar phenotype. Results Behavioral tests performed on male Sprague–Dawley rats at 1, 3, 7 and 14 days after intra-plantar MMP-2/9 inhibitor administration demonstrated that acute and chronic injections of the MMP-2/9 inhibitor induced sensitization, in a dose dependent manner, to mechanical, hot and cold stimuli as measured by von Frey filaments, Hargreaves and acetone tests, respectively. Moreover, the protein levels of mature NGF (mNGF) were increased, whereas the levels and enzymatic activity of matrix metalloproteinase 9 were reduced in the glabrous skin of the hind paw. MMP-2/9 inhibition also led to a robust sprouting of sympathetic fibers into the upper dermis but there were no changes in the density of peptidergic nociceptive afferents. Conclusions These findings indicate that localized MMP-2/9 inhibition provokes a pattern of sensitization and fiber sprouting comparable to that previously obtained following CFA injection. Accordingly, the modulation of endogenous NGF levels should be considered as a potential therapeutic target for the management of inflammatory pain associated with arthritis. PMID:23889761

  8. Mesoporous silica nanoparticles as antigen carriers and adjuvants for vaccine delivery

    NASA Astrophysics Data System (ADS)

    Mody, Karishma T.; Popat, Amirali; Mahony, Donna; Cavallaro, Antonino S.; Yu, Chengzhong; Mitter, Neena

    2013-05-01

    Vaccines have been at the forefront of improving human health for over two centuries. The challenges faced in developing effective vaccines flow from complexities associated with the immune system and requirement of an efficient and safe adjuvant to induce a strong adaptive immune response. Development of an efficient vaccine formulation requires careful selection of a potent antigen, efficient adjuvant and route of delivery. Adjuvants are immunological agents that activate the antigen presenting cells (APCs) and elicit a strong immune response. In the past decade, the use of mesoporous silica nanoparticles (MSNs) has gained significant attention as potential delivery vehicles for various biomolecules. In this review, we aim to highlight the potential of MSNs as vaccine delivery vehicles and their ability to act as adjuvants. We have provided an overview on the latest progress on synthesis, adsorption and release kinetics and biocompatibility of MSNs as next generation antigen carriers and adjuvants. A comprehensive summary on the ability of MSNs to deliver antigens and elicit both humoral and cellular immune responses is provided. Finally, we give insight on fundamental challenges and some future prospects of these nanoparticles as adjuvants.

  9. Flagellin A Toll-Like Receptor 5 Agonist as an Adjuvant in Chicken Vaccines

    PubMed Central

    Bajwa, Preety; Deb, Rajib; Chellappa, Madhan Mohan; Dey, Sohini

    2014-01-01

    Chicken raised under commercial conditions are vulnerable to environmental exposure to a number of pathogens. Therefore, regular vaccination of the flock is an absolute requirement to prevent the occurrence of infectious diseases. To combat infectious diseases, vaccines require inclusion of effective adjuvants that promote enhanced protection and do not cause any undesired adverse reaction when administered to birds along with the vaccine. With this perspective in mind, there is an increased need for effective better vaccine adjuvants. Efforts are being made to enhance vaccine efficacy by the use of suitable adjuvants, particularly Toll-like receptor (TLR)-based adjuvants. TLRs are among the types of pattern recognition receptors (PRRs) that recognize conserved pathogen molecules. A number of studies have documented the effectiveness of flagellin as an adjuvant as well as its ability to promote cytokine production by a range of innate immune cells. This minireview summarizes our current understanding of flagellin action, its role in inducing cytokine response in chicken cells, and the potential use of flagellin as well as its combination with other TLR ligands as an adjuvant in chicken vaccines. PMID:24451328

  10. Vaccine adjuvants--understanding molecular mechanisms to improve vaccines.

    PubMed

    Egli, Adrian; Santer, Deanna; Barakat, Khaled; Zand, Martin; Levin, Aviad; Vollmer, Madeleine; Weisser, Maja; Khanna, Nina; Kumar, Deepali; Tyrrell, Lorne; Houghton, Michael; Battegay, Manuel; O'Shea, Daire

    2014-01-01

    Infectious pathogens are responsible for high utilisation of healthcare resources globally. Attributable morbidity and mortality remains exceptionally high. Vaccines offer the potential to prime a pathogen-specific immune response and subsequently reduce disease burden. Routine vaccination has fundamentally altered the natural history of many frequently observed and serious infections. Vaccination is also recommended for persons at increased risk of severe vaccine-preventable disease. Many current nonadjuvanted vaccines are poorly effective in the elderly and immunocompromised populations, resulting in nonprotective postvaccine antibody titres, which serve as surrogate markers for protection. The vaccine-induced immune response is influenced by: (i.) vaccine factors i.e., type and composition of the antigen(s), (ii.) host factors i.e., genetic differences in immune-signalling or senescence, and (iii.) external factors such as immunosuppressive drugs or diseases. Adjuvanted vaccines offer the potential to compensate for a lack of stimulation and improve pathogen-specific protection. In this review we use influenza vaccine as a model in a discussion of the different mechanisms of action of the available adjuvants. In addition, we will appraise new approaches using "vaccine-omics" to discover novel types of adjuvants. PMID:24844935

  11. Optimization of physiological properties of hydroxyapatite as a vaccine adjuvant.

    PubMed

    Hayashi, Masayuki; Aoshi, Taiki; Kogai, Yasumichi; Nomi, Daisuke; Haseda, Yasunari; Kuroda, Etsushi; Kobiyama, Kouji; Ishii, Ken J

    2016-01-12

    Various particles such as Alum or silica are known to act as an adjuvant if co-administered with vaccine antigens. Several reports have demonstrated that the adjuvanticity is strongly affected by the physicochemical properties of particles such as the size, shape and surface charge, although the required properties and its relationship to the adjuvanticity are still controversial. Hydroxyapatite particle (HAp) composed of calcium phosphate has been shown to work as adjuvant in mice. However, the properties of HAp required for the adjuvanticity have not been fully characterized yet. In this study, we examined the role of size or shape of HAps in the antibody responses after immunization with antigen. HAps whose diameter ranging between 100 and 400 nm provided significantly higher antibody responses than smaller or larger ones. By comparison between sphere and rod shaped HAps, rod shaped HAps induced stronger inflammasome-dependent IL-1β production than the sphere shaped ones in vitro. However, sphere- and rod-shaped HAp elicited comparable antibody response in WT mice. Vice versa, Nlrp3(-/-), Asc(-/-) or Caspase1(-/-) mice provided comparable level of antibody responses to HAp adjuvanted vaccination. Collectively, our results demonstrated that the size rather than shape is a more critical property, and IL-1β production via NLRP3 inflammasome is dispensable for the adjuvanticity of HAps in mice. PMID:26667613

  12. [Development of Nucleic Acid-Based Adjuvant for Cancer Immunotherapy].

    PubMed

    Kobiyama, Kouji; Ishii, Ken J

    2015-09-01

    Since the discovery of the human T cell-defined tumor antigen, the cancer immunotherapy field has rapidly progressed, with the research and development of cancer immunotherapy, including cancer vaccines, being conducted actively. However, the disadvantages of most cancer vaccines include relatively weak immunogenicity and immune escape or exhaustion. Adjuvants with innate immunostimulatory activities have been used to overcome these issues, and these agents have been shown to enhance the immunogenicity of cancer vaccines and to act as mono-therapeutic anti-tumor agents. CpG ODN, an agonist for TLR9, is one of the promising nucleic acid-based adjuvants, and it is a potent inducer of innate immune effector functions. CpG ODN suppresses tumor growth in the absence of tumor antigens and peptide administration. Therefore, CpG ODN is expected to be useful as a cancer vaccine adjuvant as well as a cancer immunotherapy agent. In this review, we discuss the potential therapeutic applications and mechanisms of CpG ODN for cancer immunotherapy. PMID:26469159

  13. Freund's adjuvants: relationship of arthritogenicity and adjuvanticity in rats to vehicle composition

    PubMed Central

    Whitehouse, M. W.; Orr, K. J.; Beck, Frances W. J.; Pearson, C. M.

    1974-01-01

    Over a hundred compounds and natural materials were examined for their ability to induce arthritis in rats when mixed with heat-killed delipidated Mycobacteria tuberculosis. Many of these materials were also assessed for (CMI) adjuvant activity by their ability to induce allergic encephalomyelitis (EAE) in rats when mixed with guinea-pig spinal cord, both with and without added M. tuberculosis. Cyclization and/or the presence of oxygen atoms, or double bonds reduced (or abolished) the arthritogenic potential and adjuvanticity of alkanes>C10. Esters/triglycerides of fatty acids >C12, retinol acetate (not palmitate) and vitamins E and K showed co-arthritogenic and adjuvant activity. Other active lipids included squalene and cholesterol oleate, which are both present in human sebum. Sebaceous lipids may therefore perhaps function as natural adjuvants if resorbed during abrasion and infection. Squalane (perhydrosqualene), pristane and hexadecane were excellent substitutes for mineral oil in preparing arthritogenic adjuvants from various mycobacteria, C. rubrum and N. asteroides. These oily compounds were also very effective adjuvants per se, in the absence of bacterial material or emulsifier, for inducing EAE in Lewis rats. PMID:4214125

  14. Targeted vaccine adjuvants based on modified cholera toxin.

    PubMed

    Lycke, Nils

    2005-09-01

    The present review describes immunomodulation with targeted adjuvants that will allow for the development of efficacious mucosal vaccines. We have studied cholera toxin (CT) and derivatives thereof, to rationally design vaccine adjuvant vectors that are both highly efficacious as well as safe and non-toxic. Two strategies were exploited; the first using CT or the enzymatically inactive receptor-binding B-subunit of CT (CTB) and the second, using CTA1 or an enzymatically inactive mutant CTA1R7K., that was linked, in a fusion protein, to the B-cell targeting moiety, DD, from Staphylococcus areus proteinA. Our studies provide compelling evidence that delivery of Ag in the absence of ADP-ribosylation can promote tolerance, whereas, ADP-ribosyltransferase-active conjugates, prevent tolerance but induce IgA immunity. Our analysis revealed unique subsets of mucosal and systemic DC that appeared to be responsible for the ADP-ribosyltransferase sensitive dichotomy between tolerance and IgA immunity. Whether targeting of B cells suffice for tolerance-induction or requires participation of DCs, is at present an unresolved issue. Nevertheless, enzymatic modulation differentiates and matures the DC to promote CD4 T cell help for IgA B cell development. Ag-presentation in the absence of enzyme, as seen with CTA1R7K-DD, expands specific T cells to a similar extent as enzymatically active CTA1-DD, but fails to recruit help for germinal center expansion of activated B cells. We have given special attention to the genes that adjuvants turn on using Affymetrix technology. In particular, modulation of the expression of co-stimulatory molecules on the targeted APC; CD80, CD86, CD83 and B7RP-1, play important roles for the effect of the ADP-ribosylating CTA1-based adjuvants for the development of tolerance or active IgA immunity. PMID:16178769

  15. Early adjuvant radiotherapy in the treatment of atypical meningioma.

    PubMed

    Jenkinson, Michael D; Waqar, Mueez; Farah, Jibril Osman; Farrell, Michael; Barbagallo, Giuseppe M V; McManus, Robin; Looby, Seamus; Hussey, Deirdre; Fitzpatrick, David; Certo, Francesco; Javadpour, Mohsen

    2016-06-01

    Atypical meningiomas have a greater propensity to recur than benign meningiomas and the benefits of early adjuvant radiotherapy are unclear. Existing studies report conflicting results. This retrospective cohort study evaluated the role of early adjuvant radiotherapy following surgical resection of atypical meningioma. A triple center case-note review of adults with newly-diagnosed atypical meningiomas between 2001 and 2010 was performed. Pathology diagnosis was made according to the World Health Organization classification in use at the time of surgery. Patients with multiple meningiomas, neurofibromatosis type 2 and radiation-induced meningiomas were excluded. Extent of resection was defined as gross total resection (GTR; Simpson Grade I-III) or subtotal resection (STR; Simpson Grade IV-V). Survival analysis was performed using the Kaplan-Meier method. One hundred thirty-three patients were identified with a median age of 62years (range 22-86years) and median follow-up of 57.4months (range 0.1-152.2months). Tumors were mostly located in the convexity (50.4%) or falcine/parasagittal regions (27.1%). GTR (achieved in 85%) was associated with longer progression free survival (PFS) (5year PFS 81.2% versus 40.08%, log-rank=11.117, p=0.001) but not overall survival (OS) (5year OS 76.6% versus 39.7%, log-rank=3.652, p=0.056). Following GTR, early adjuvant radiotherapy was administered to 28.3% of patients and did not influence OS (5year OS 77.0% versus 75.7%, log-rank=0.075, p=0.784) or PFS (5year PFS 82.0% versus 79.3%, log-rank=0.059, p=0.808). Although extent of resection emerged as an important prognostic variable, early adjuvant radiotherapy did not influence outcome following GTR of atypical meningiomas. Prospective randomized controlled trials are planned. PMID:26775147

  16. Congenital Sensorineural Deafness in Australian Stumpy-Tail Cattle Dogs Is an Autosomal Recessive Trait That Maps to CFA10

    PubMed Central

    Sommerlad, Susan; McRae, Allan F.; McDonald, Brenda; Johnstone, Isobel; Cuttell, Leigh; Seddon, Jennifer M.; O'Leary, Caroline A.

    2010-01-01

    Background Congenital sensorineural deafness is an inherited condition found in many dog breeds, including Australian Stumpy-tail Cattle Dogs (ASCD). This deafness is evident in young pups and may affect one ear (unilateral) or both ears (bilateral). The genetic locus/loci involved is unknown for all dog breeds. The aims of this study were to determine incidence, inheritance mechanism, and possible association of congenital sensorineural deafness with coat colour in ASCD and to identify the genetic locus underpinning this disease. Methodology/Principal Findings A total of 315 ASCD were tested for sensorineural deafness using the brain stem auditory evoked response (BAER) test. Disease penetrance was estimated directly, using the ratio of unilaterally to bilaterally deaf dogs, and segregation analysis was performed using Mendel. A complete genome screen was undertaken using 325 microsatellites spread throughout the genome, on a pedigree of 50 BAER tested ASCD in which deafness was segregating. Fifty-six dogs (17.8%) were deaf, with 17 bilaterally and 39 unilaterally deaf. Unilaterally deaf dogs showed no significant left/right bias (p = 0.19) and no significant difference was observed in frequencies between the sexes (p = 0.18). Penetrance of deafness was estimated as 0.72. Testing the association of red/blue coat colour and deafness without accounting for pedigree structure showed that red dogs were 1.8 times more likely to be deaf (p = 0.045). The within family association between red/blue coat colour and deafness was strongly significant (p = 0.00036), with red coat colour segregating more frequently with deafness (COR = 0.48). The relationship between deafness and coat speckling approached significance (p = 0.07), with the lack of statistical significance possibly due to only four families co-segregating for both deafness and speckling. The deafness phenotype was mapped to CFA10 (maximum linkage peak on CFA10 −log10 p-value = 3

  17. ISCOMATRIX™ adjuvant reduces mucosal tolerance for effective pulmonary vaccination against influenza

    PubMed Central

    Timothy, Andrea A; Tokanovic, Ana; Snibson, Kenneth J; Edwards, Stirling J; Pearse, Martin J; Scheerlinck, Jean-Pierre Y; Sutton, Philip

    2015-01-01

    While most pathogens infect via mucosal surfaces, most current vaccines are delivered by injection. This situation remains despite awareness of the potential benefits of mucosal delivery for inducing protection against mucosa-infecting pathogens. A major obstacle to the development of such vaccines is the paucity of safe and effective adjuvants that induce mucosal responses in non-rodents. Previously we demonstrated in sheep the potency of pulmonary-delivered influenza ISCOMATRIX™ vaccine, which induces both mucosal and systemic immunity, even with low antigen doses. In the current study, lung pre-exposure to influenza antigen alone significantly reduced the immune response to subsequent pulmonary-delivered influenza ISCOMATRIX™ vaccine. A single dose of influenza antigen, delivered to the lung without exogenous adjuvant, upregulated IL-10 expression in bronchoalveolar lavage cells and FOXP3 expression in lung tissue, suggestive of induction of a regulatory T cell (Treg) response. However, this effect was inhibited by addition of ISCOMATRIX™ adjuvant. Moreover, effective pulmonary immunization with influenza ISCOMATRIX™ vaccine was associated with a depletion of Treg markers within lung tissues. Lung exposure to influenza antigen induced a localized mucosal tolerance that reduced the efficacy of subsequent influenza ISCOMATRIX™ vaccination. An important role of ISCOMATRIX™ adjuvant in pulmonary vaccination appears to be the depletion of Treg in lung tissues. Pulmonary vaccination remains capable of inducing a strong immune response against mucosal pathogens, but likely requires an adjuvant to overcome mucosal tolerance. ISCOMATRIX™ appears to have considerable potential as a mucosal adjuvant for use in humans, a major unmet need in mucosal vaccine development. PMID:25692970

  18. Mechanisms of aluminum adjuvant toxicity and autoimmunity in pediatric populations.

    PubMed

    Tomljenovic, L; Shaw, C A

    2012-02-01

    Immune challenges during early development, including those vaccine-induced, can lead to permanent detrimental alterations of the brain and immune function. Experimental evidence also shows that simultaneous administration of as little as two to three immune adjuvants can overcome genetic resistance to autoimmunity. In some developed countries, by the time children are 4 to 6 years old, they will have received a total of 126 antigenic compounds along with high amounts of aluminum (Al) adjuvants through routine vaccinations. According to the US Food and Drug Administration, safety assessments for vaccines have often not included appropriate toxicity studies because vaccines have not been viewed as inherently toxic. Taken together, these observations raise plausible concerns about the overall safety of current childhood vaccination programs. When assessing adjuvant toxicity in children, several key points ought to be considered: (i) infants and children should not be viewed as "small adults" with regard to toxicological risk as their unique physiology makes them much more vulnerable to toxic insults; (ii) in adult humans Al vaccine adjuvants have been linked to a variety of serious autoimmune and inflammatory conditions (i.e., "ASIA"), yet children are regularly exposed to much higher amounts of Al from vaccines than adults; (iii) it is often assumed that peripheral immune responses do not affect brain function. However, it is now clearly established that there is a bidirectional neuro-immune cross-talk that plays crucial roles in immunoregulation as well as brain function. In turn, perturbations of the neuro-immune axis have been demonstrated in many autoimmune diseases encompassed in "ASIA" and are thought to be driven by a hyperactive immune response; and (iv) the same components of the neuro-immune axis that play key roles in brain development and immune function are heavily targeted by Al adjuvants. In summary, research evidence shows that increasing concerns

  19. Co-adjuvant effects of plant polysaccharide and propolis on chickens inoculated with Bordetella avium inactivated vaccine.

    PubMed

    Yang, Ya; Wei, Kai; Yang, Shifa; Li, Bing; Zhang, Yongbing; Zhu, Fujie; Wang, Di; Chi, Shanshan; Jiang, Xiaodong; Zhu, Ruiliang

    2015-01-01

    Taishan Pinus massoniana pollen polysaccharide (TPPPS), propolis (PP) and aloe polysaccharide (AP), used as adjuvants, have been proven to possess immunity-enhancing functions. However, their collaborative immunomodulatory effects are largely unknown. To determine which combination can induce the best effects, the three adjuvants were separately or conjointly added into Bordetella avium inactivated vaccines to investigate their co-adjuvant effects on vaccinated chickens. We found that, among all six adjuvant-treated vaccine inoculated groups (TPPPS, PP, AP, TPPPS-PP, PP-AP and TPPPS-AP), the chickens inoculated with TPPPS, PP or TPPPS-PP adjuvant vaccines showed significantly higher levels of antibody titre, cytokine, lymphocyte transformation and peripheral blood T-lymphocyte count than those of non-adjuvant vaccine inoculated groups (P < 0.05), indicating the good immune-enhancing effects of TPPPS and PP. The TPPPS-PP group showed the highest levels of antibody titres and interleukin-2 (IL-2) at 14-28 days post the first inoculation (dpi), lymphocyte transformation rates (LTRs) at 14-35 dpi, CD4(+) T-lymphocyte counts at 14-42 dpi, and CD8(+) T-lymphocyte counts at 28 dpi. The results revealed that B. avium inactivated vaccine used conjointly with TPPPS and PP induced the strongest humoral and cellular immune responses. Thus, there was a synergistic effect between TPPPS and PP on enhancing immunity, which suggests that they can be used as a novel adjuvant formulation for the development of poultry vaccines. PMID:25989924

  20. Extended Adjuvant Therapy for Breast Cancer

    Cancer.gov

    An NCI Cancer Currents blog on findings from a recent clinical trial which showed that extending adjuvant therapy with an aromatase inhibitor can have important benefits for some women with early-stage cancer.

  1. Adjuvant Bisphosphonates for Postmenopausal Breast Cancer

    Cancer.gov

    A summary of a meta-analysis of randomized trials of bisphosphonates as adjuvant therapy for women with early-stage breast cancer that shows the drugs can reduce the rate of disease recurrence in bone.

  2. [Rectal cancer and adjuvant chemotherapy: which conclusions?].

    PubMed

    Bachet, J-B; Rougier, P; de Gramont, A; André, T

    2010-01-01

    Adenocarcinoma of the rectum represents about a third of cases of colorectal cancer, with an annual incidence of 12,000 cases in France. On the contrary of colon cancer, the benefice of adjuvant chemotherapy in rectal cancer has not been definitively proved, more because this question was assessed in few recent studies than because negative results. Preoperative radiochemotherapy is now the reference treatment for mid and lower rectal cancers, and allow to increase the local control without improvement of progression free survival and overall survival. The data of the "historical studies" of adjuvant treatment in rectal cancer published before 1990, of the meta-analysis of adjuvant trials in rectal cancer and of the QUASAR study suggest that adjuvant chemotherapy with fluoropyrimidines (intravenous or oral), in absence of pre-operative treatment, decrease the risk of metastatic relapse after curative surgery for a rectal cancer of stage II or III. This benefice seems similar to the one observed in colon cancer. In the EORTC radiotherapy group trial 22921, an adjuvant chemotherapy with 5-fluorouracil and low dose of leucovorin was not associated with a significantly improvement of overall survival but, despite the fact that only 42.9% of patients received all planed cycles, the progression free survival was increased (not significantly) in groups receiving adjuvant chemotherapy. The French recommendations are to discuss the indication of adjuvant chemotherapy by fluoropyrimidines in cases of stage III rectal cancer on histopathologic reports and no chemotherapy in case of stade II. Despite the fact that none study have assessed a combination of fluoropyrimidines and oxaliplatin in adjuvant setting in rectal cancer, like in colon cancer, the Folfox4, modified Folfox6 or Xelox regimens are valid options in stage III (experts opinion). In cases of pathologic complete remission or in absence of involved nodes, the benefice of adjuvant chemotherapy is not assessed. In

  3. A novel locus for canine osteosarcoma (OSA1) maps to CFA34, the canine orthologue of human 3q26.

    PubMed

    Phillips, Jeffrey C; Lembcke, Luis; Chamberlin, Tamara

    2010-10-01

    Spontaneous tumors in dogs share many of the same features of their human orthologues including clinical behavior, response to treatment, and molecular defects. It is therefore natural to consider the use of dogs and their spontaneous malignancies in the study of complex disease such as cancer. Scottish Deerhounds are a giant breed of dogs that exhibit a high incidence of bone cancer. Our previous work suggested that osteosarcoma within this breed could be explained by the presence of a major gene of dominant effect. Herein, we use a whole genome mapping approach to evaluate a four-generation pedigree of Scottish Deerhounds for linkage of their osteosarcoma phenotype. Using this approach we found evidence of linkage (Z(max)=5.766) between their phenotype and markers located on CFA34, in a region syntenic to human chromosome 3q26. The identification of this locus provides novel insight into the genetic basis of osteosarcoma in both canines and humans. PMID:20647041

  4. Local innate immune responses in the vaccine adjuvant-injected muscle.

    PubMed

    Liang, Frank; Loré, Karin

    2016-04-01

    Inducing a high magnitude of antibodies, possibly in combination with T-cell responses that offer epitope breadth over prolonged periods of time is likely a prerequisite for effective vaccines against severe diseases such as HIV-1 infection, malaria and tuberculosis. A much better understanding of the innate immune mechanisms that are critical for inducing desired responses to vaccination would help in the design of novel vaccines. The majority of human vaccines are administered into the muscle. In this brief review, we focus on the initial innate immune events that occur locally at the site of intramuscular vaccine delivery, and how they are influenced by clinically approved vaccine adjuvants. In particular, the effects on cell mobilization, cell activation and vaccine antigen uptake are reviewed. Understanding how distinct adjuvants enhance and tailor vaccine responses would facilitate the selection of the best-suited adjuvant to improve vaccine efficacy to a given pathogen. PMID:27195117

  5. Local innate immune responses in the vaccine adjuvant-injected muscle

    PubMed Central

    Liang, Frank; Loré, Karin

    2016-01-01

    Inducing a high magnitude of antibodies, possibly in combination with T-cell responses that offer epitope breadth over prolonged periods of time is likely a prerequisite for effective vaccines against severe diseases such as HIV-1 infection, malaria and tuberculosis. A much better understanding of the innate immune mechanisms that are critical for inducing desired responses to vaccination would help in the design of novel vaccines. The majority of human vaccines are administered into the muscle. In this brief review, we focus on the initial innate immune events that occur locally at the site of intramuscular vaccine delivery, and how they are influenced by clinically approved vaccine adjuvants. In particular, the effects on cell mobilization, cell activation and vaccine antigen uptake are reviewed. Understanding how distinct adjuvants enhance and tailor vaccine responses would facilitate the selection of the best-suited adjuvant to improve vaccine efficacy to a given pathogen. PMID:27195117

  6. In silico identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination.

    PubMed

    Bayry, Jagadeesh; Tchilian, Elma Z; Davies, Matthew N; Forbes, Emily K; Draper, Simon J; Kaveri, Srini V; Hill, Adrian V S; Kazatchkine, Michel D; Beverley, Peter C L; Flower, Darren R; Tough, David F

    2008-07-22

    Adjuvants are substances that enhance immune responses and thus improve the efficacy of vaccination. Few adjuvants are available for use in humans, and the one that is most commonly used (alum) often induces suboptimal immunity for protection against many pathogens. There is thus an obvious need to develop new and improved adjuvants. We have therefore taken an approach to adjuvant discovery that uses in silico modeling and structure-based drug-design. As proof-of-principle we chose to target the interaction of the chemokines CCL22 and CCL17 with their receptor CCR4. CCR4 was posited as an adjuvant target based on its expression on CD4(+)CD25(+) regulatory T cells (Tregs), which negatively regulate immune responses induced by dendritic cells (DC), whereas CCL17 and CCL22 are chemotactic agents produced by DC, which are crucial in promoting contact between DC and CCR4(+) T cells. Molecules identified by virtual screening and molecular docking as CCR4 antagonists were able to block CCL22- and CCL17-mediated recruitment of human Tregs and Th2 cells. Furthermore, CCR4 antagonists enhanced DC-mediated human CD4(+) T cell proliferation in an in vitro immune response model and amplified cellular and humoral immune responses in vivo in experimental models when injected in combination with either Modified Vaccinia Ankara expressing Ag85A from Mycobacterium tuberculosis (MVA85A) or recombinant hepatitis B virus surface antigen (rHBsAg) vaccines. The significant adjuvant activity observed provides good evidence supporting our hypothesis that CCR4 is a viable target for rational adjuvant design. PMID:18621704

  7. Toxicity and occupational health hazards of coal fly ash (CFA). A review of data and comparison to coal mine dust.

    PubMed

    Borm, P J

    1997-12-01

    Coal fly ashes (CFA) are complex particles of a variable composition, which is mainly dependent on the combustion process, the source of coal and the precipitation technique. Toxic constituents in these particles are considered to be metals, polycyclic aromatic hydrocarbons and silica. The purpose of this review was to study the in vitro and in vivo data on coal fly ash and relate the studied endpoints to the role of (crystalline) silica, considering its recent classification as a human carcinogen. For most of the effects coal mine dust was chosen as a reference, since it contains up to 10% of crystalline silica (alpha-quartz) and is well studied both in vivo and in vitro. Most studies on fly ash toxicity were not designed to elucidate the effect of its silica-content nor did they include coal mine dust as a reference. Taking this into account, both in vitro and in vivo experimental studies show lower toxicity, inflammatory potential and fibrogenicity of CFA compared to silica and coal mine dust. Although in vitro and in vivo studies suggest genotoxic effects of fly ash, the data are limited and do not clarify the role of silica. Epidemiological studies in fly ash exposed working populations have found no evidence for effects commonly seen in coal workers (pneumoconiosis, emphysema) with the exception of airway obstruction at high exposure. In conclusion, the available data suggest that the hazard of coal fly ash is not to be assessed by merely adding the hazards of individual components. A closer investigation of 'matrix' effects on silica's toxicity in general seems an obligatory step in future risk assessment on fly ashes and other particles that incorporate silica as a component. PMID:9375525

  8. Experimental modulation of the reactivity of pleural milky spots (Kampmeier's foci) by Freund's adjuvants, betamethasone and mycobacterial infection.

    PubMed Central

    Pereira, A de D; Aguas, A P; Oliveira, M J; Cabral, J M; Grande, N R

    1994-01-01

    We studied the response of milky spots in the parietal pleura of the rat and mouse to intrapleural instillation of immunomodulatory agents such as complete or incomplete Freund's adjuvants and betamethasone, and also to infection by mycobacteria (M. avium). Both incomplete (mineral oil) and complete (mineral oil plus dead mycobacteria) adjuvants, as well as M. avium infection, induced a striking increase in the size and cellularity of the pleural milky spots whereas betamethasone caused a slight atrophy. The extensive inflammatory infiltrates observed after adjuvant injection differed between milky spots reactive to complete and incomplete Freund's adjuvants. Fifteen days after adjuvant administration, the pleural milky spots of rats were still enlarged and hypercellular but differences were noted in the size of milky spots of the pleura between the 2 adjuvant treatments: animals submitted to injection of complete Freund's adjuvant showed an increase in the size of milky spots from d 3 to d 15, while the size of milky spots of the incomplete Freund's adjuvant treated group showed a decrease in size from d 3 to d 15. The milky spots at d 15 were well organised: reticulin fibres permeated the whole area of the milky spot and the different cell types were evenly distributed. Histiocytes, which were previously confined to the inner layer, were now the main cell type in all areas of milky spots. A moderate number of mast cells and a few eosinophils were also seen. Complete Freund's adjuvant caused the formation of granulomas in the milky spots, a change that was not detected in animals treated with incomplete adjuvant.(ABSTRACT TRUNCATED AT 250 WORDS) Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 PMID:7649783

  9. Applications of nanomaterials as vaccine adjuvants

    PubMed Central

    Zhu, Motao; Wang, Rongfu; Nie, Guangjun

    2014-01-01

    Vaccine adjuvants are applied to amplify the recipient's specific immune responses against pathogen infection or malignancy. A new generation of adjuvants is being developed to meet the demands for more potent antigen-specific responses, specific types of immune responses, and a high margin of safety. Nanotechnology provides a multifunctional stage for the integration of desired adjuvant activities performed by the building blocks of tailor-designed nanoparticles. Using nanomaterials for antigen delivery can provide high bioavailability, sustained and controlled release profiles, and targeting and imaging properties resulting from manipulation of the nanomaterials’ physicochemical properties. Moreover, the inherent immune-regulating activity of particular nanomaterials can further promote and shape the cellular and humoral immune responses toward desired types. The combination of both the delivery function and immunomodulatory effect of nanomaterials as adjuvants is thought to largely benefit the immune outcomes of vaccination. In this review, we will address the current achievements of nanotechnology in the development of novel adjuvants. The potential mechanisms by which nanomaterials impact the immune responses to a vaccine and how physicochemical properties, including size, surface charge and surface modification, impact their resulting immunological outcomes will be discussed. This review aims to provide concentrated information to promote new insights for the development of novel vaccine adjuvants. PMID:25483497

  10. Adjuvant activity of CpG-ODN formulated as a liquid crystal.

    PubMed

    Sánchez Vallecillo, María F; Ullio Gamboa, Gabriela V; Palma, Santiago D; Harman, María F; Chiodetti, Ana L; Morón, Gabriel; Allemandi, Daniel A; Pistoresi-Palencia, María C; Maletto, Belkys A

    2014-03-01

    The adjuvants approved in human vaccine with recombinant/purified antigens induce weak cellular immune response and so the development of new adjuvant strategies is critical. CpG-ODN has successfully been used as an adjuvant (phase I-III clinical trials) but its bioavailability needs to be improved. We investigated the adjuvant ability of CpG-ODN formulated with a liquid crystal nanostructure of 6-O-ascorbyl palmitate (Coa-ASC16). Mice immunized with OVA/CpG-ODN/Coa-ASC16 elicited a potent specific IgG1, IgG2a, Th1 and Th17 cellular response without systemic adverse effects. These responses were superior to those induced by OVA/CpG-ODN (solution of OVA with CpG-ODN) and to those induced by the formulation OVA/CpG-ODN/Al(OH)3. Immunization with OVA/CpG-ODN/Coa-ASC16 resulted in a long-lasting cell-mediated immune response (at least 6.5 months). Furthermore, Coa-ASC16 alone allows a controlled release of CpG-ODN in vitro and induces local inflammatory response, independent of TLR4 signaling, characterized by an influx of neutrophils and Ly6C(high) monocytes and pro-inflammatory cytokines. Remarkably, the adjuvant capacity of CpG-ODN co-injected with Coa-ASC16 (OVA/CpG-ODN plus Coa-ASC16) was similar to the adjuvant activity of OVA/CpG-ODN, supporting the requirement for whole formulation to help CpG-ODN adjuvanticity. These results show the potential of this formulation, opening a new avenue for the development of better vaccines. PMID:24382332

  11. Exercise as an Adjuvant Therapy for Hematopoietic Stem Cell Mobilization

    PubMed Central

    Emmons, Russell; Niemiro, Grace M.; De Lisio, Michael

    2016-01-01

    Hematopoietic stem cell transplant (HSCT) using mobilized peripheral blood hematopoietic stem cells (HSPCs) is the only curative strategy for many patients suffering from hematological malignancies. HSPC collection protocols rely on pharmacological agents to mobilize HSPCs to peripheral blood. Limitations including variable donor responses and long dosing protocols merit further investigations into adjuvant therapies to enhance the efficiency of HSPCs collection. Exercise, a safe and feasible intervention in patients undergoing HSCT, has been previously shown to robustly stimulate HSPC mobilization from the bone marrow. Exercise-induced HSPC mobilization is transient limiting its current clinical potential. Thus, a deeper investigation of the mechanisms responsible for exercise-induced HSPC mobilization and the factors responsible for removal of HSPCs from circulation following exercise is warranted. The present review will describe current research on exercise and HSPC mobilization, outline the potential mechanisms responsible for exercise-induced HSPC mobilization, and highlight potential sites for HSPC homing following exercise. We also outline current barriers to the implementation of exercise as an adjuvant therapy for HSPC mobilization and suggest potential strategies to overcome these barriers. PMID:27123008

  12. Formulation, High Throughput In Vitro Screening and In Vivo Functional Characterization of Nanoemulsion-Based Intranasal Vaccine Adjuvants

    PubMed Central

    Wong, Pamela T.; Leroueil, Pascale R.; Smith, Douglas M.; Ciotti, Susan; Bielinska, Anna U.; Janczak, Katarzyna W.; Mullen, Catherine H.; Groom, Jeffrey V.; Taylor, Erin M.; Passmore, Crystal; Makidon, Paul E.; O’Konek, Jessica J.; Myc, Andrzej; Hamouda, Tarek; Baker, James R.

    2015-01-01

    Vaccine adjuvants have been reported to induce both mucosal and systemic immunity when applied to mucosal surfaces and this dual response appears important for protection against certain pathogens. Despite the potential advantages, however, no mucosal adjuvants are currently approved for human use. Evaluating compounds as mucosal adjuvants is a slow and costly process due to the need for lengthy animal immunogenicity studies. We have constructed a library of 112 intranasal adjuvant candidate formulations consisting of oil-in-water nanoemulsions that contain various cationic and nonionic surfactants. To facilitate adjuvant development we first evaluated this library in a series of high-throughput, in vitro assays for activities associated with innate and adaptive immune activation in vivo. These in vitro assays screened for the ability of the adjuvant to bind to mucin, induce cytotoxicity, facilitate antigen uptake in epithelial and dendritic cells, and activate cellular pathways. We then sought to determine how these parameters related to adjuvant activity in vivo. While the in vitro assays alone were not enough to predict the in vivo adjuvant activity completely, several interesting relationships were found with immune responses in mice. Furthermore, by varying the physicochemical properties of the surfactant components (charge, surfactant polar head size and hydrophobicity) and the surfactant blend ratio of the formulations, the strength and type of the immune response generated (TH1, TH2, TH17) could be modulated. These findings suggest the possibility of using high-throughput screens to aid in the design of custom adjuvants with unique immunological profiles to match specific mucosal vaccine applications. PMID:25962136

  13. Increased ability to induce long-term potentiation of spinal dorsal horn neurones in monoarthritic rats.

    PubMed

    Vikman, Kristina S; Duggan, Arthur W; Siddall, Philip J

    2003-11-14

    Long-term potentiation (LTP) of transmission of impulses in unmyelinated (C-fibre) primary afferents by prior tetanic conditioning stimulation has been demonstrated in the dorsal horn of the spinal cord. Since this potentiation has been proposed to be relevant to the increased responsiveness of spinal neurones associated with peripheral inflammation (central sensitisation), the present experiments compared the induction of LTP in normal rats and rats with monoarthritis. Monoarthritis was induced by injection of complete Freund's adjuvant (CFA) into the left ankle joint of 12 rats. All animals showed behavioural signs of thermal hyperalgesia and were used for electrophysiological experiments after 4-8 days. In each animal, extracellular recordings were obtained from a single, wide dynamic range (WDR) dorsal horn neurone. High frequency tetanic conditioning stimulation of the sciatic nerve gave varying effects on the C-fibre-evoked responses of neurones in the normal rats, with potentiation in two, no change in five and a depression in five. By contrast, conditioning stimulation in rats with inflammation produced a long-lasting potentiation of C-fibre-evoked responses in 11 out of 12 neurones, with no effect in one. The ease with which LTP was induced in animals with inflammation supports the proposal that the underlying mechanisms of LTP are similar to those of the central sensitisation associated with peripheral inflammation. PMID:14568329

  14. Adjuvant effects of saponins on animal immune responses*

    PubMed Central

    Rajput, Zahid Iqbal; Hu, Song-hua; Xiao, Chen-wen; Arijo, Abdullah G.

    2007-01-01

    Vaccines require optimal adjuvants including immunopotentiator and delivery systems to offer long term protection from infectious diseases in animals and man. Initially it was believed that adjuvants are responsible for promoting strong and sustainable antibody responses. Now it has been shown that adjuvants influence the isotype and avidity of antibody and also affect the properties of cell-mediated immunity. Mostly oil emulsions, lipopolysaccharides, polymers, saponins, liposomes, cytokines, ISCOMs (immunostimulating complexes), Freund’s complete adjuvant, Freund’s incomplete adjuvant, alums, bacterial toxins etc., are common adjuvants under investigation. Saponin based adjuvants have the ability to stimulate the cell mediated immune system as well as to enhance antibody production and have the advantage that only a low dose is needed for adjuvant activity. In the present study the importance of adjuvants, their role and the effect of saponin in immune system is reviewed. PMID:17323426

  15. RLJ-NE-299A: a new plant based vaccine adjuvant.

    PubMed

    Khajuria, Anamika; Gupta, Amit; Singh, Surjeet; Malik, Fayaz; Singh, Jaswant; Suri, K A; Satti, N K; Qazi, G N; Srinivas, V K; Gopinathan; Ella, Krishna

    2007-03-30

    Alum has been in use since long as an adjuvant for vaccines. However, its use as a vaccine adjuvant offers limitation in supporting cell mediated response. Therefore, a new plant based product RLJ-NE-299A from Picrorhiza kurroa reported for its immunostimulatory activity, has been explored for its potential as an alternative adjuvant. In order to compare the adjuvant activity with alum, antigen-specific immune responses were evaluated following immunization with a formulation containing hepatitis B surface antigen (HBsAg) adjuvanted with RLJ-NE-299A and alum in mice. The adjuvant RLJ-NE-299A up-regulated remarkably the expression of Th1 cytokines IL-2, IL-12, IFN-gamma, TNF alpha and Th2 cytokine IL-4 in lymph node cell cultures after 2 weeks of primary immunization with HBsAg. Further, the levels of both immunoglobulins IgG2a (Th1) and IgG1 (Th2) subtypes increased profoundly in blood sera of mice immunized with HBsAg/RLJ-NE-299A. The results indicated that RLJ-NE-299A has strong potential to increase both cell mediated and humoral immune responses and is capable of sustaining the total antigen-specific antibody response. Besides, the RLJ-NE-299A provides a signal to gear up both CD4 helper cells (Th1 and Th2) and CD8 cells populations, which may have important implications for vaccination against hepatitis B virus. Variable doses of RLJ-NE-299A (0.312-40 microg) containing vaccine antigen (HBsAg) were well tolerated with optimum T cell response at 2.5 microg/ml. Not only this, the adjuvant was also able to induce cellular immune responses to HBsAg as evidenced by Th1 and Th2 cytokines upregulation, which enabled mice to overcome the unresponsiveness to antigen HBsAg encountered with alum-adjuvanted vaccine in otherwise non-responding mice population. The study presents evidence that the HPLC standardized fraction RLJ-NE-299A, is an adjuvant of choice over alum in improving and maintaining the improved immune status against HBsAg, and may also prove useful

  16. Montanide ISA 71 VG is Advantageous to Freund's Adjuvant in Immunization Against S. aureus Infection of Mice.

    PubMed

    Klimka, A; Michels, L; Glowalla, E; Tosetti, B; Krönke, M; Krut, O

    2015-05-01

    The enormous capacity of Staphylococcus aureus to acquire antibiotic resistance makes it a permanent task to search for and to develop new anti-infectives. One of the possible approaches is the early active immunization of risk patients and animal stocks to prevent S. aureus infections. Based on a S. aureus proteome screen with S. aureus-specific human antiserum, we have previously identified several anchorless cell wall proteins to be used as novel vaccine candidates. To develop an efficient anti-S. aureus vaccine, the supplemented adjuvants Montanide(™) ISA 71 VG and ISA 206 were compared to Freund's adjuvant in terms of handling, induction of cytokine profile, triggering antigen-specific immunoglobulin production of different IgG subclasses and provision of increased survival rates in our S. aureus sepsis mouse model. Immunization with ISA 71 VG in comparison with Freund's adjuvant induced slightly delayed but comparably strong increase of antigen-specific antibody titres and conferred protective effect against S. aureus challenge. In contrast using ISA 206 as adjuvant, significantly lower IgG titres and consequently, no protective effect against S. aureus infection were observed. Handling and tolerability of the Montanide is superior to Freund's adjuvant. Montanide(™) ISA 71 VG can serve as an effective adjuvant replacement for Freund's adjuvant in research with a prospective usage in animal and human vaccines against bacterial pathogens. PMID:25689117

  17. Reduced MyD88 dependency of ISCOMATRIX™ adjuvant in a DNA prime-protein boost HIV vaccine

    PubMed Central

    Buglione-Corbett, Rachel; Pouliot, Kimberly; Marty-Roix, Robyn; Li, Wei; West, Kim; Wang, Shixia; Morelli, Adriana Baz; Lien, Egil; Lu, Shan

    2014-01-01

    ISCOMATRIX™ adjuvant is an integrated adjuvant system due to its ability to both facilitate antigen delivery and immunomodulate the innate and adaptive immune responses to vaccination. ISCOMATRIX™ adjuvant strongly induces both humoral and cell-mediated immunity in formulation with a range of antigens in pre-clinical and clinical evaluations. In this study, we describe the adaptive and innate immune responses associated with ISCOMATRIX™ adjuvant in the context of a previously described HIV-1 vaccine, DP6-001. The DP6-001 vaccine consists of a unique pentavalent HIV-1 Env DNA prime-protein boost regimen. This study demonstrates the potent induction of vaccine-specific antibodies in a mouse model, as well as broadly neutralizing antibodies in immunized rabbits. In addition, we identify a potentially critical role for DNA priming in the induction of the vaccine-specific immune response as well as the serum cytokine profiles associated with ISCOMATRIX™ adjuvant. Most interestingly, DNA prime immunizations made ISCOMATRIX™ adjuvant less dependent on the central innate immune adaptor MyD88, revealing a previously unknown mechanism that may expand our knowledge on the use of adjuvants. PMID:24513632

  18. Evaluation of Montanide ISA 71 VG adjuvant during profilin vaccination against experimental coccidiosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chickens were immunized subcutaneously with an Eimeria recombinant profilin protein plus ISA 70 VG (ISA 70) or ISA 71 VG (ISA 71) water-in-oil adjuvants, or with profilin alone, and comparative RNA microarray hybridizations were performed to ascertain global transcriptome changes induced by profilin...

  19. Synthetic Self-Adjuvanting Glycopeptide Cancer Vaccines

    NASA Astrophysics Data System (ADS)

    Payne, Richard; McDonald, David; Byrne, Scott

    2015-10-01

    Due to changes in glycosyltransferase expression during tumorigenesis, the glycoproteins of cancer cells often carry highly truncated carbohydrate chains compared to those on healthy cells. These glycans are known as tumor-associated carbohydrate antigens, and are prime targets for use in vaccines for the prevention and treatment of cancer. Herein, we review the state-of-the-art in targeting the immune system towards tumor-associated glycopeptide antigens via synthetic self adjuvanting vaccines, in which the antigenic and adjuvanting moieties of the vaccines are present in the same molecule. The majority of the self-adjuvanting glycopeptide cancer vaccines reported to date employ antigens from mucin 1, a protein which is highly over-expressed and aberrantly glycosylated in many forms of cancer. The adjuvants used in these vaccines predominantly include lipopeptide- or lipoamino acid-based TLR2 agonists, although studies investigating stimulation of TLR9 and TLR4 are also discussed. Most of these adjuvants are highly lipophilic, and, upon conjugation to antigenic peptides, provide amphiphilic vaccine molecules. The amphiphilic nature of these vaccine constructs can lead to the formation of higher-order structures by vaccines in solution, which are likely to be important for their efficacy in vivo.

  20. Beyond antigens and adjuvants: formulating future vaccines.

    PubMed

    Moyer, Tyson J; Zmolek, Andrew C; Irvine, Darrell J

    2016-03-01

    The need to optimize vaccine potency while minimizing toxicity in healthy recipients has motivated studies of the formulation of vaccines to control how, when, and where antigens and adjuvants encounter immune cells and other cells/tissues following administration. An effective subunit vaccine must traffic to lymph nodes (LNs), activate both the innate and adaptive arms of the immune system, and persist for a sufficient time to promote a mature immune response. Here, we review approaches to tailor these three aspects of vaccine function through optimized formulations. Traditional vaccine adjuvants activate innate immune cells, promote cell-mediated transport of antigen to lymphoid tissues, and promote antigen retention in LNs. Recent studies using nanoparticles and other lymphatic-targeting strategies suggest that direct targeting of antigens and adjuvant compounds to LNs can also enhance vaccine potency without sacrificing safety. The use of formulations to regulate biodistribution and promote antigen and inflammatory cue co-uptake in immune cells may be important for next-generation molecular adjuvants. Finally, strategies to program vaccine kinetics through novel formulation and delivery strategies provide another means to enhance immune responses independent of the choice of adjuvant. These technologies offer the prospect of enhanced efficacy while maintaining high safety profiles necessary for successful vaccines. PMID:26928033

  1. Systemic adjuvant therapies in renal cell carcinoma.

    PubMed

    Buti, Sebastiano; Bersanelli, Melissa; Donini, Maddalena; Ardizzoni, Andrea

    2012-10-01

    Renal cell carcinoma (RCC) is one of the ten most frequent solid tumors worldwide. Recent innovations in the treatment of metastatic disease have led to new therapeutic approaches being investigated in the adjuvant setting. Observation is the only current standard of care after radical nephrectomy, although there is evidence of efficacy of adjuvant use of vaccine among all the strategies used. This article aims to collect published experiences with systemic adjuvant approaches in RCC and to describe the results of past and ongoing phase III clinical trials in this field. We explored all the systemic treatments, including chemotherapy, immunotherapy and targeted drugs while alternative approaches have also been described. Appropriate selection of patients who would benefit from adjuvant therapies remains a crucial dilemma. Although the international guidelines do not actually recommend any adjuvant treatment after radical surgery for RCC, no conclusions have yet been drawn pending the results of the promising ongoing clinical trials with the target therapies. The significant changes that these new drugs have made on advanced disease outcome could represent the key to innovation in terms of preventing recurrence, delaying relapse and prolonging survival after radical surgery for RCC. PMID:25992216

  2. CpG DNA as mucosal adjuvant.

    PubMed

    McCluskie, M J; Davis, H L

    1999-09-01

    We have previously found synthetic oligodeoxynucleotides (ODN) containing immunostimulatory CpG motifs to be a potent adjuvant to protein administered by intramuscular injection or intranasal inhalation to BALB/c mice. Herein we have further evaluated the potential of CpG ODN as a mucosal adjuvant to purified hepatitis B surface antigen (HBsAg) when administered alone or with cholera toxin (CT). CpG ODN and CT both augmented systemic (humoral and cellular) and mucosal immune responses against HBsAg, and these could be further enhanced with higher doses of adjuvant or boosting. Overall, antibody isotypes with CT alone were predominantly IgG1 (Th2-like) whereas they were predominantly IgG2a (Th1-like) with CpG ODN alone or in combination with CT. Results from this study indicate that stimulatory CpG ODN are promising new adjuvants for mucosal vaccination strategies, whether used alone or in combination with other mucosal adjuvants. PMID:10506647

  3. Clinical evaluation of CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases and cancer.

    PubMed

    Scheiermann, Julia; Klinman, Dennis M

    2014-11-12

    Synthetic oligonucleotides (ODN) that express unmethylated "CpG motifs" trigger cells that express Toll-like receptor 9. In humans this includes plasmacytoid dendritic cells and B cells. CpG ODN induce an innate immune response characterized by the production of Th1 and pro-inflammatory cytokines. Their utility as vaccine adjuvants was evaluated in a number of clinical trials. Results indicate that CpG ODN improve antigen presentation and the generation of vaccine-specific cellular and humoral responses. This work provides an up-to-date overview of the utility of CpG ODN as adjuvants for vaccines targeting infectious agents and cancer. PMID:24975812

  4. Public health implications of contamination of Franc CFA (XAF) circulating in Buea (Cameroon) with drug resistant pathogens

    PubMed Central

    2014-01-01

    Background Studies in different parts of the world have implicated money as a vehicle for transmission of pathogens. Such information which is necessary to facilitate infection control strategies is lacking in many sub-Saharan countries including Cameroon. This study analyzed the Franc de la Communauté Financiere d’Afrique (Franc CFA), the currency used in Cameroon and other countries in the Central African sub-region, as a potential vehicle for transmission of pathogenic bacteria and fungi, particularly drug-resistant strains, to generate findings which could create awareness on currency contamination and serve as a guide when formulating health policies on currency. Methods Two hundred and thirteen currency samples representing various denominations of notes and coins randomly collected from diverse sources in Buea, Cameroon were analyzed for bacteria and fungi. The sensitivity of bacterial isolates to antibiotics was tested using the disc diffusion method. The relationship between contamination and physical state, source or denomination of currency was assessed using the χ2 test. All statistics were discussed at 0.05 significance level. Results Two hundred (93.9%) samples were contaminated with notes (96.6%) showing higher contamination than coins (88.2%). Uncirculated (mint) samples showed no contamination. There was a significant difference (P˂0.05) in contamination with respect to currency denomination, physical state and source. All samples from butchers and patients/personnel in hospitals were contaminated. Lower denominations showed significantly higher (P = 0.008) levels of contamination than higher denominations. Dirty currency was more contaminated than clean currency. Nine bacterial species were isolated. Coagulase-negative Staphylococcus (CoNS) (54.9%) and Staphylococcus aureus (20.1%) predominated. Among the fungi detected, Aspergillus sp (17.3%) and Penicillium sp (15.9%) showed higher frequency of occurrence. Bacteria were susceptible (100

  5. [Immunological adjuvants. Determinant factors in the efficacy-toxicity ratio of the contemporary vaccines].

    PubMed

    Batista-Duharte, Alexander; Lastre, Miriam; Pérez, Oliver

    2014-02-01

    To achieve effective and safe vaccines for the prevention of not yet controlled or re-emergent infectious diseases, one of the more importance aspects is to have immunological adjuvants that allow inducing a protective immune response with an appropriate safety profile. Since 1926 the aluminium compounds have been used as adjuvants for human vaccines, and only in the last 10 years have some new products been registered. Although there an enormous quantity of proposed candidates, the toxicity is the main factor that has limited their introduction into the clinic. In this work the mechanism of action are updated, and the toxicity of the immunological adjuvants are revised, especially those that have obtained clinical approval or are close to getting it. PMID:23332294

  6. A potent adjuvant effect of CD40 antibody attached to antigen

    PubMed Central

    Barr, Tom A; Mccormick, Adele L; Carlring, Jennifer; Heath, Andrew W

    2003-01-01

    There is great potential for novel vaccines based on recombinant proteins and synthetic peptides. Unfortunately these antigens often lack the immunogenicity of whole, killed pathogens used in traditional vaccines. Thus there is strong interest in the identification of immunological adjuvants with low reactogenicity, but high potency, to enhance immune responses and realize the potential of these new vaccine strategies. CD40 antibodies have been shown to have adjuvant effects when administered at very high doses. These large doses are impractical and induce a cascade of cytokine release giving rise to septic shock-like symptoms, as well as splenomegaly and polyclonal antibody production. We show here that a very small amount of CD40 antibody can exhibit potent adjuvant effects when attached to soluble antigen. The lack of detectable systemic effects indicates that this method may be a powerful and practical means of enhancing the efficacy of recombinant vaccines. PMID:12709021

  7. Pancreatic adenocarcinoma upregulated factor serves as adjuvant by activating dendritic cells through stimulation of TLR4.

    PubMed

    Kang, Tae Heung; Kim, Young Seob; Kim, Seokho; Yang, Benjamin; Lee, Je-Jung; Lee, Hyun-Ju; Lee, Jaemin; Jung, In Duk; Han, Hee Dong; Lee, Seung-Hyun; Koh, Sang Seok; Wu, T-C; Park, Yeong-Min

    2015-09-29

    Dendritic cell (DC) based cancer vaccines represent a promising immunotherapeutic strategy against cancer. To enhance the modest immunogenicity of DC vaccines, various adjuvants are often incorporated. Particularly, most of the common adjuvants are derived from bacteria. In the current study, we evaluate the use of a human pancreatic cancer derived protein, pancreatic adenocarcinoma upregulated factor (PAUF), as a novel DC vaccine adjuvant. We show that PAUF can induce activation and maturation of DCs and activate NFkB by stimulating the Toll-like receptor signaling pathway. Furthermore, vaccination with PAUF treated DCs pulsed with E7 or OVA peptides leads to generation of E7 or OVA-specific CD8+ T cells and memory T cells, which correlate with long term tumor protection and antitumor effects against TC-1 and EG.7 tumors in mice. Finally, we demonstrated that PAUF mediated DC activation and immune stimulation are dependent on TLR4. Our data provides evidence supporting PAUF as a promising adjuvant for DC based therapies, which can be applied in conjunction with other cancer therapies. Most importantly, our results serve as a reference for future investigation of human based adjuvants. PMID:26336989

  8. Pancreatic adenocarcinoma upregulated factor serves as adjuvant by activating dendritic cells through stimulation of TLR4

    PubMed Central

    Yang, Benjamin; Lee, Je-Jung; Lee, Hyun-Ju; Lee, Jaemin; Jung, In Duk; Han, Hee Dong; Lee, Seung-Hyun; Koh, Sang Seok; Wu, T.-C.; Park, Yeong-Min

    2015-01-01

    Dendritic cell (DC) based cancer vaccines represent a promising immunotherapeutic strategy against cancer. To enhance the modest immunogenicity of DC vaccines, various adjuvants are often incorporated. Particularly, most of the common adjuvants are derived from bacteria. In the current study, we evaluate the use of a human pancreatic cancer derived protein, pancreatic adenocarcinoma upregulated factor (PAUF), as a novel DC vaccine adjuvant. We show that PAUF can induce activation and maturation of DCs and activate NFkB by stimulating the Toll-like receptor signaling pathway. Furthermore, vaccination with PAUF treated DCs pulsed with E7 or OVA peptides leads to generation of E7 or OVA-specific CD8+ T cells and memory T cells, which correlate with long term tumor protection and antitumor effects against TC-1 and EG.7 tumors in mice. Finally, we demonstrated that PAUF mediated DC activation and immune stimulation are dependent on TLR4. Our data provides evidence supporting PAUF as a promising adjuvant for DC based therapies, which can be applied in conjunction with other cancer therapies. Most importantly, our results serve as a reference for future investigation of human based adjuvants. PMID:26336989

  9. Adjuvant radiation for soft tissue sarcomas.

    PubMed

    Dickie, Colleen I; Haas, Rick; O'Sullivan, Brian

    2015-01-01

    Over recent decades, limb-preservation surgery in combination with radiotherapy achieves local control rates exceeding 90% for extremity soft tissue sarcoma (STS). Local control is not as successful for retroperitoneal sarcoma (approximately 60%) despite aggressive surgical approaches including en bloc resection of uninvolved adjacent organs combined with intensity modulated radiotherapy (IMRT). This review will discuss the indications for adjuvant radiation therapy (RT) for primary presentation of soft tissue sarcoma: "What," referring to the type and manner of planning and delivery of RT; "When," referring to the timing and scheduling of RT; and "Why," referring to the rationale for the use of RT will be addressed. From a practical stand point, this Educational Chapter on "adjuvant RT" will focus on pre- and postoperative RT in the context of gross total resection for extremity and retroperitoneal soft tissue sarcoma, the two most frequent paradigms for the use of adjuvant RT. PMID:25993234

  10. The Effect of Different Adjuvants on Immune Parameters and Protection following Vaccination of Sheep with a Larval-Specific Antigen of the Gastrointestinal Nematode, Haemonchus contortus

    PubMed Central

    Piedrafita, David; Preston, Sarah; Kemp, Joanna; de Veer, Michael; Sherrard, Jayne; Kraska, Troy; Elhay, Martin; Meeusen, Els

    2013-01-01

    It has recently been recognised that vaccine adjuvants play a critical role in directing the nature of a vaccine induced effector response. In the present study, several adjuvants were evaluated for their ability to protect sheep after field vaccination with the larval-specific Haemonchus contortus antigen, HcsL3. Using a suboptimal antigen dose, aluminium adjuvant was shown to reduce the cumulative faecal egg counts (cFEC) and worm burden by 23% and 25% respectively, in agreement with a previous study. The addition of Quil A to the aluminium-adjuvanted vaccine brought cFEC back to control levels. Vaccination with the adjuvant DEAE-dextran almost doubled the protection compared to the aluminium-adjuvanted vaccine resulting in 40% and 41% reduction in cFEC and worm counts compared to controls. Examination of skin responses following i.d. injection of exsheathed L3, revealed that cFEC was negatively correlated with wheal size and tissue eosinophils for the DEAE-dextran and aluminium-adjuvanted groups respectively. These studies have for the first time shown the potential of DEAE-dextran adjuvant for helminth vaccines, and discovered significant cellular correlates of vaccine-induced protection. PMID:24205209

  11. The effect of different adjuvants on immune parameters and protection following vaccination of sheep with a larval-specific antigen of the gastrointestinal nematode, Haemonchus contortus.

    PubMed

    Piedrafita, David; Preston, Sarah; Kemp, Joanna; de Veer, Michael; Sherrard, Jayne; Kraska, Troy; Elhay, Martin; Meeusen, Els

    2013-01-01

    It has recently been recognised that vaccine adjuvants play a critical role in directing the nature of a vaccine induced effector response. In the present study, several adjuvants were evaluated for their ability to protect sheep after field vaccination with the larval-specific Haemonchus contortus antigen, HcsL3. Using a suboptimal antigen dose, aluminium adjuvant was shown to reduce the cumulative faecal egg counts (cFEC) and worm burden by 23% and 25% respectively, in agreement with a previous study. The addition of Quil A to the aluminium-adjuvanted vaccine brought cFEC back to control levels. Vaccination with the adjuvant DEAE-dextran almost doubled the protection compared to the aluminium-adjuvanted vaccine resulting in 40% and 41% reduction in cFEC and worm counts compared to controls. Examination of skin responses following i.d. injection of exsheathed L3, revealed that cFEC was negatively correlated with wheal size and tissue eosinophils for the DEAE-dextran and aluminium-adjuvanted groups respectively. These studies have for the first time shown the potential of DEAE-dextran adjuvant for helminth vaccines, and discovered significant cellular correlates of vaccine-induced protection. PMID:24205209

  12. Immunomodulation of TH2 biased immunity with mucosal administration of nanoemulsion adjuvant.

    PubMed

    Bielinska, Anna U; O'Konek, Jessica J; Janczak, Katarzyna W; Baker, James R

    2016-07-25

    TH2-biased immune responses are associated with inadequate protection against some pathogens and with cancer, colitis, asthma and allergy. Since most currently used vaccine adjuvants induce a TH2-biased response, this has led to interest in developing adjuvants capable of activating TH1 immunity and modulating existing TH2 responses. Immunotherapies to shift immune responses from TH2 to TH1 have generally required prolonged immunization protocols and have not induced effective TH1 responses. We have demonstrated that nanoscale emulsions (NE), a novel mucosal adjuvant, induce robust IgA and IgG antibody responses and TH1/TH17 cellular immunity resulting in protection against a variety of respiratory and mucosal infections. Because intranasal (i.n.) delivery of NE adjuvant consistently induces TH1/TH17 biased responses, we hypothesized that NE could be used as a therapeutic vaccine to redirect existing TH2 polarized immunity towards a more balanced TH1/TH2 profile. To test this, a TH2 immune response was established by intramuscular immunization of mice with alum-adjuvanted hepatitis B surface antigen (HBs), followed by a single subsequent i.n. immunization with NE-HBs. These animals exhibited increased TH1 associated immune responses and IL-17, and decreased TH2 cytokines (IL-4 and IL-5) and IgG1. NE immunization induced regulatory T cells and IL-10, and IL-10 was required for the suppression of TH2 immunity. These data demonstrate that NE-based vaccines can modulate existing TH2 immune responses to promote TH1/TH17 immunity and suggest the potential therapeutic use of NE vaccines for diseases associated with TH2 immunity. PMID:27317451

  13. Comparison of the amelioration effects of two enzyme inducers on the inflammatory process of experimental allergic encephalitis (EAE) using immunohistochemical technique.

    PubMed

    El-Gouhary, I; Mohamed, A; Suleiman, S; Benghuzzi, H

    2005-01-01

    Experimental Allergic Encephalitis (EAE) is a T-cell mediated autoimmune disease, which resembles the human disease Multiple Sclerosis (MS) in rodents. The infiltration of inflammatory cells and the induction of astrocyte proliferation correlate with EAE severity. Oxidative stress is postulated to have a role in the onset and progression of MS. Therefore, by reducing oxidative stress via phase II enzymes inducers; namely the butylhydroxyanisole (BHA) and Thymoquinone (glutathione inducer), the inflammation could be ameliorated. EAE was induced in Lewis rats using Myelin Basic Protein (MBP) and complete Freund's adjuvant (CFA). Animals were placed into 1. those on normal rat chow, 2. those on rat chow containing BHA, 3. those receiving concomitant five day injection of thymoquinone days 1-5 post-EAE induction, 4. those receiving five doses of thymoquinone injected at day 12-17 post-EAE induction. Twenty-nine days later, animals from each group were sacrificed and tissues collected for immunohistochemistry using the anti-glial fibrillary acid (GFAP) antibody to examine the amelioration effect these two agents have on the inflammatory process occurring in EAE by examining the astrocyte proliferation in the Central Nervous System (CNS). PMID:15850135

  14. Treatment with Adenosine Receptor Agonist Ameliorates Pain Induced by Acute and Chronic Inflammation.

    PubMed

    Montes, Guilherme Carneiro; Hammes, Nathalia; da Rocha, Miguel Divino; Montagnoli, Tadeu Lima; Fraga, Carlos Alberto Manssour; Barreiro, Eliezer J; Sudo, Roberto Takashi; Zapata-Sudo, Gisele

    2016-08-01

    Rheumatoid arthritis is an inflammatory autoimmune condition, and tumor necrosis factor-α (TNF-α) plays an important role in its pathophysiology. In vitro, (E)-N'-(3,4-dimethoxybenzylidene)-N-methylbenzohydrazide (LASSBio-1359) has exhibited anti-TNF-α properties, and in vivo these effects are mediated via activation of adenosine receptor. This work investigates the antinociceptive action of LASSBio-1359 in murine models of acute and chronic inflammatory pain. Male mice received an intraperitoneal injection of LASSBio-1359 and then were evaluated in formalin- and carrageenan-induced paw edema assays. Complete Freund's adjuvant (CFA) was used to induce a mouse model of monoarthritis. These mice were treated with LASSBio-1359 by oral gavage to evaluate thermal and mechanical hyperalgesia. TNF-α and inducible nitric oxide synthase (iNOS) expression as well as histologic features were analyzed. The time of reactivity to formalin in the neurogenic phase was reduced from 56.3 ± 6.0 seconds to 32.7 ± 2.2 seconds and 23.8 ± 2.6 seconds after treatment with LASSBio-1359 at doses of 10 mg/kg and 20 mg/kg, respectively. A reversal of the antinociceptive action of LASSBio-1359 was observed in the inflammatory phase after treatment with ZM 241385 [4-(2-[7-amino-2-(2-furly)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol], an adenosine A2A antagonist. Carrageenan-induced thermal and mechanical hyperalgesia were reduced after treatment with LASSBio-1359. Similarly, CFA-induced thermal and mechanical hyperalgesia were reduced after treatment with LASSBio-1359 (25 and 50 mg/kg). Levels of TNF-α and iNOS expression increased in the monoarthritis model and were normalized in animals treated with LASSBio-1359, which was also associated with beneficial effects in the histologic analysis. These results suggest that LASSBio-1359 represents an alternative treatment of monoarthritis. PMID:27194479

  15. Carbohydrate-Monophosphoryl Lipid A Conjugates Are Fully Synthetic Self-Adjuvanting Cancer Vaccines Eliciting Robust Immune Responses in Mouse

    PubMed Central

    Wang, Qianli; Zhou, Zhifang; Tang, Shouchu; Guo, Zhongwu

    2011-01-01

    Tumor-associated carbohydrate antigens (TACAs) are useful targets in the development of therapeutic cancer vaccines. However, a serious problem with them is the poor immunogenicity. To overcome the problem, a monophosphorylated derivative of Neisseria meningitidis lipid A was explored as a potential carrier molecule and built-in adjuvant for the construction of structurally defined fully synthetic glycoconjugate vaccines. Some paradigm-shifting discoveries about the monophosphoryl lipid A (MPLA)-TACA conjugates were that they elicited robust IgG antibody responses, indicating T cell-mediated immunity, without an external adjuvant and that an external adjuvant, e.g., Titermax Gold, actually reduced, instead of promoting, the immunological activity of the conjugates. The induced antibodies were proved to bind selectively to target tumor cells. MPLA was therefore demonstrated to be a powerful built-in immunostimulant and adjuvant for an all new design of fully synthetic glycoconjugate cancer vaccines. PMID:22013921

  16. [Adjuvant chemotherapy of adults soft tissue sarcomas].

    PubMed

    Bui-Nguyen, B; Italiano, A; Delva, F; Toulmond, M

    2010-06-01

    The main progress in the management of soft tissue sarcomas have been obtained in the field of local control. Although the main evolutive, vital, risk of these diseases is metastatic dissemination, efficacy of adjuvant chemotherapy remains a controversial issue. Thus, adjuvant chemotherapy cannot be considered as a standard for any situation. The last results of clinical trials, meta-analysis and population studies are presented and discussed in this article. New therapeutic strategies are to be developed to prevent metastases in soft tissue sarcomas. This needs a better understanding of the biology of those tumors, of metastases risk factors and of the determinants of systemic therapies efficacy in these tumors. PMID:20547481

  17. Nod2-mediated recognition of the microbiota is critical for mucosal adjuvant activity of cholera toxin.

    PubMed

    Kim, Donghyun; Kim, Yun-Gi; Seo, Sang-Uk; Kim, Dong-Jae; Kamada, Nobuhiko; Prescott, Dave; Philpott, Dana J; Rosenstiel, Philip; Inohara, Naohiro; Núñez, Gabriel

    2016-05-01

    Cholera toxin (CT) is a potent adjuvant for inducing mucosal immune responses. However, the mechanism by which CT induces adjuvant activity remains unclear. Here we show that the microbiota is critical for inducing antigen-specific IgG production after intranasal immunization. After mucosal vaccination with CT, both antibiotic-treated and germ-free (GF) mice had reduced amounts of antigen-specific IgG, smaller recall-stimulated cytokine responses, impaired follicular helper T (TFH) cell responses and reduced numbers of plasma cells. Recognition of symbiotic bacteria via the nucleotide-binding oligomerization domain containing 2 (Nod2) sensor in cells that express the integrin CD11c (encoded by Itgax) was required for the adjuvanticity of CT. Reconstitution of GF mice with a Nod2 agonist or monocolonization with Staphylococcus sciuri, which has high Nod2-stimulatory activity, was sufficient to promote robust CT adjuvant activity, whereas bacteria with low Nod2-stimulatory activity did not. Mechanistically, CT enhanced Nod2-mediated cytokine production in dendritic cells via intracellular cyclic AMP. These results show a role for the microbiota and the intracellular receptor Nod2 in promoting the mucosal adjuvant activity of CT. PMID:27064448

  18. [ADJUVANTED INFLUENZA VACCINES: DATA FROM DIRECT COMPARATIVE STUDIES].

    PubMed

    Chernikova, M I; Vasiliev, Yu M

    2015-01-01

    Vaccines are the cornerstone of influenza control, however available vaccines are subject to certain limitations. Adjuvanted vaccines are a promising approach, however available adjuvants have a suboptimal effectiveness and safety profile. Data from direct comparative trials are necessary for selection of optimal adjuvants among currently available and search for novel safe and effective adjuvants for next generation influenza vaccines. Data from published direct comparative studies of adjuvants for influenza vaccines are summarized, a lack of such studies is noted, especially those using adequate methods and designs and comparing adjuvants of major groups (nature/source and mechanism of action). Several promising approaches of adjuvant research and development could be identified: chitosan-based adjuvants, oil-in-water emulsions and multi-component formulations (depot + immune modulating components). PMID:26829860

  19. Xylaria hypoxylon Lectin as Adjuvant Elicited Tfh Cell Responses.

    PubMed

    Kang, J; Zuo, Y; Guo, Q; Wang, H; Liu, Q; Liu, Q; Xia, G; Kang, Y

    2015-11-01

    Foot-and-mouth disease (FMD) caused by FMD virus (FMDV) is a major health and economic problem in the farming industry. Vaccination of livestock against this highly infectious viral disease is crucial, and inactivated FMD vaccine has been effective at controlling infection. However, accumulated data show that the inactivated vaccine generates weak immune responses and that the oil formulation results in undesirable side effects. Mushroom lectins have recently been shown to display adjuvant effects when incorporated into DNA vaccines. In this study, to enhance the cellular immune response of FMDV antigen (146S), C57BL/6 mice were immunized with 146S combined with Xylaria hypoxylon lectin (XHL). The oil formulation (146S/Oil) was served as control group. Strong humoral immune responses were elicited in mice immunized with 146S/XHL as shown by high 146S antigen-specific IgG levels, and also in 146S/Oil group. Interestingly, XHL in conjunction with inactivated FMD vaccine activated strong Th1 and Tc1 cell responses, especially Tfh cell responses, in immunized mice. XHL stimulated dendritic cell maturation by upregulating expression of major histocompatibility complex II (MHCII) molecules and co-stimulatory molecules CD40 and CD86 in immunized mice. No XHL-specific IgG or inflammatory factors were detected indicating the safety of XHL as an adjuvant. Taken together, these results suggest the effectiveness of XHL at inducing cellular immune responses and therefore confirm its suitability as an adjuvant for inactivated FMD vaccine. PMID:26289530

  20. Hubble Space Telescope Imaging of the Circumnuclear Environments of the CfA Seyfert Galaxies: Nuclear Spirals and Fueling

    NASA Technical Reports Server (NTRS)

    Pogge, Richard W.; Martini, Paul

    2002-01-01

    We present archival Hubble Space Telescope (HST) images of the nuclear regions of 43 of the 46 Seyfert galaxies found in the volume limited,spectroscopically complete CfA Redshift Survey sample. Using an improved method of image contrast enhancement, we created detailed high-quality " structure maps " that allow us to study the distributions of dust, star clusters, and emission-line gas in the circumnuclear regions (100-1000 pc scales) and in the associated host galaxy. Essentially all of these Seyfert galaxies have circumnuclear dust structures with morphologies ranging from grand-design two-armed spirals to chaotic dusty disks. In most Seyfert galaxies there is a clear physical connection between the nuclear dust spirals on hundreds of parsec scales and large-scale bars and spiral arms in the host galaxies proper. These connections are particularly striking in the interacting and barred galaxies. Such structures are predicted by numerical simulations of gas flows in barred and interacting galaxies and may be related to the fueling of active galactic nuclei by matter inflow from the host galaxy disks. We see no significant differences in the circumnuclear dust morphologies of Seyfert 1s and 2s, and very few Seyfert 2 nuclei are obscured by large-scale dust structures in the host galaxies. If Sevfert 2s are obscured Sevfert Is, then the obscuration must occur on smaller scales than those probed by HST.

  1. Lactic acid bacteria as adjuvants for sublingual allergy vaccines.

    PubMed

    Van Overtvelt, Laurence; Moussu, Helene; Horiot, Stéphane; Samson, Sandrine; Lombardi, Vincent; Mascarell, Laurent; van de Moer, Ariane; Bourdet-Sicard, Raphaëlle; Moingeon, Philippe

    2010-04-01

    We compared immunomodulatory properties of 11 strains of lactic acid bacteria as well as their capacity to enhance sublingual immunotherapy efficacy in a murine asthma model. Two types of bacterial strains were identified, including: (i) potent inducers of IL-12p70 and IL-10 in dendritic cells, supporting IFN-gamma and IL-10 production in CD4+ T cells such as Lactobacillus helveticus; (ii) pure Th1 inducers such as L. casei. Sublingual administration in ovalbumin-sensitized mice of L. helveticus, but not L. casei, reduced airways hyperresponsiveness, bronchial inflammation and proliferation of specific T cells in cervical lymph nodes. Thus, probiotics acting as a Th1/possibly Treg, but not Th1 adjuvant, potentiate tolerance induction via the sublingual route. PMID:20175969

  2. HIV Envelope Trimer Specific Immune Response Is Influenced by Different Adjuvant Formulations and Heterologous Prime-Boost

    PubMed Central

    Apostólico, Juliana de Souza; Boscardin, Silvia Beatriz; Yamamoto, Márcio Massao; de Oliveira-Filho, Jethe Nunes; Kalil, Jorge; Cunha-Neto, Edecio; Rosa, Daniela Santoro

    2016-01-01

    The development of a preventive vaccine against human immunodeficiency virus (HIV-1) infection is the most efficient method to control the epidemic. The ultimate goal is to develop a vaccine able to induce specific neutralizing, non-neutralizing antibodies and cellular mediated immunity (CMI). Humoral and CMI responses can be directed to glycoproteins that are normally presented as a trimeric spike on the virus surface (gp140). Despite safer, subunit vaccines are normally less immunogenic/effective and need to be delivered together with an adjuvant. The choice of a suitable adjuvant can induce effective humoral and CMI that utterly lead to full protection against disease. In this report, we established a hierarchy of adjuvant potency on humoral and CMI when admixed with the recombinant HIV gp140 trimer. We show that vaccination with gp140 in the presence of different adjuvants can induce high-affinity antibodies, follicular helper T cells and germinal center B cells. The data show that poly (I:C) is the most potent adjuvant to induce specific CMI responses evidenced by IFN-γ production and CD4+/CD8+ T cell proliferation. Furthermore, we demonstrate that combining some adjuvants like MPL plus Alum and MPL plus MDP exert additive effects that impact on the magnitude and quality of humoral responses while mixing MDP with poly (I:C) or with R848 had no impact on total IgG titers but highly impact IgG subclass. In addition, heterologous DNA prime- protein boost yielded higher IgG titers when compare to DNA alone and improved the quality of humoral response when compare to protein immunization as evidenced by IgG1/IgG2a ratio. The results presented in this paper highlight the importance of selecting the correct adjuvant-antigen combination to potentiate desired cells for optimal stimulation. PMID:26727218

  3. Identification of an ideal adjuvant for receptor-binding domain-based subunit vaccines against Middle East respiratory syndrome coronavirus.

    PubMed

    Zhang, Naru; Channappanavar, Rudragouda; Ma, Cuiqing; Wang, Lili; Tang, Jian; Garron, Tania; Tao, Xinrong; Tasneem, Sumaiya; Lu, Lu; Tseng, Chien-Te K; Zhou, Yusen; Perlman, Stanley; Jiang, Shibo; Du, Lanying

    2016-03-01

    Middle East respiratory syndrome (MERS), an emerging infectious disease caused by MERS coronavirus (MERS-CoV), has garnered worldwide attention as a consequence of its continuous spread and pandemic potential, making the development of effective vaccines a high priority. We previously demonstrated that residues 377-588 of MERS-CoV spike (S) protein receptor-binding domain (RBD) is a very promising MERS subunit vaccine candidate, capable of inducing potent neutralization antibody responses. In this study, we sought to identify an adjuvant that optimally enhanced the immunogenicity of S377-588 protein fused with Fc of human IgG (S377-588-Fc). Specifically, we compared several commercially available adjuvants, including Freund's adjuvant, aluminum, Monophosphoryl lipid A, Montanide ISA51 and MF59 with regard to their capacity to enhance the immunogenicity of this subunit vaccine. In the absence of adjuvant, S377-588-Fc alone induced readily detectable neutralizing antibody and T-cell responses in immunized mice. However, incorporating an adjuvant improved its immunogenicity. Particularly, among the aforementioned adjuvants evaluated, MF59 is the most potent as judged by its superior ability to induce the highest titers of IgG, IgG1 and IgG2a subtypes, and neutralizing antibodies. The addition of MF59 significantly augmented the immunogenicity of S377-588-Fc to induce strong IgG and neutralizing antibody responses as well as protection against MERS-CoV infection in mice, suggesting that MF59 is an optimal adjuvant for MERS-CoV RBD-based subunit vaccines. PMID:25640653

  4. Recurrent Pericarditis, an Unexpected Effect of Adjuvant Interferon Chemotherapy for Malignant Melanoma

    PubMed Central

    Marmoush, Fady; Shafi, Muhammad Ismail; Shah, Ashish

    2016-01-01

    Drug-induced pericarditis is a well-described cardiac pathology that can result from a variety of medications; however, interferon-mediated pericarditis is extremely rare. We present a case of a young female with recurrent pericarditis due to interferon therapy. The role of interferon in adjuvant chemotherapy is well known and yields good effect, but this case highlights the very uncommon phenomena of interferon induced pericarditis and the significant distress it can cause. PMID:27418981

  5. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Adjuvants for pesticide chemicals. 582.99...

  6. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Adjuvants for pesticide chemicals. 582.99...

  7. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ....99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001 (c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Adjuvants for pesticide chemicals. 182.99...

  8. 21 CFR 172.710 - Adjuvants for pesticide use dilutions.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Adjuvants for pesticide use dilutions. 172.710... HUMAN CONSUMPTION Other Specific Usage Additives § 172.710 Adjuvants for pesticide use dilutions. The following surfactants and related adjuvants may be safely added to pesticide use dilutions by a grower...

  9. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ....99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.910 and 40 CFR 180.920, which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Adjuvants for pesticide chemicals. 182.99...

  10. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Adjuvants for pesticide chemicals. 582.99...

  11. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Adjuvants for pesticide chemicals. 582.99...

  12. 21 CFR 172.710 - Adjuvants for pesticide use dilutions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Adjuvants for pesticide use dilutions. 172.710... HUMAN CONSUMPTION Other Specific Usage Addit